Enveloped DNA viruses

Herpesviruses
Herpes simplex viruses (HSV)
Structure
 Spherical iscoahedron
 Double-stranded DNA, linear
 Enveloped
 Replication from nucleus
 Encode many enzymes
 Establish latent infections
 Lifelong persistence
 Death in immunocompromised patients
 Alpha

Summary of replicative cycle

1. HSV-1 binds to heparan sulfate on the cell surface and then to second receptor nectin
2. Following fusion the nucleocapsid and tegument proteins are released in the
cytoplasm
3. genome DNA enters the nucleus along with tegument protein VP16
4. the linear genome now becomes circular
5. VP16 interacts with cellular transcription factors to activate transcription of IE genes
6. IE mRNA is translated into IE proteins that regulate the synthesis of early proteins
such as DNA polymerase and thymidine kinase.

Latently infected cells

1. Circular HSV DNA resides in the nucleus and is not integrated into cellular DNA
2. Transcription of HSV DNA is limited to a few latency-associated transcripts(LATS)
3. Reactivation of viral replication can occur at a later time when the genes encoding
LATS are excised

Pathogenesis
1. The virus replicates in the skin mucous membrane at the initial site of infection then
migrates up the neuron by retrograde axonal flow and becomes latent in the sensory
ganglion cells
2. During latency most viral DNA is located in the cytoplasm rather than integrated into
the nucleus
3. The virus can be reactivated by hormonal changes, trauma, stress, fever at which
times it travels down the neuron and replicates in the skin causing lesions.
4. The typical skin lesion is vesicle which contains serous fluid and multinucleated giant
cells are found at the base of lesions

Laboratory diagnosis
 The  virus is identified by fluorescent antibody staining of the infected cells or by
detecting virus-specific glycoproteins (ELISAs). 
  HSV-1 can be distinguished from HSV-2 by using monoclonal antibody against
glycoprotein G often in an ELISA test.
 A rapid presumptive diagnosis  -the presence of multinucleated giant cells –Tzanck
smear
 If herpes encephalitis is suspected, a rapid diagnosis can be made by detecting HSV
DNA in the spinal fluid by using PCR assay. 
 Diagnosis of primary infections  -by significant rise in antibody titer

Treatment
 Acyclovir (acycloguanosine, Zovirax)

o encephalitis and systemic disease caused by HSV-1

o primary and recurrent genital herpes

o neonatal infections caused by HSV-2

o  it shortens the duration of the lesions and reduces the extent of shedding of
the virus 
 Foscarnet can be used in resisrant  cases
 Valacyclovir (Valtrex) and famciclovir (Famvir)are used in the treatment of genital

herpes and in the suppression of recurrences .

Clinical findings
 Both HSV-1 and HSV-2 infections are associated with erythema multiforme
 The rash is thought to be an immune-mediated reaction to the presence of HSV
antigens. 
 Acyclovir is useful in preventing recurrent episodes of multiforme, probably by
reducing the amount of HSV antigens

HSV-1
General properties
Transmission- via saliva
Lesions above the waist, primarily of the eyes and face
Latent in trigeminal ganglion

Clinical findings
Gingivostomatitis  
o Occurs primarily in children and is characterized by fever, irritability, and
vesicular lesions in the mouth. 
o The primary disease is more severe and lasts longer than recurrences. 
o The lesions heal spontaneously in 2 to 3 weeks.
o Many children have asymptomatic primary infections.
Herpes labialis (fever blisters or cold sores) 
 Is the milder, recurrent form and is characterized by crops of vesicles, usually
at the mucocutaneous junction of the lips or nose
 Recurrences frequently reappear at the same site
Keratoconjunctivitis

o corneal ulcers and lesions of the conjunctival epithelium. Recurrences can lead

to scarring and blindness.

 Encephalitis  

o Is characterized by a necrotic lesion in one temporal lobe. 

o Fever, headache, vomiting, seizures, and altered mental status are typical
clinical features.

Herpetic whitlow 

o is a pustular lesion of the skin of the finger or hand. It can occur in medical
personnel as a result of contact with patient’s lesions.

Herpes gladiatorum, 

o is characterized by vesicular lesions on the head, neck, and trunk.

 Eczema herpeticum (Kaposi’s varicelliform eruption) 

o  an infection of the skin of a patient with atopic dermatitis. Vesicular lesions
are seen at the site of the atopic dermatitis (eczema). 

Disseminated infections,

o esophagitis and pneumonia, occur in immunocompromised patients with

depressed T-cell function

HSV-2
General properties
Transmission- via sexual contact
Lesions below the waist, primarily of the genitals
Latent in lumbar and sacral ganglia
May cause meningitis

Clinical findings
Genital herpes 
o Genitals: redness, swelling, tingling, pain, pruritus
o is characterized by painful vesicular lesions of the male and female genitals
and anal area 
 o The lesions are more severe and protracted in primary disease than in
recurrences. 
o Primary infections are associated with fever and inguinal adenopathy. 
o Many infections are asymptomatic (i.e., many people have antibody to HSV-2
but have no history of disease).
Neonatal herpes  -
o originates from contact with vesicular lesions within the birth canal or
asymptomatic shedding of HSV-2 can infect the child during birth.
o Neonatal herpes varies from severe disease (e.g., disseminated lesions or
encephalitis) to milder local lesions (skin, eye, mouth) to asymptomatic
infection.
o Both HSV-1 and HSV-2 can cause  severe neonatal infections 

Varicella zuster virus (VZV)

General properties
VZV is structurally and morphologically similar to other herpesviruses but is antigenically
different. It has a single serotype. 

VZV, causes varicella (chickenpox),  remains latent, primarily in the trigeminal or thoracic
ganglion cells. It can recur in the form of the painful vesicles of zoster (shingles),usually on
the face or trunk. Transmission- respiratory droplets, direct contact with lesions,
transplacental Alpha

Pathogenesis
VZV enters the respiratory tract → replicates in the local lymph nodes → primary viremia →
spleen and liver → secondary viremia → skin (rash) 

Clinical findings
Varicella (chickenpox)

After an incubation period of 14 to 21 days, brief prodromal symptoms of fever and malaise
occur.  A papulovesicular rash then appears in crops on the trunk and spreads to the head and
extremities. The rash evolves from papules to vesicles, pustules, and, finally, crusts. Itching
(pruritus) is a prominent symptom, especially when vesicles are present

Complications- skin- Bacterial superinfection; impetigo, phlegmon, necrotizing fascitis.

Reactivation of latent VZV results in shingles (herpes zoster), Scarring.

Central nervous system- encephalitis

Lungs- pneumonia

Reye’s syndrome, characterized by encephalopathy and liver degeneration, is associated with

VZV and influenza B virus infection

Congenital varicella syndrome (infection during first and second trimester) :Hypertrophic

scars (cicatricial skin lesions); Limb defects (e.g., hypoplasia); cataracts; cortical atrophy 

Zoster (shingles)

Herpes zoster results from the reactivation of latent varicella-zoster virus (VZV) infection
within the dorsal root ganglia and most frequently occurs in the elderly or
immunocompromised. Localized dermatomal pain that persists for more than one month after
a zoster.

Clinical findings: dermatomal distribution, typically affecting 1–3 dermatomes on one side of
the body (most commonly affects the cervical, trigeminal, thoracic, and lumbar dermatomes),
pain usually described as “burning”, “throbbing”, or “stabbing”. Erythematous
maculopapular rash that quickly evolves into vesicular lesions 

Herpes zoster ophthalmicus:

Reactivation of ophthalmic division of trigeminal nerve. Intraocular infections, Hutchinson

sign on the nose. Complication leads to blindness.

Herpes zoster oticus:

Reactivation of VZV in the geniculate ganglion affecting seventh and eight cranial nerves
also known as Ramsay Hunt syndrome. Vestibulocochlear nerve involvement → vertigo and
sensorineural hearing loss. Facial nerve involvement → facial paralysis
Post herpetic neuralgia is the most common neurological complication of VZV infection.

In Immunosuppressed patients, life-threatening disseminated infections such as pneumonia

can occur.

Laboratory diagnosis
A presumptive diagnosis can be made by using the Tzanck smear. Multinucleated giant cells
are seen in VZV as well as HSV lesions

The definitive diagnosis is made by isolation of the virus in cell culture and identification
with specific antiserum. 

Treatment and prevention

Treatment- Acyclovir; Disease caused by acyclovir-resistant strains of VZV can be treated
with foscarnet

Prevention- Varivax -to prevent varicella; Zostavax -to prevent zoster. Both contain live,
attenuated VZV, but the zoster vaccine contains 14 times more virus than the varicella
vaccine. VZIG (varicella-zoster immunoglobulin) for postexposure prophylaxis of the
immunocompromised

Cytomegalovirus (CMV)
General properties
 Beta
 Single serotype
 Multinucleated giant cells are formed
 Intranuclear inclusions (owl’s eye cells)
  Enters latent state in monocytes and can be reactivated when cell-mediated immunity
is decreased. Persists in kidney

Transmission- blood transfusions, sexual, transplacental, perinatal, any kind of body fluids,
transplant- transmitted infections.

replicative cycle
similar to herpesviruses, difference is that mRNAs brought into the infected cell by the
parental virion

Pathogenesis
 Infection of the fetus can cause cytomegalic inclusion disease, characterized by
multinucleated giant cells with prominent intranuclear inclusions. Infection of the
fetus occurs mainly when a primary infection occurs in the pregnant woman.
Congenital abnormalities are more common when a fetus is infected during the first
trimester than later in gestation
 Reactivation of CMV from the latent state in cervical cells can result in infection of
the newborn during passage through the birth canal. CMV infection causes an
immunosuppressive effect by inhibiting T cells. 
 CMV establishes latency by producing microRNAs that inhibit the translation of
mRNAs required for viral replication. The CMV genome encodes a protein and an
RNA that have the ability to inhibit apoptosis in infected cells. Inhibition of apoptosis
allows the infected cell to survive

Clinical findings
Immunocompetent- 90% are asymptomatic, in 10% causes heterophil negative
mononucleosis which is characterized by fever, lethargy, abnormal lymphocytes, sore throat,
cervical lymphadenopathy, hepatomegaly, splenomegaly.

Immunocompromised- systemic infections: pneumonitis, hepatitis, esophagitis. In AIDS

colitis with bloodydiarrhea and retinitis. Also encephalitis

Congenital- infants infected with CMV during gestation cytomegalic inclusion disease such
as  microcephaly, seizures, deafness, jaundice, and purpura, chorioretinitis
hepatosplenomegaly, mental retardation, the purpuric lesions -“blueberry muffin” due to
thrombocytopenia, hepatosplenomegaly

Laboratory diagnosis
Culturing via shell vials with use of immunofluorescent antibody; inclusion bodies owl’s eye
shape; in infants PCR of amniotic fluid

Treatment
Ganciclovir- treatment for retinitis, pneumonia in patients with AIDS

Valganciclovir- retinitis
 Epstein-barr virus (EBV)
General properties
 Infects mainly lymphoid cells, primarily B lymphocytes, also epithelial cells of
pharynx resulting in sore throat
 In latently infected cells, EBV DNA is in the nucleus and is not integrated into
cellular DNA
 Transmission- primarily exchange of saliva

Pathogenesis
EBV infects B lymphocytes and mucosal epithelium via the CD21 receptor  (complement
receptor 2 CR2); 

The infection first occurs in the oropharynx and then spreads to the blood, where it
infects B lymphocytes. Cytotoxic T lymphocytes react against the infected B cells.

EBV remains latent within B lymphocytes

Clinical findings
Infectious mononucleosis- fever, sore throat, lymphadenopathy, splenomegaly.

Hairy leukoplakia- hairy surface on lateral sides of the tongue

Associated with several cancers- Burkitt’s lymphoma, Hodgkin’s lymphoma,

nasopharyngeal carcinoma.

Another EBV-associated disease is post-transplant lymphoproliferative disorder (PTLD).

Laboratory diagnosis
Abnormal lymphocytes seen on smear. Heterophilic antibody test- for early mononucleosis

EBV- specific antibody test- diagnosis for difficult cases

Monospot test- Detects heterophile antibodies produced in response to EBV infection using
RBCs from sheep or horses. Positive test is if agglutination happens. Specificity 100%,
sensitivity 85%

HHV-6 AND HHV-7

Desease - Roseola infantum ( Sixth disease, Pseudorubella)

Infection is characterized by high fever, maculopapular rash. The rash generally appears

mainly on the trunk, but sometimes spreads to the face and extremities, and fades within two
days. 
Febrile seizures are a possible complication of infection; however, most patients recover
from these seizures without any adverse outcome.

Human herpesvirus 8 (kaposi’s sarcoma-associated

herpesvirus)
A double-stranded DNA herpesvirus primarily associated with primary effusion lymphoma
and Kaposi sarcoma in patients who are HIV-positive. the most common cancer in patients
with AIDS.

A protein encoded by HHV-8 called latency-associated nuclear antigen (LANA) inactivates

RB and p53 tumor suppressor proteins, which causes malignant transformation of endothelial
cells

Transmitted orally or sexually.

Transmitted orally or sexually.

Hepatitis B virus
General properties
Hepadnavirus family, enveloped, partially double stranded DNA circular DNA genome.
HBsAG- envelope contains surface antigen
HBcAG- core antigen, contains DNA dependent DNA polymerase (reverse transcriptase)
HBeAG- is soluble and is released from infected cells into the blood, is an important
indicator of transmissibility

Transmission
Via blood- needle-stick injury, sexual transmission, perinatally from mother to newborn

replicative cycle
1. Entry of the virion into the cell and its uncoating

2. Virion DNA polymerase synthesizes the missing portion of DNA

3. Double-stranded closed-circular DNA is formed in the nucleus

4. This DNA serves as a template for mRNA synthesis by cellular RNA polymerase

5. a full-length positive-strand transcript is made, which is the template for the minus
strand of the progeny DNA

6. The minus strand then serves as the template for the plus strand of the genome DNA.

7. RNA-dependent DNA synthesis catalyzed by reverse transcriptase takes place

within the newly assembled virion core in the cytoplasm.
 8. Some of the progeny DNA integrates into the host cell genome, and this seems likely
to be the DNA that maintains the carrier state.

Pathogenesis
After entering the blood, the virus infects hepatocytes, and viral antigens are displayed on the
surface of the cells. Cytotoxic T cells mediate an immune attack against the viral
antigens, and inflammation and necrosis occur.

Clinical findings
Chronic active hepatitis can cause cirrhosis, hepatic cell carcinoma, polyarteritis nodosum
glomerulonephritis.

Laboratory diagnosis
Early Acute hepatitis- +HBsAg; - +HBeAg;+ anti HBcAg IgM.

Late acute hepatitis- +HBsAg; - +HBeAg;+ anti HBcAg IgM;+ anti HBc; +anti- HBe

Chronic transmissible hepatitis- +HBsAg; +HBeAg; + anti HBcAg IgG

Chronic nontransmissible- +HBsAg; + anti HBcAg IgG

Resolved- +anti HBc; +anti HBs; +anti HBe

Vaccinated- +anti HBs

Treatment
Acute- no treatment, resolves by itself

Chronic-  lamivudine (Epivir-HBV), entecavir (Baraclude) or tenofovir (Viread) are the drugs
of choice. They are nucleoside analogues that inhibit the reverse transcriptase of HBV. 

prevention
two types of vaccine exist-

1. The vaccine (e.g., Recombivax) contains HBsAg produced in yeasts by recombinant

DNA techniques.
2. A vaccine called Twinrix that contains both HBsAg and inactivated HAV provides
protection against both hepatitis B and hepatitis A.

Hepatitis B immune globulin (HBIG) contains a high titer of HBsAb.

 It is used to provide immediate, passive protection to individuals known to be exposed

to HBsAg-positive blood

Both vaccine and HBIG are given to newborn whose mother is HBs AG positive
Nonenveloped DNA viruses
 Adeno viruse
General properties
Nonenveloped double stranded linear DNA virus; icosahedral nucleocapsid; they are only
viruses with fiber protruding from capsid, this fiber contains viral attachment protein which
acts as hemagglutinin. Pentons and fiber protein are the main type- specific antigen.

replicative cycle
attachment- via fiber; penetration by endocytosis, uncoating in the cytoplasm, viral DNA
moves to the nucleus, replication and translation, viral assembly occurs in the nucleus, the
virus id released by lysis of the cell.

Replication- translation

Host cell DNA-dependent RNA polymerase transcribes the early genes. Early mRNA is
translated into nonstructural proteins in the cytoplasm–including a DNA polymerase and
others that affect transcription and replication of the viral genome.

Viral DNA replication in the nucleus, late mRNA is transcribed and then translated into
structural virion proteins.

Transmission
Aerosol droplet; fecal-oral route; direct inoculation of conjuctivas

Outbreaks occur among the military recruits.

 Types 3, 4, 7, and 21 cause respiratory disease 

 Types 8 and 19 cause epidemic keratoconjunctivitis; 

 Types 11 and 21 cause hemorrhagic cystitis;

 Types 40 and 41 cause infantile gastroenteritis

Pathogenesis
Adenoviruses infect the mucosal epithelium of several organs  (e.g., the respiratory tract
[both upper and lower], the gastrointestinal tract, and the conjunctivas)

Acute infection lead to death of the cell; latent infection is adenoidal and tonsillar tissues of
the throat

Viremia (especially in immunocompromised) may occur and spread to distant organs such as
kidney, bladder, liver and lymphoid tissue
 Clinical findings
Upper and lower respiratory tract diseases :

o Pharyngitis

o  Pharyngoconjunctival Fever (PCF),  

o the common cold

o Pneumonia.

Ocular infections

o Follicular conjunctivitis (“pink eye”) –(swimming pool conjunctivitis)

o Keratoconjunctivitis -epidemic keratoconjunctivitis

Gastroenteritis 

Hemorrhagic cystitis -acute hemorrhagic cystitis in children, especially boys.

Some adenoviruses cause sarcomas in rodents.

Laboratory diagnosis
Isolation of the virus in cell culture- intranuclear inclusion bodies;

Detection of a fourfold or greater rise in antibody titer

prevention
live non attenuated vaccines against 4,7,21 serotypes are only used in military

The vaccine virus infects the gastrointestinal tract, where it causes an asymptomatic infection
and induces immunity to respiratory disease.
 Parvovirus
General properties
B19 nonenveloped single stranded DNA virus, it is negative strand. There are two types
defective and nondefective.

The defective parvoviruses (e.g., adeno-associated virus) require a helper virus for
replication. 

The nondefective parvoviruses are best illustrated by B19 virus which is clinically important
–erythroparvovirus. Parvovirus B19 has a tropism for erythroid progenitor cell. The cellular 
receptor for B19 is blood group P antigen (on erythrocytes, megakaryocytes, endothelial
cells, placenta, fetal liver and heart)

replicative cycle
1. Attach to host receptors to infect erythroid progenitor cells initiating endocytosis of the
virion
2. Microtubular transport of viron toward the nucleus
3. The viral ssDNA genome penetrates into the nucleus and is converted into dsDNA by
cellular enzymes
4. dsDNA transcription gives rise to viral mRNAs when host cell enters S phase and
translated to produce viral proteins
5. virions are released by cell lysis

Virus replicates in red cell precursors

Transmission
Transmitted by respiratory route; transplacental transmission; blood donated transfusions

Pathogenesis
Infects two types of cells:
RBC precursors in the bone marrow, which accounts aplastic anemia
Endothelial cells in blood vessels which accounts for rash associated erythema infectiosum
Immune complexes composed of virus and IgM or IgG- rash and arthritis

Clinical findings
Erythema infectiosum (slapped cheek syndrome, fifth disease)

 bright red rash that is most prominent  on the cheeks accompanied

  by low-grade fever, runny nose (coryza), and sore throat. 

 Erythematous rash appears on the body.

 Once the rash has appeared, the infected individual is no longer contagious 

Aplastic anemia
  This occurs in patients with sickle cell anemia
 Results in reduced amount of hemoglobin & RBC's due to the virus killing precursor
cells in the bone marrow

Fetal infections

 If a woman is infected with B19 virus during the first or second trimester of
pregnancy, the virus may cross the placenta and infect the fetus.

 Infection during the first trimester is associated with fetal death, 

 infection during the second trimester leads to hydrops fetalis.

Arthritis-----Parvovirus B19 infection in adults, especially women, can cause arthritis mainly
involving the small joints of the hands and feet , It resembles rheumatoid arthritis.

Laboratory diagnosis
IgM antibodies, fetal infections by PCR of amniotic fluid

prevention
Pooled immune globulins may have a beneficial effect on chronic B19 infection in patients
with immunodeficiencies.

Papilomavirus
General properties
dsDNA circular, naked, icosahedral.

 Skin warts are caused primarily by HPV-1 through HPV-4, 

 Genital warts are usually caused by HPV-6 and HPV-11.

 HPV-16 or HPV-18 is found most frequently in cervical carcinomas

 replicative cycle
Replication is divided in two distinct steps  that are linked to the differentiation state of the
host epithelial cell:

 HPV initially infects the cells of the basal layer in the skin, but no virus is produced
by those cells. 

 Infectious virus particles are found in the terminally differentiated squamous cells
rather than in the basal cells.

Transmission
Skin-to-skin contact, genital contact, vertical transmission (causes warts in the mouth and in
the respiratory tract, especially on the larynx, of the infant.)

Risk factors- immunodeficiency, unprotected sex, a lot of sexual partners, early age at first
sexual activity

Pathogenesis
Virus infects basal layer of the skin and mucous membranes. Hyperkeratosis leads to the
formation of the “wart”. Papillomaviruses infect squamous epithelial cells and induce within
those cells a characteristic cytoplasmic vacuole. These vacuolated cells, called koilocytes, are
the hallmark of infection by these viruses. 

However, HPV infection is associated with carcinoma of the uterine cervix and penis. The
proteins encoded by viral genes E6 and E7 interfere with the growth-inhibitory activity of the
proteins encoded by the p53 and RB tumor suppressor genes and thereby contribute to
oncogenesis by these viruses.

Clinical findings
Cutaneous warts-

 Common warts (serotype 2 and 4) found on hands and fingers

 Plantar warts (serotype 1) found on soles of feet

Genital warts caused by HPV6 AND 11 which also causes respiratory tract papillomas

Carcinoma of the uterine cervix, the penis, and the anus, as well as premalignant lesions
called intraepithelial neoplasia, are associated with infection by HPV-16 and HPV-18.

Laboratory diagnosis
the presence of koilocytes in the lesions indicates HPV infection

Pap test.

Dysplastic squamous cells characterized by well-defined, clear, balloon-like, perinuclear halo

and hyperchromasia

Pcr
 Treatment
Genital warts- podophyllin, alpha interferon, cidofovir

Skin warts- liquid nitrogen

prevention
Gardasil, a recombinant vaccine against four types of HPV, contains the capsid proteins of
types 6 and 11, which cause genital warts, and types 16 and 18, which are the two most
common causes of cervical, penile, and anal carcinoma. 

Cervarix is also a recombinant vaccine but contains the proteins only of types 16 and 18. 
Positive sense RNA viruses
 Hepatitis A virus
General properties
Enterovirus classified in picornavirus family, nonenveloped single stranded RNA genome

replicative cycle
Enter the host cell via receptor-mediated endocytosis

Uncoating -Positive-sense RNA viral genome is released into the cytoplasm, which acts as
an mRNA.

This genomic viral mRNA is translated into a polyprotein

This polypeptide is cleaved by a virus-encoded protease in multiple steps to form both the
capsid proteins of the progeny virions and several noncapsid proteins including an RNA-
dependent RNA polymerase.

Replication of the genome -synthesis of a complementary negative strand, which then serves
as the template for the positive strands

Some of these positive strands function as mRNA to make more viral proteins, and the
remainder become progeny virion genome RNA.

Assembly of the progeny virions occurs by coating of the genome RNA with capsid proteins

released upon cell death.

Transmission
Fecal-oral route, contaminated water or food, raw or steamed shellfish

Clinical findings
Fever, anorexia, nausea, vomiting, and jaundice, Dark urine, pale feces, and elevated
transaminase levels. Most cases resolve spontaneously in 2 to 4 weeks. Hepatitis A has a
short incubation period (3–4 weeks). Most HAV infections are asymptomatic No chronic
hepatitis or chronic carrier state occurs. There is no predisposition to hepatocellular
carcinoma.

Laboratory diagnosis
IgM antibody detection or fourfold increase in IgG antibody titer

prevention
Active immunization with a vaccine containing inactivated HAV

A combination vaccine against both HAV and HBV called Twinrix is available
Passive immunization with immune serum globulin prior to infection or within 14 days after
exposure can prevent or mitigate the disease

passive–active immunization -If an unimmunized person must travel to an endemic area

within 4 weeks

Hepatitis C virus
General properties
Enveloped virus, family flavivirus, single stranded positive polarity RNA

replicative cycle
The replication of HCV in the liver is enhanced by a liver-specific micro-RNA called miR-
122. This micro-RNA acts by increasing the synthesis of HCV mRNA.

Transmission
Primarily via blood, during child birth, needles

Pathogenesis
Antibodies against HCV are made, but approximately 75% of patients are chronically
infected and continue to produce virus for at least 1 year.

The rate of chronic carriage of HCV is much higher than the rate of chronic carriage of HBV.

Laboratory diagnosis
Antibodies to HCV in ELISA, RIBA as a confirmatory test

Treatment
Acute- peginterferon alfa

Chronic- pegasys, ribavin and protease inhibitor

Sofosbuvir- for chronic, It is a uridine analogue that inhibits the RNA polymerase of HCV.
 Hepatitis D virus
General properties
HDV is unusual in that it is a defective virus. It cannot replicate by itself because it does not
have the genes for its envelope protein. HBV is the helper virus for HDV. HDV can replicate
only in cells also infected with HBV because HDV uses the surface antigen of HBV (HBsAg)
as its envelope protein.

Enveloped single stranded RNA negative polarity. It encodes delta antigen

replicative cycle
The HDV RNA genome is replicated and transcribed in the nucleus by cellular enzymes,
whose specificity is probably modified by complexing with the delta protein. This phase of
HDV replication is independent of HBV, whose only helper function is to supply HBsAg for
the envelope

Virus attaches to host receptors though Major surface antigen.

Fusion of virus membrane with the vesicle membrane; ribonucleocapsid is released in the
cytoplasm and migrates to the nucleus.

Transcription of S-HDAg, promoting viral transcription and replication

Symmetrical rolling circle replication by host DNA-dependent RNA polymerase II

later, genomic RNA is edited by host ADAR1(RNA editing enzyme), leading to L-HDAg
expression which induce packaging of HDV genome at the RE.

Budding by helper HBV proteins.

Transmission
Sexually, blood, perinatally
 Clinical findings
A person can either be infected with both HDV and HBV at the same time (i.e., be
“coinfected”) or be previously infected with HBV and then “superinfected” with HDV.

Hepatitis in patients coinfected with HDV and HBV is more severe than in those infected
with HBV alone

Laboratory diagnosis
Delta antigen or IgM antibody

Nonenveloped RNA viruses

Poliovirus
General properties
Family of picornavirus which are nonenveloped, single stranded RNA genome which has
positive polarity.

Enterovirus. Three serologic types, Protection from disease requires the presence of antibody
against each of the three types

replicative cycle
Enter the host cell via receptor-mediated endocytosis. Uncoating -Positive-sense RNA viral
genome is released into the cytoplasm, which acts as an mRNA. This genomic viral mRNA is
translated into a polyprotein. This polypeptide is cleaved by a virus-encoded protease in
multiple steps to form both the capsid proteins of the progeny virions and several noncapsid
proteins including an RNA-dependent RNA polymerase. Replication of the genome -
synthesis of a complementary negative strand, which then serves as the template for the
positive strands. Some of these positive strands function as mRNA to make more viral
proteins, and the remainder become progeny virion genome RNA. Assembly of the progeny
virions occurs by coating of the genome RNA with capsid proteins. released upon cell death.

Transmission
Fecal oral route, replicates in oropharynx and intestinal tract
 Pathogenesis
Replication in the oropharynx and small intestine, especially in lymphoid tissue, than the
virus spreads through the bloodstream to the central nervous system. It can also spread
retrograde along nerve axons. In the central nervous system, poliovirus preferentially
replicates in the motor neurons located in the anterior horn of the spinal cord. Death of these
cells results in paralysis of the muscles. The virus also affects the brainstem, leading to
“bulbar” poliomyelitis (with respiratory paralysis), but rarely damages the cerebral cortex.
Infection provides lifelong type-specific immunity.

Clinical findings
Abortive poliomyelitis - a mild, febrile illness characterized by headache, sore throat,
nausea, and vomiting. Most patients recover spontaneously

Nonparalytic poliomyelitis - aseptic meningitis with fever, headache, and a stiff

neck. This also usually resolves spontaneously

Paralytic poliomyelitis: flaccid paralysis or respiratory paralysis. Painful muscle spasms

also occur. The motor nerve damage is permanent, but some recovery of muscle function
occurs as other nerve cells take over.

Paralytic polio: meninges and meningoencephalitis. If the spinal cord is also involved -
meningomyeloencephalitis. No permanent carrier state occurs following infection by
poliovirus, but virus excretion in the feces can occur for several months.

Laboratory diagnosis
A rise in antibody titer. CSF will show high protein, pleocytosis, normal glucose

prevention
live vaccine- reversion of the attenuated virus to virulence will occur and disease may ensure,
can cause disease in immunodeficient, must be kept refrigereated

enhanced polio vaccine- inactivated vaccine combined with diphtheria- tetanus-pertussis

vaccine, induces IgA immunity.

Vaccine derived poliovirus- VDPV strains have lost their attenuation by acquiring genes from
wild-type enteroviruses by recombination

Passive immunization- with immune serum globulin is available for protection of

unimmunized individuals known to have been exposed. Passive immunization of newborns as
a result of passage of maternal IgG antibodies across the placenta also occurs.

Coxsackie viruses
General properties
The classification of Coxsackie viruses into group A or B is based on pathogenicity in mice.
Group A viruses cause widespread myositis and flaccid paralysis, which is rapidly fatal,
Group B viruses cause generalized, less severe lesions of the heart, pancreas, and central
nervous system and focal myositis. At least 24 serotypes of Coxsackie virus A and 6
serotypes of Coxsackie virus B are recognized.

Replicative Cycle - similar to that of poliovirus

replicative cycle
fecal-oral route, respiratory aerosols, replicate in the oropharynx and intestinal tract

Pathogenesis
Group A viruses - predilection for skin and mucous membranes

Group B viruses cause disease in various organs such as the heart, pleura, pancreas and liver.

Both group A and B viruses can affect the meninges and the motor neurons to cause
paralysis.

From their original site of replication in the oropharynx and gastrointestinal tract, they
disseminate via the bloodstream. Immunity following infection is provided by type-specific
IgG antibody.

Clinical findings
Group A–Specific Diseases

 Herpangina is characterized by fever, sore throat, and tender vesicles in the

oropharynx. 

 Hand-foot-and-mouth disease is characterized by a vesicular rash on the hands and

feet and ulcerations in the mouth, mainly in children.

Group B–Specific Diseases

 Pleurodynia characterized by fever and severe pleuritic-type chest pain. 

 Myocarditis and pericarditis are characterized by fever, chest pain, and signs of
congestive failure. 

 Diabetes in mice can be caused by pancreatic damage as a result of infection with

Coxsackie virus B4. This virus is suspected to have a similar role in juvenile diabetes
in humans.

Diseases Caused by Both Groups - aseptic meningitis, mild paresis, and acute flaccid
paralysis similar to poliomyelitis. Upper respiratory infections, pharyngitis, and minor febrile
illnesses with or without rash can occur also.

Laboratory diagnosis
PCR)–based test for enteroviral RNA in the spinal fluid is useful for making a prompt
diagnosis of viral meningitis
 Echoviruses
Enteric Cytopathic Human Orphan viruses cause a variety of diseases:
 aseptic meningitis 
 Upper respiratory tract infection
 Febrile illness with and without rash
 Infantile diarrhea
 Hemorrhagic conjunctivitis

They are transmitted by the fecal–oral route and occur worldwide. Are one of the leading
causes of aseptic (viral) meningitis - along with Coxsackie viruses
The diagnosis is made by isolation of the virus in cell culture.

Rhinovirus
General properties
more than 100 serologic types. replicate better at 33°C than at 37°C
they are acid-labile.
Replicative Cycle - similar to that of poliovirus

Transmission
 Direct mode  - via aerosols of respiratory droplets. 
 Indirect mode  - respiratory droplets are deposited on the hands or on a surface and
then transported by fingers to the nose or eyes
The common cold - the most common human infection

Pathogenesis
 The portal of entry is the upper respiratory tract, the infection is limited to that
region. 
 Rhinoviruses rarely cause lower respiratory tract disease, probably because they grow
poorly at 37°C.
 Immunity is serotype-specific and is a function of nasal secretory IgA rather than
humoral antibody.

Clinical findings
An incubation period of 2 to 4 days
Sneezing, nasal discharge, sore throat, cough, and headache are common. A chilly sensation
may occur
The illness lasts about 1 week.
other viruses such as coronaviruses, adenoviruses, influenza C virus, and Coxsackie viruses
also cause the common cold syndrome
 caliciviruse
General properties
A nonenveloped virus with an icosahedral nucleocapsid. Norovirus has a nonsegmented,
single-stranded, positive-polarity RNA genome. There is no polymerase within the virion.
Five genogroups have been identified.

Transmission
Fecal oral, ingestion of contaminated seafood or water. Infection is enhanced by several
features of the virus: low infectious dose, excretion of virus in the stool both before the onset
of symptoms and for several weeks after recovery

Pathogenesis
 Norovirus infection is typically limited to the mucosal cells of the intestinal tract.

 Watery diarrhea without red cells or white cells occurs. 

 Immunity following infection appears to be brief, and reinfection can occur. 

Clinical findings
 sudden onset of vomiting and diarrhea accompanied by low-grade fever and
abdominal cramping.
 Non bloody watery diarrhea

Rotavirus
General properties
segmented, double-stranded RNA genome surrounded by a double-layered icosahedral capsid
without an envelope. Virion contains RNA dependent RNA polymerase. The outer surface
protein (also known as the viral hemagglutinin) is the type-specific antigen and elicits
protective antibody.

replicative cycle
Attachement of the viral VP4 protein to host receptors mediates clathrin-mediated
endocytosis of the virus into the host cell.
After entry of the virion into the cell, the RNA-dependent RNA polymerase synthesizes
mRNA from each of the 11 segments within the cytoplasm.
The 11 mRNAs are translated into the corresponding number of structural and nonstructural
proteins.
One of these, an RNA polymerase, synthesizes minus strands that will become part of the
genome of the progeny virus.
Capsid proteins form an incomplete capsid around the minus strands,
then the plus strands of the progeny genome segments are synthesized.
The virus is released from the cytoplasm by lysis of the cell
 Pathogenesis
 Rotavirus replicates in the mucosal cells of the small intestine, resulting in the
excess secretion of fluids and electrolytes into the bowel lumen

 The consequent loss of salt, glucose, and water leads to diarrhea

 No inflammation occurs, and the diarrhea is nonbloody.

Clinical findings
 Rotavirus infection is characterized by nausea, vomiting, and watery, nonbloody
diarrhea. 

 Gastroenteritis is most serious in young children, in whom dehydration and

electrolyte imbalance are a major concern.

prevention
 A live, attenuated vaccine (Rotarix), which contains the single most

common rotavirus serotype (G1) causing disease in the United States. 

A live reassortant vaccine (Rotateq), which contains five rotavirus strains.

HIV
General properties
Family retroviruses, lentivirus group.
Virion contains type D core surrounded by an envelope containing virus specific
glycoproteins gp120 and gp41, the genome is diploid, single stranded positive polarity RNA

Structure
The viral envelope is composed of a lipid membrane and contains 2 virus-specific
glycoproteins:
gp 120: protrudes from the surface and is responsible for viral binding to host cell receptors.
 gp 41: is embedded in the envelope and mediates the fusion of the viral envelope with cell
membrane at the time of infection.
RNA-dependent DNA polymerase (reverse transcriptase), Integrase, Protease
The gag gene encodes the internal “core” proteins, the most important of which is the p24
protein -it is the antigen in the initial serological test
The pol gene encodes several proteins, including the virion “reverse transcriptase”,
integrase, protease
The env gene encodes gp160, a precursor glycoprotein that is cleaved to form the two
envelope (surface) glycoproteins, gp120 and gp41
Three genes encoding structural proteins: gag, pol, and env
six regulatory genes: tat and rev, are required for replication,
nef, vif, vpr, and vpu, -“accessory” genes
long terminal repeat (LTR)

replicative cycle
entry: Binding of the virion gp120 envelope protein to the CD4 protein on the cell surface.
The virion gp120 protein then interacts with a second protein on the cell surface, one of the
chemokine receptors (CCR5 and CXCR4).the virion gp41 protein mediates fusion of the viral
envelope with the cell membrane, the virion core containing the nucleocapsid, RNA genome,
and reverse transcriptase enters the cytoplasm.
Chemokine receptor: The T cell–tropic strains of HIV bind to CXCR4, the macrophage-
tropic strains bind to CCR5.

Transmission
 Sexual contact: Disruption of mucosal surfaces by sexually transmitted diseases,
particularly those such as syphilis and chancroid that result in genital ulcerations, may
greatly facilitate HIV-1 infection.

 Blood transfusions

 Contaminated needles

 Vertical transmission

Pathogenesis
HIV infects helper T cells (CD4-positive cells) and kills them, resulting in suppression of
cell-mediated immunity. This predisposes the host to various opportunistic infections and
certain cancers such as Kaposi’s sarcoma and lymphoma.

The initial infection of the genital tract occurs in dendritic cells that line the mucosa, after
which the local CD4-positive helper T cells become infected.

HIV infection also targets a subset of CD4-positive cells called Th17 cells-important
mediators of mucosal immunity, The loss of Th17 cells predisposes HIV-infected individuals
to bloodstream infections by bacteria in the normal flora of the colon

HIV also infects brain monocytes and macrophages, producing multinucleated giant cells and
significant central nervous system symptoms

The main immune response to HIV infection consists of cytotoxic CD8- positive
lymphocytes. Total number increases and then decreases -loss of anti-HIV activity, These
cells respond to the initial infection and control it for many years.
 Three main mechanisms

1. integration of viral DNA into host cell DNA, resulting in a persistent infection;

2. a high rate of mutation of the env gene; 

3. the production of the Tat and Nef proteins that downregulate class I MHC proteins
required for cytotoxic T cells to recognize and kill HIV-infected cells.

Clinical findings
Acute stage: mononucleosis like picture, maculopapular rash on trunk, arms and legs.
Leukopenia, highly transmissible at this stage. PCR detects on this stage

Latent stage: asymptomatic, complications AIDS-related complex (ARC), persistent,

generalized lymphadenopathy (swollen lymph nodes); diarrhea; chronic fevers; night sweats;
and weight loss.

Non- AIDS- defining conditions: when CD4+ count is below 500 cells/mm3)Oral
candidiasis: creamy, white patches on the mucous membranes of the mouth that can be
scraped off. Oral hairy leukoplakia: lesions that cannot be scraped off located mainly on the
lateral borders of the tongue ;triggered by Epstein-Barr virus. HPV-related: squamous cell
carcinoma of the anus (common in men who have sex with men) or cervix

Late stage: progression to AIDS increasingly rapid decline in CD4+ count, accompanied by
loss of immune capacity. manifested by a decline in the number of CD4 cells to below
200/μL an increase in the frequency and severity of opportunistic infections.

End stage AIDS: Cell types other than CD4+ lymphocytes can be infected by HIV.For
example, microglia are the HIV-infected cells present in brains of patients with AIDS
encephalopathy, which typically evolves over a period of 1 year, with gradual deterioration
resulting in severe dementia. HIV infection of blood cell progenitors in the bone marrow
leads to the anemia seen in most AIDS patients. Opportunistic infections in AIDS
Malignancies associated with AIDS; The two most characteristic manifestations of AIDS are
Pneumocystis pneumonia and Kaposi’s sarcoma

 
 Laboratory diagnosis
ELISA- antibodies to viral proteins than western blot assay they are often false negative in
the first two months and false positive in newborns

the PCR is a very sensitive and specific technique that can be used to detect HIV DNA within
infected cells

Viral load tests determine the amount of viral RNA in the plasma.

AIDS diagnosis: AIDS diagnosis ≤ 200 CD4+ cells/mm3 (normal: 500–1500 cells/mm3).
HIV-positive with AIDS-defining condition

Treatment
Combined antiretroviral therapy- to restore immunologic function by increasing the CD4
count, which reduces opportunistic infections and certain malignancies (2) to reduce viral
load, which reduces the chance of transmission to others.

Rubella virus
General properties
Togavirus, causes rubella and congenital rubella syndrome(characterized by congenital
malformations). Single-stranded positive-strand enveloped RNA virus, An icosahedral
nucleocapsid, Surface spikes contain hemagglutinin. Antibody against hemagglutinin
neutralizes infectivity. The virus has a single antigenic type

transmission
respiratory droplets, transplacentally, Nasopharynx - local lymph nodes - via the blood -
internal organs and skin. rash may be due to antigen/antibody–mediated vasculitis.
 Clinical findings
 Asymptomatic in ∼ 50% of cases
 An incubation period of 14 to 21 days
 The clinical presentation begins with nonspecific flu-like symptoms and post-
auricular and/or suboccipital lymphadenopathy.
  An exanthem phase may overlap or follow; 
 this phase is characterized by a rash that typically starts behind the ears and
progresses distally, developing into a generalized maculopapular rash. 
 The rash typically lasts 3 days
 Polyarthritis
Congenital rubella syndrome
 Rubella virus is teratogen -agent that can disturb the development of an embryo or
fetus
 When a nonimmune pregnant woman is infected during the first trimester,
especially the first month, significant congenital malformations can occur
 The malformations are widespread and involve primarily the heart (e.g., patent
ductus arteriosus), the eyes (e.g., cataracts), and the brain (e.g., deafness and mental
retardation).
 Additional features include low birth weight, purpura/petechiae, a blueberry
muffin rash, hepatosplenomegaly, osteitis, microcephaly, and other ocular
manifestations 
 (e.g., salt and pepper retinopathy, microphthalmos, congenital glaucoma).

lab diagnosis
serological test, PCR, ability to interfere with echovirus CPE. In a pregnant woman exposed
to rubella virus, the presence of IgM antibody indicates recent infection
a 1:8 or greater titer of IgG antibody indicates immunity and consequent protection of the
fetus. Amniocentesis –for identification of definite fetal infection

Treatment and prevention

Prevention involves immunization with the live, attenuated vaccine. MMR vaccine. Immune
serum globulins (IG) can be given to pregnant women in the first trimester

 
Negative sense RNA viruses
 Measles (rubeola)
General properties
Paramyxovirus, single stranded RNA negative sense, helical nucleocapsid, outer lipoprotein
envelope, virion contains RNA dependent RNA polymerase.

This virus causes measles, a disease characterized by a maculopapular rash. The virion has
two types of envelope spikes: Hemagglutinin and fusion protein, has a single serotype

Replicative cycle
 Absorption to the cell surface via its hemagglutinin
 Virion envelope fuses with the cell membrane by the action of the fusion
glycoprotein
 Virus penetrates and uncoats 
 virion RNA polymerase transcribes the negative-strand genome into mRNA
 Multiple mRNAs are synthesized, each of which is translated into the specific viral
proteins
 The helical nucleocapsid is assembled 
 Matrix protein mediates the interaction with the envelope 
 Virus is released by budding from the cell membrane.

Transmission
Respiratory droplets,

Pathogenesis
 The primary site of infection is the respiratory epithelium of the nasopharynx
o Spreads to lymph nodes 
o Virus enters the blood  and  spreads to the all part of body  and infects
reticuloendothelial cells, where it replicates again 
o It then spreads via the blood to the skin.
 The rash is caused primarily by cytotoxic T cells attacking the measles virus–
infected vascular endothelial cells in the skin
 Multinucleated giant cells are characteristic of the lesions.
 Lifelong immunity

Clinical findings
Incubation period  - 10 to 14 days, The first stage is the prodrome - fever, cough, coryza
(runny nose), and conjunctivitis, Photophobia (the eyes are physically sensitive to the light),
Koplik’s spots –(small white spots on bright red mucous membranes of the mouth and throat)
The end of the prodrome is marked by the onset of the rash
The measles rash is the most distinctive clinical sign of measles, and is erythamatous and
maculopapular in nature
Complications- encephalitis (deafness and mental retardation), measles pneumonia, and
bacterial pneumonia, subacute sclerosing panencephalitis. Measles during pregnancy can lead
to miscarriage, early delivery or low birth weight

Lab diagnosis
Serology -a greater than fourfold rise in antibody titer can be used to diagnose difficult cases.
PCR assay is also used.

Prevention
Immunization with live attenuated vaccine, First dose between 12 & 15 months of age
maternal antibody in the child can neutralize the virus
Immune globulin can be used early in the incubation period.

Mumps virus
General properties
Causes mumps parotid gland swelling, negative sense ss RNA, helical, enveloped, single
serotype, two types of envelope spikes: hemagglutinin and neuraminidase activities, with
cell-fusing and hemolytic activities. Replicative cycle similar to measles virus.

Transmission
Via respiratory droplets

Pathogenesis
 The virus infects the upper respiratory tract
  Infection is widespread in the body and may involve not only the parotid glands but
also the pancreas, CNS, and testes
 in some cases, meninges 
 Orchitis (inflammation of the testis) caused by mumps virus may cause sterility.
 Clinical findings
 Incubation period- 18 to 21 days. Prodromal stage- fever, malaise and anorexia. Late
symptoms- tender swelling of the parotid glands, The disease is typically benign and
resolves spontaneously within 1 week
 Complications
o orchitis in postpubertal males, which, if bilateral, can result in sterility
o meningitis, which is usually benign, self-limited, and without sequelae

lab diagnosis
A fourfold rise in antibody titer in either the hemagglutination inhibition or the CF test is
diagnostic. PCR assay can also be used. A mumps skin test based on delayed hypersensitivity

prevention
live, attenuated vaccine, MMR(measles, mumps, rubella) vaccine

respiratory syncytial virus

General properties
The most important cause of pneumonia and bronchiolitis in infants. An important cause of
otitis media in children. An important cause of pneumonia in the elderly and in patients with
chronic cardiopulmonary diseases. One piece of single stranded RNA, helical nucleocapsid,
outer lipoprotein envelope, virion contains RNA dependent RNA polymerase. Its surface
spikes are fusion proteins -No hemagglutinins and neuraminidases
The fusion protein causes cells to fuse, forming multinucleated giant cells (syncytia)
Subgroup A and subgroup B. Antibody against the fusion protein neutralizes infectivity

transmission
respiratory droplets and by direct contact of contaminated hands with the nose or mouth.
causes outbreaks of respiratory infections every winter. RSV also causes outbreaks of
respiratory infections in hospitalized infants

pathogenesis
 RSV infection in infants is more severe and more often involves the lower
respiratory tract than in older children and adults. 
 The infection is localized to the respiratory tract; 
 Viremia does not occur
 Most individuals have multiple infections caused by RSV, indicating that immunity
is incomplete

Clinical findings
 In infants, RSV is an important cause of lower respiratory tract diseases such as
bronchiolitis and pneumonia
 In young children  - an important cause of otitis media.
 In older children and young, healthy adults -respiratory tract infections such as the
common cold and bronchitis.
  In adults with chronic cardiopulmonary diseases- severe lower respiratory tract
disease, including pneumonia.

lab diagnosis
An enzyme immunoassay (“rapid antigen test”) that detects the presence of RSV antigens in
respiratory secretions.
A reverse transcriptase polymerase chain reaction (RT-PCR) test

Treatment and prevention

 Aerosolized ribavirin (Virazole) is recommended for severely ill hospitalized infants
 A combination of ribavirin and hyperimmune globulins against RSV
 There is no vaccine.
 Passive immunization with a monoclonal antibody directed against the fusion
protein of RSV (palivizumab, Synagis) can be used for prophylaxis in premature or
immunocompromised infants.Hyperimmune globulins (RespiGam) are also
available for prophylaxis in these infants and in children with chronic lung disease

Parainfluenza virus
General properties
in children: croup (acute laryngotracheobronchitis), laryngitis, bronchiolitis, and pneumonia
in adults a disease resembling the common cold.
a typical paramyxovirus: One piece of single-stranded RNA; A helical nucleocapsid; An
outer lipoprotein envelope.The virion contains an RNA dependent RNA polymerase.
The surface spikes consist of hemagglutinin (H), neuraminidase (N), and fusion (F) proteins
The fusion protein mediates the formation of multinucleated giant cells. Antibody to either
the H or the F protein neutralizes infectivity.
Transmission: respiratory droplets

pathogenesis
These viruses cause upper and lower respiratory tract disease without viremia.
A large proportion of infections are subclinical.
Parainfluenza viruses 1 and 2 are major causes of croup.
Parainfluenza virus 3 - lower respiratory tract infection
Parainfluenza virus 4 rarely causes disease, except for the common cold.

Clinical findings
 main cause of croup in children younger than 5 years of age. 
 Croup is characterized by a harsh cough and hoarseness. 
 In addition to croup, these viruses cause a variety of respiratory diseases such as the
common cold, pharyngitis, laryngitis, otitis media, bronchitis, and pneumonia

lab diagnosis
isolating the virus in cell culture or by observing a fourfold or greater rise in antibody titer.
PCR assay can also be used.
 Rabies virus
General properties
This virus causes rabies, an encephalitis. It has single-stranded RNA with negative polarity
enclosed within a bullet-shaped capsid surrounded by a lipoprotein envelope containing
knob-like glycoprotein (G).the virion contains an RNA-dependent RNA polymerase. Rabies
virus has a single antigenic type. Rabies virus has a broad host range: It can infect all
mammals, but only certain mammals are important sources of infection for humans

Replicative cycle
 Rabies virus attaches to the acetylcholine receptor on the cell surface.
 fusion of the viral envelope with the endosomal membrane and uncoating and
release of the nucleocapsid in the cytoplasm 
 virion-associated RNA-dependent RNA polymerase transcribes the genome to
make several mRNAs in the cytoplasm.

transmission
by the bite of dogs, bats, spread through saliva of rabid animal after bite injury. Via aerosols-
bat secretions

pathogenesis
 The virus multiplies locally at the bite site, Rabies is a neurotropic virus, infects the
sensory neurons 
 Moves by axonal transport to the central nervous system.The virus multiplies in
the central nervous system 
 then travels down the peripheral nerves to the salivary glands and other organs
 From the salivary glands, it enters the saliva to be transmitted by the bite. 
 There is no viremic stage.Within the central nervous system, encephalitis develops,
with the death of neurons and demyelination

Clinical findings
 The incubation period varies, according to the location of the bite, from 2 weeks to
16 weeks or longer
 The prodrome stage -Flu-like symptoms; fever, malaise, and changes in sensation at
the bite site called paresthesias
 Rabies manifests as either of two forms: “furious” (encephalitic) or “dumb”
(paralytic).
Encephalitic- most common
 Hydrophobia: Rabies patients experience involuntary, painful pharyngeal muscle
spasms when trying to drink; later on in the disease, the sight of water alone may
provoke nausea or vomiting.
 CNS symptoms
 Anxiety, agitation, and combativeness alternating with calm periods
 Confusion and hallucinations
 Photophobia
 Seizures
 ↑ Muscle tone and reflexes with nuchal rigidity
 Autonomic symptoms (e.g., hypersalivation, hyperhidrosis)
 Coma and death within days to weeks of the development of neurological symptoms
Paralytic
 Flaccid paralysis
 ascending paralysis similar to that of Guillain-Barré syndrome and
culminating in cardiac and respiratory arrest
 Paraplegia
 Respiratory failure and death

lab diagnosis
 infection in the animal 
 examination of brain tissue by using either PCR assay, fluorescent antibody
to rabies virus, or histologic staining of Negri bodies in the cytoplasm of
hippocampal neurons
 Rabies in humans
 by fluorescent antibody staining of a biopsy specimen, usually taken from
the skin of the neck at the hairline;
 by isolation of the virus from saliva, spinal fluid, and brain tissue;
  by a rise in titer of antibody to the virus. 

Treatment and prevention

 The rabies vaccine contains inactivated virus

 There are two approaches to prevention of rabies in humans -preexposure and
postexposure immunization
 Preexposure immunization with rabies vaccine - individuals in high-risk groups
 Postexposure immunization involves the use of both the vaccine and human rabies
immune globulin
 There is no antiviral therapy for a patient with rabies. Only supportive treatment is
available
 Differential diagnosis
 Measles: Patients present with a dark red, erythematous, maculopapular, partially
confluent exanthem, which spreads from behind the ears to the rest of the body.
 Scarlet fever: Patients present with a fine, light red, maculopapular rash. The
exanthem begins on the neck and disseminates to the whole body. The patient's face
may be red with perioral sparing. After 1–2 days, the exanthem becomes scarlet-
colored, and partially confluent. The rash is most pronounced in the axilla and groin. 
 Rubella (German measles): Patients typically present with a nonconfluent, pink,
maculopapular exanthem, which, like measles, extends from behind the ears to the
rest of the body.
  Erythema infectiosum (fifth disease): A confluent, maculopapular rash appears only
in ¼ of patients. It may take on a lace-like, reticular appearance over time.
Additionally, patients present with diffuse redness of the face with perioral sparing
(slapped-cheek rash).
  Roseola infantum (sixth disease): Three days of high fever are followed by a sudden
decrease in temperature and development of a patchy, rose-pink, macular exanthem.
The rash originates on the trunk and neck, and may spread to the face and extremities
in some cases.

 Varicella (chickenpox): The exanthem affects the whole body, typically spreading to
the scalp as well. Various stages of the rash occur simultaneously, which leads to the
characteristic clinical finding known as “starry sky.”

Tumor viruses
Human T- cell lymphotropic virus
General properties
Retrovirus family, enveloped with reverse transcriptase, two copies of single stranded
positive polarity RNA, does not kill t cells, causes malignant transformation that
“immortalizes” the infected T cells and allows them to proliferate in an uncontrolled manner.

The three structural genes common to all retroviruses - gag, pol, and env. Two regulatory
genes, tax and rex. Envelope proteins are gp46 and gp21

The Tax protein has two activities: 

o (1) stimulates viral mRNA synthesis; 

o  (2) stimulates the production of interleukin-2 (IL-2) and the IL-2

receptor. The increase in levels of IL-2 and its receptor stimulates the T cells
to continue growing, thus increasing the likelihood that the cells will become
malignant. 
The Tax protein also responsible for enhancing the transcription of protooncogenes resulting
in transformation

The Rex protein similar to HIV Rev, is a posttranscriptional activator that increases
transport of structural protein mRNAs from nucleus to cytoplasm.

Transmission
Intravenous drug use, sexual contact, breast feeding, blood transfusion, Transmission is
thought to occur primarily by the transfer of infected cells rather than free, extracellular
virus

Pathogenesis
adult T-cell leukemia/lymphoma (ATL)

o HTLV infection of CD4- positive T lymphocytes induces malignant

transformation

o HTLV remains latent within the malignant T cells

o The transformed cells typically do not produce HTLV progeny viruses

HAM- HTLV-associated myelopathy, or tropical spastic paraparesis (TSP), which is a

demyelinating disease of the brain and spinal cord, especially the motor neurons. It is
believed that the mechanisms of HAM/TSP are immune mediated, including an autoimmune
reaction-induced damage of the neurons as well as cytotoxic T-cell–induced killing of
neurons.

Clinical findings
 Adult T-cell leukemia/lymphoma (ATL): There is a long period of latency (about 20-
30 years) before onset of ATLL. ATL is characterized by lymphadenopathy,
hepatosplenomegaly, lytic bone lesions, and skin lesions. These features are caused by
proliferating T cells infiltrating these organs. Patients with ATL often have reduced
cell-mediated immunity, and opportunistic infections with fungi and viruses are
common. in the blood, the malignant T cells have a distinct “flower-shaped” nucleus
 HTLV-associated myelopathy (HAM): Loss of motor function : gait disturbance (,
gait stiffness/spasticity), weakness of the lower limbs, and low back pain.  Loss of
bowel and bladder control. Progression of symptoms occurs slowly over a period of
years. T cells with a “flower-shaped” nucleus can be found in the spinal fluid

Laboratory diagnosis
 antibodies against the virus in the patient’s serum using the ELISA test

 The Western blot assay is used to confirm a positive ELISA result. 

 PCR assay can detect the presence of HTLV RNA or DNA within infected cells.

 ATL is diagnosed by finding malignant T cells in the lesions. 

  The diagnosis of HAM -presence of HTLV antibody in the spinal fluid or finding
HTLV nucleic acids in cells in the spinal fluid.

Hepatitis c
predisposes to hepatocellular carcinoma. HCV is an RNA virus that has no oncogene and
forms no DNA intermediate during replication. It does cause chronic hepatitis, which seems
likely to be the main predisposing event.

Papilloma virus
dsDNA virus, circular, Naked, icosahedral. Carcinogenesis by HPV involves two proteins
encoded by HPV genes E6 and E7 that interfere with the activity of the proteins encoded by
two tumor suppressor genes, p53 and Rb (retinoblastoma), found in normal cells. Certain
types of HPV, especially types 16 and 18, are implicated as the cause of carcinoma of the
cervix, penis, and anus.

Merkel cell polyomavirus

 a carcinoma of Merkel cells in the skin. The carcinoma occurs most often on skin
exposed to the sun such as the face and neck. Immunosuppressed individuals and the
elderly are predisposed to this cancer. Members of the polyomavirus family are small,
nonenveloped, double-stranded DNA viruses known to cause cancer in animals.
Infection with MCPV is common as indicated by the presence of antibody to the virus
in many healthy blood donors.

 The early region is expressed soon after infection of cells; it contains genes that code
for early proteins—SV40 large tumor (T) antigen, which is necessary for the
replication of viral DNA in permissive cells, and  the small tumor (t) antigen.. One or
two of the T antigens are the only viral gene products required for transformation of
cells. The late region consists of genes that code for the synthesis of coat protein; they
have no role in transformation and usually are not expressed in transformed cells
 The gene for the large T antigen is mutated so the virus cannot replicate but the T
antigen continues to be synthesized.The T antigen causes the cell to become
malignant by inhibiting tumor suppressor proteins such as p53 and RB. Because
MCPV does not replicate in the carcinoma cells, patients are not infectious to others.

Epstein barr
EBV, the cause of infectious mononucleosis, transforms B lymphocytes in culture and causes
lymphomas in marmoset monkeys. It is also associated with nasopharyngeal carcinoma , with
thymic carcinoma and B-cell lymphoma, burkitt’s lymphoma.

Cells with Burkitt’s lymphoma contain EBV DNA and EBV nuclear antigen. Only a small
fraction of the many copies of EBV DNA is integrated; 
 Slow viruses and prions
Prions
Small, filterable infectious particles that contain protein but no detectable nucleic acid.Prion
proteins (PrPC) are encoded by the host genome. PrPC is found in neuronal synapses, binds
copper, has unknown function. Prion proteins become infectious and pathogenic (PrPSc) as a
result of protein conformational changes. PrPSc aggregates and accumulates in diseased
brain. Highly resistant to inactivation by heat, formaldehyde, and ultraviolet Sensitive to
protein- and lipid-disrupting agents - they are inactivated by hypochlorite, NaOH, and
autoclaving.

 The normal prion protein (PRPC, or prion protein cellular) has a significant amount
of alpha-helical conformation
 When conformation changes to a beta-pleated sheet (known as PrPSC, or prion
protein scrapie), it aggregate into filaments, which disrupt neuron function and
cause cell death.
 Specific cellular RNAs enhance the conversion of the normal alpha-helical form
to the pathologic beta-pleated sheet form

 Both sheet form have the same amino acid sequence but different conformation

Transmissible spongiform encephalopathies (TSE)

 Chronic, progressive, invariably fatal central nervous system degeneration.
 Brain pathology is spongiform encephalopathy—large vacuoles in cortex and
cerebellum give brain a sponge-like appearance. Affected areas contain microscopic
insoluble amyloid, fibrils and macrocrystalline arrays known as amyloid plaques.
 No signs of a host immune response.
 Can arise spontaneously or by ingestion of infected tissue.
 Kuru

 characterized by progressive tremors and ataxia but not dementia.

 It occurs only among the Fore tribes in New Guinea
 Disease could have been acquired: 
o by eating the brains 
o  via cuts in the skin that occurred during the preparation of the brains

Creutzfeldt-Jakob disease (CJD)

 The spongiform changes are the result of neuronal vacuolation and neuronal loss
rather than demyelination
 Was acquired by ingestion
 The finding of a normal brain protein called 14-3-3 in the spinal fluid supports the
diagnosis.

  main clinical findings of CJD are dementia, ataxia, aphasia, visual loss, and
hemiparesis. A presumptive diagnosis  -by detecting spongiform changes in a brain
biopsy specimen. Amyloid plaques are also seen in some cases
 Are suspected of being involved in the pathogenesis of other important diseases of the
central nervous system, such as Alzheimer’s disease and Parkinson’s disease.

Progressive multifocal leukoencephalopathy

 PML- is a fatal demyelinating disease of the white matter (i.e.,
leukoencephalopathy) and involves multiple areas of the brain (i.e., multifocal).
 The clinical picture includes visual field defects, mental status changes, and
weakness. The disease rapidly progresses to blindness, dementia, and coma, and
most patients die within 6 months.
 It occurs primarily in individuals with compromised cell-mediated immunity
 PML is caused by JC virus, a member of the polyomavirus family.

 JC virus infects and kills oligodendroglia, causing demyelination

 The virus persists in the kidney and is excreted in the urine.

Subacute sclerosing panencephalitis (SSPE)

 a slowly progressive disease characterized by inflammatory lesions in many areas of
the brain.
 It is a rare disease of children who were infected by measles virus several years
earlier

 SSPE is a persistent infection by a variant of measles virus that cannot complete its
replication. The evidence for this is as follows:
(1) Inclusion bodies containing helical nucleocapsids, which react with antibody to
measles virus, are seen in the affected neurons.

(2) A virus very similar to measles virus can be induced from these cells by cocultivation
with permissive cells in culture. (3) Patients have high titers of measles antibody in the
blood and spinal fluid.

Parasites intestinal and urogenital

Entamoeba histolytica
General properties
Causes amebic dysentery and liver abscess, The trophozoite (has two nucleus and a centra;
nucleolus) is found within the intestinal and extraintestinal lesions and in diarrheal stools.
The cyst (has four nucleus) predominates in non-diarrheal stools

Transmission
Fecal-oral route by contaminated food and water

Pathogenesis
 The ingested cysts differentiate into trophozoites in the ileum and colonize the
cecum and colon.
 The trophozoites invade the colonic epithelium and secrete enzymes that cause
localized necrosis
 muscularis layer- a typical “flask-shaped” ulcer forms that destroy large areas of
the intestinal epithelium
 can spread to the liver (most often), lung, and brain

clinical findings
 Dysentery (i.e., bloody, mucus-containing diarrhea)
o Granulomatous lesion called an ameboma  may form in the colon. 
o These lesions can resemble an adenocarcinoma of the colon
 Amebic abscess of the liver is characterized by right-upper-quadrant pain, weight
loss, fever, and a tender, enlarged liver
 Right-lobe abscesses can penetrate the diaphragm and cause lung disease.

Laboratory diagnosis
 Diagnosis  -finding either trophozoites in diarrheal stools or cysts in formed stools
 PCR
 Serologic tests
 Treatment and prevention
Metronidazole or tinidazole. Mechanism of action: creates free radicals within the bacterial
cell → DNA-strand breaks; bactericidal and antiprotozoal effect

Giardia lamblia
General properties

Causes giardiasis, clinical findings watery, foul-smelling diarrhea. nausea, anorexia,

flatulence, and abdominal cramps persisting for weeks or months.

The life cycle consists of two stages: the trophozoite and the cyst. The trophozoite is pear-
shaped with two nuclei, four pairs of flagella, and a suction disk with which it attaches to the
intestinal wall. The oval cyst is thick-walled with four nuclei and several internal fibers.

Transmission

fecal-oral route by contaminated food and water

Pathogenesis

 does not invade the mucosa and does not enter the bloodstream
 causes inflammation of the duodenal mucosa, leading to malabsorption of protein
and fat.
 Steatorrhea and malabsorption with flattening of the villi often accompanied by
profound weight loss, are the dominant pathological consequences of chronic
infection

 The incidence is high among children in day care centers and among patients in
mental hospitals

Laboratory diagnosis

 Finding trophozoites or cysts or both in diarrheal stools

 ELISA
 String test

Treatment

Metronidazole or quinacrine hydrochloride

 Cryptosporidium hominis
General properties

Causes cryptosporidiosis, main symptom watery diarrhea, severe diarrhea in

immunocompromised patients. Within the intestine Oocysts release sporozoites, which form
trophozoites. Several stages ensue, involving the formation of schizonts and merozoites.
Eventually microgametes and macrogametes form; these unite to produce a zygote, which
differentiates into an oocyst.

Transmission

by fecal–oral transmission of oocysts from either human sources (primarily) or from

animal sources

Laboratory diagnosis

Oocysts in fecal smears when using a modified Kinyoun acid-fast stain. A test for
Cryptosporidium antigen in the stool

Treatment

Nitazoxanide for patients not infected HIV

Trichomonas vaginalis
General properties

Causes trichomoniasis, pear shaped with central nucleus and four anterior flagella, only exists
as trophozoite. Transmitted by sexual conact

Clinical features

The incubation period is 5– 28 days.Symptoms often begin or worsen during periods and
include vaginal discharge (may be smelly or itchy), dyspareunia, dysuria, and lower
abdominal discomfort. Signs include vulvar erythema, yellow/ green or frothy vaginal
discharge, vaginal inflammation, and punctate haemorrhages on the cervix (‘strawberry
cervix’). Complications of vaginal trichomoniasis include vaginitis emphysematosa (gas-
filled blebs in the vaginal wall), vaginal cuff cellulitis after hysterectomy, premature labour,
and low- birthweight infants.
 Laboratory diagnosis

 In a wet mount of vaginal (or prostatic) secretions

 Culture remains the most sensitive technique, and trichomonads can be cultured on a
variety of media;

Treatment

Metronidazole for both partners to prevent reinfection

Blood and tissue sporozoans

Toxoplasma gondii
General properties
Causes toxoplasmosis, including congenital toxoplasmosis, obligate intracellular sporozoan,
host is domestic cat, intermediate host humans and other mammals.

Transmission
Oral ingestion- The oocysts are excreted in the feces of cats (final host) and are orally
ingested by other mammals such as humans, hoofed animals, and birds (intermediate hosts).
Primary models- cat feces, raw or undercooked meat, unpasteurized milk,
Vertical transmission- transplacental
Horizontal transmission- organ or blood transfusion

Cycle
The oocyst
 The oocyst possesses a thick wall that makes it resistant to most environmental
challenges
 In its immature form, the center of the cyst lacks internal structure.
  With maturation, two sporocysts appear, and later four sporozoites may be discerned
within each sporocyst. 
 This form is responsible for the fecal–oral route of transmission of the parasites from
felines to other warm-blooded animals.
Tissue cyst
 Cysts The contained organisms, referred to as bradyzoite (that are contained in tissue
Cysts in muscle and brain tissue and in the eye.)
 Tissue cysts are resistant to digestive enzymes and, like oocysts, are infectious to the
animal that ingests them. 
 They survive normal refrigerator temperatures but are killed by freezing  and by
normal cooking temperatures
Cycle
 T. gondii circulates between cats, which excrete oocysts in the feces that are eaten by
mice, but also by domestic animals such as pigs and sheep. 
  Cysts form in tissue such as muscle and brain. The natural cycle is completed when
cats eat mice.
  Humans are accidental hosts. 
 They can be infected by the ingestion of under-cooked pork and lamb containing
tissue cysts in muscle or by ingestion of food contaminated with cat feces containing
oocysts

cycle in cats
 The cycle begins with the ingestion of cysts in raw meat 
 Bradyzoites are released from the cysts in the small intestine,  infect the mucosal
cells, and differentiate into male and female gametocytes
 These gametes fuse to form oocysts that are excreted in cat feces
 Oocysts sporulate outside the host, producing haploid sporozoites, the infectious stage
for the intermediate host
  The cycle is completed when soil contaminated with cat feces is accidentally
ingested.

Pathogenesis
 In the small intestine of humans the cysts rupture and release forms invade the gut
wall
 Sporozoites are released by exposure of the oocyst to digestive enzymes in the small
intestine.
 they are ingested by macrophages and differentiate into trophozoites (as tachyzoites). 
 Tachyzoites directly destroy cells, particularly parenchymal and reticuloendothelial
cells

 Cell-mediated immunity usually limits the spread of tachyzoites, but  protective

immunity does not result in the elimination of the parasite. Rather, in response to host
defense mechanisms tachyzoites are forced to differentiate into a
 second asexual stage known as the bradyzoite.
 Bradyzoites lie dormant in the tissues for as long as host defenses remain active. 
 Although all tissues can harbor tissue cysts, the brain, kidney, heart, and liver are
favored sites for the long-term survival of the tissue cyst

 bradyzoites are formed and released from ruptured tissue cysts

 bradyzoites cause local inflammation with blockage of blood vessels and necrosis.
 Transplacental transmission from an infected mother to the fetus occurs
 Congenital infection of the fetus occurs only when the mother is infected during
pregnancy –only trophozoites pass through the placenta

Clinical features
congenital toxoplasmosis, acquired acute toxoplasmosis in the immunocompetent individual,
and  toxoplasmosis in the immunocompromised patient
Most primary infections in immunocompetent adults are asymptomatic, Some resemble
infectious mononucleosis 
o by generalized lymphadenopathy, with predominant enlargement of the
cervical nodes, sometimes associated with a low-grade fever
Immunosuppressed patients (e.g., AIDS):  primary infection or reactivation in previously
infected individuals Cerebral toxoplasmosis (the most common neurological AIDS-defining
illness, symptomatic usually if CD4 count < 100 cells/μL, Fever, Headache, Mental
status changes, Seizures, Focal neurological deficits.

Chorioretinitis- Acute toxoplasmosis; yellow-white retinal lesion; vitreous reaction;

concomitant vasculitis; defects in the visual field at the site of inflammation
Congenital infection- Transmission typically occurs when a woman acquires a primary
infection while pregnant. Transmission to the fetus is lowest when acute infection occurs
during the first trimester, with only ~6% of fetuses acquiring infection.
The percentage rises with gestational age of the fetus to over 70% if infection is acquired late
in the third trimester. Fetal damage is most severe when infection occurs early in the
pregnancy. Infection later in pregnancy constitutes the majority of congenital toxoplasmosis
with most affected children asymptomatic.
They may show the less severe pathological consequences of infection several months to
years later.

Congenital infection can result in  abortion, stillbirth, Chorioretinitis, Diffuse intracranial

calcifications, Hydrocephalus

Laboratory diagnosis
Giemsa stain- crescent shaped trophozoits during acute infection. PCR: sample is taken from
amniotic fluid in case of suspected intrauterine disease
CT/MRI of the brain for suspected cerebral toxoplasmosis (multiple ring-enhancing
lesions )

Treatment
patient with chorioretinitis - combination of sulfadiazine and pyrimethamine
Trimethoprim-sulfamethoxazole -to prevent Toxoplasma encephalitis in patients infected
with HIV infection

Pneumocystis jiroveci
General properties
important cause of pneumonia in immunocompromised individuals. In tissue, it appears as a
cyst that resembles the cysts of protozoa, transmission- inhalation

Pathogenesis
 The presence of cysts in the alveoli induces an inflammatory response. 

Clinical features

 The sudden onset of fever, nonproductive cough, dyspnea, and tachypnea is

typical of Pneumocystis pneumonia
 Extrapulmonary Pneumocystis infections occur in the late stages of AIDS and affect
primarily the liver, spleen, lymph nodes, and bone marrow. 
 Laboratory diagnosis

finding the typical cysts by microscopic examination of lung tissue or fluids obtained by
bronchoscopy, bronchial lavage, or open lung biopsy

The chest Xray shows a diffuse interstitial pneumonia with “ground glass” infiltrates bilateral
-Chest x-ray

Treatment

combination of trimethoprim and sulfamethoxazole

prevention- Trimethoprim-sulfamethoxazole or aerosolized pentamidine (inhibits DNA

synthesis )

Plasmodium
General properties

Malaria is caused by four plasmodia: Plasmodium vivax, Plasmodium ovale, Plasmodium

malariae, and Plasmodium falciparum. 

The plasmodia are Apicomplexa in which the sexual and asexual cycles of reproduction are
completed in different host species.The vector and definitive host for plasmodia is the
female Anopheles mosquito

There are two phases in the life cycle: the sexual cycle, which occurs primarily in
mosquitoes, The sexual cycle is called sporogony because sporozoites are produced  the
asexual cycle, which occurs in humans – the intermediate hosts.the asexual cycle is called
schizogony because schizonts are made.

Transmission

Mosquito bites, across placenta , blood transfusion, intravenous drug use.

Life cycle

exo-erythrocyte stage - occurs in the liver

introduction of sporozoites into the blood from the saliva of the biting mosquito.The
sporozoites are taken up by hepatocytes within 30 minutes, in which asexual multiplication
takes place In this process, the sporozoite develops into a multinuclear, large schizont
(meront) described as a tissue schizont. Following cytoplasmic division merozoites are
produced. Merozoites are released from the liver cells and infect red blood cells. P. vivax
and P. ovale produce a latent form (hypnozoite) in the liver; this form is the cause of relapses
seen with vivax and ovale malaria
the erythrocytic phase-

the organism differentiates into a ring-shaped trophozoite. The ring form grows into an
ameboid form and then differentiates into a schizont filled with merozoites. After release, the
merozoites infect other erythrocytes. The periodic release of merozoites causes the typical
recurrent symptoms of chills, fever, and sweats seen in malaria patients. Some merozoites
develop into male and others into female gametocytes.

The sexual cycle begins in the human red blood cells when merozoites develop into male and
others into female gametocytes. The gametocyte-containing red blood cells are ingested by
the female Anopheles mosquito and, within her gut, produce a female macrogamete and eight
spermlike male microgametes. After fertilization, the diploid zygote differentiates into a
motile ookinete , than into an oocyst within which many haploid sporozoites are produced.
The sporozoites are released and migrate to the salivary glands

pathogenesis

destruction of red blood cells, Red cells are destroyed, by the release of the merozoites, by
the action of the spleen - lyse them. Parasitized erythrocytes are phagocytosed by a
stimulated reticuloendothelial system or are destroyed at the time of parasite-induced cell
rupture, releasing toxic products. sequestration of erythrocytes within the enlarging spleen,
and accelerated clearance of nonparasitized cells all appear to contribute to the anemia.

Malaria caused by P. falciparum is more severe than that caused by other plasmodia.
Occlusion of the capillaries with aggregates of parasitized red cells leads to life-threatening
hemorrhage and necrosis, particularly in the brain (cerebral malaria). extensive hemolysis and
kidney damage occur, with resulting hemoglobinuria, “blackwater fever”(dark color of the
patient’s urine). The hemoglobinuria can lead to acute renal failure.

 P. falciparum causes a high level of parasitemia -can infect red cells of all ages
 P. vivax infects only reticulocytes 
  P. malariae infects only mature red cells;

Carriers of sickle-cell mutation, Individuals with either certain Duffy antigens or no Duffy
antigens are resistant to P. vivax, Other hemoglobinopathies (e.g., thalassemia, HbC) have
partial resistance against malaria

Clinical findings
Fever, chills, headache, myalgias, arthalgias, The fever spike, which can reach 41°C, is
frequently accompanied by shaking chills, nausea, vomiting, and abdominal pain
Splenomegaly is seen in most patients.

Untreated malaria is a result of cerebral malaria and blackwater fever

 Laboratory diagnosis
microscopic examination of blood, using both thick and thin Giemsa-stained smears. the thin
smear -species identification -The gametocytes of P. falciparum are crescent-shaped
(“banana-shaped”), whereas those of the other plasmodia are spherical

treatment
chloroquine, primaquine
Chemoprophylaxis of malaria for travelers to areas where chloroquine-resistant P. falciparum
is endemic consists of mefloquine or doxycycline

Blood and tissue

hemoflagellates
Trypanosoma cruzi
General properties
Chaga’s disease. Vector is reduviid bug, reservoir host- human. also called kissing bug
because it typically bites around the mouth or eyes
T. cruzi is shed in the feces of the reduviid bug; feces is then rubbed into the bite site while
scratching
Transmission- blood transfusion, vector, organ transplant, congenitally from an infected
mother to the fetus across the placenta.

Cycle
 The cycle in the reduviid bug- ingestion of trypomastigotes in the blood of the
reservoir host
 In the insect gut, they multiply and differentiate first into epimastigotes and then into
trypomastigotes
 When the bug bites again, the site is contaminated with feces containing
trypomastigotes which enter the blood of the person and form non flagellated -
amastigotes within host cells
 myocardial, glial, and reticuloendothelial cells are the most frequent sites of
infection

pathogenesis
 The amastigotes can kill cells and cause inflammation, consisting mainly of
mononuclear cells. 
 Cardiac muscle is the most frequently and severely affected tissue. 
 In addition, neuronal damage leads to cardiac arrhythmias and loss of tone in the
colon (megacolon) and esophagus (megaesophagus). 
 During the acute phase, there are both trypomastigotes in the blood and amastigotes
intracellularly in the tissues.
  In the chronic phase, the organism persists in the amastigote form
 Clinical findings
The acute phase of Chagas’ disease -facial edema and a nodule (chagoma) near the bite,
fever, lymphadenopathy, and hepatosplenomegaly. A bite around the eye can result in
unilateral palpebral swelling called Romaña’s sign. 
chronic form with myocarditis and megacolon. Death from chronic Chagas’ disease is usually
due to cardiac arrhythmias or heart failure.
Latent stage- May continue for the life, Later can cause cardiac or gastrointestinal disease
Congenital Chagas disease
Acute or chronic

Laboratory diagnosis
Presence of trypomastigotes in thick or thin films of the patient’s blood. Chronic disease -
Xenodiagnosis and serologic tests are used.

Treatment
acute phase - nifurtimox, which kills trypomastigotes in the blood but is much less effective
against amastigotes in tissue.
Benznidazole is an alternative drug.

Trypanosoma gambiense and rhodesiense

cause sleeping sickness (African trypanosomiasis).The vector for both is the tsetse fly,
Glossina, but different species of fly are involved for each. Humans are the reservoir for T.
gambiense, T. rhodesiense has reservoirs in both domestic and wild animals

Cycle

life cycle in the tsetse fly: ingestion of trypomastigotes in a blood meal from the reservoir
host, They multiply in the insect gut - migrate to the salivary glands, where they
transform into epimastigotes, multiply further, and then form metacyclic trypomastigotes,
which are transmitted by the tsetse fly bite

life cycle in humans: are injected into the skin, where they enter the bloodstream,
differentiate into blood-form trypomastigotes, these species are rarely found as
amastigotes in tissue

pathogenesis

 trypomastigotes spread from the skin through the blood to the lymph nodes and the
brain.
  The typical somnolence (sleeping sickness) progresses to coma as a result of a
demyelinating encephalitis.
 In the acute form, a cyclical fever spike occurs that is related to antigenic variation
 Clinical findings

 Hemolymphatic stage
o Trypanosomal chancre 
o Intermittent fever
o Painless lymphadenopathy 
o Annular maculopapular rash
o Headache, arthralgia, myalgia
 Neurologic phase
o Sleep inversion 
o Behavioral changes (psychosis, apathy)
o Ataxia
o Decreased consciousness progressing to coma

Laboratory diagnosis

 microscopic examination of the blood (either wet films or thick or thin smears)
reveals trypomastigotes
 The presence of trypanosomes in the spinal fluid, coupled with an elevated protein
level and pleocytosis, indicates the encephalitic stage.
 Serologic tests, especially the ELISA for IgM antibody, can be helpful.

Leishmania donovani
General properties
cause of kala-azar (visceral leishmaniasis). The life cycle involves the sandfly as the vector

cycle
sandfly sucks blood from an infected host, it ingests macrophages-containing amastigotes
amastigotes differentiate into promastigotes in the gut
They multiply and then migrate to the pharynx.

After an infected sandfly bites a human, the promastigotes are engulfed by macrophages,
where they transform into amastigotes
Amastigotes can remain in the cytoplasm of macrophages because they can prevent fusion of
the vacuole with lysosomes
The infected cells die and release progeny amastigotes that infect other macrophages and
reticuloendothelial cells. The cycle is completed when the fly ingests macrophages containing
the amastigotes.

pathogenesis

In visceral leishmaniasis, the organs of the reticuloendothelial system (liver, spleen, and
bone marrow) are the most severely affected, results in anemia, leukopenia, and
thrombocytopenia.
 Clinical findings

 Visceral leishmaniasis
 Kala-azar (Hindi for “black fever”)
 Symptoms begin with intermittent fever, weakness, and weight loss.
 Massive enlargement of the spleen
 Anemia, leukopenia, and thrombocytopenia become more profound , weakness,
infection, and gastrointestinal bleeding occur. 

 Localized cutaneous leishmaniasis:Incubation period: weeks to months, solitary or

multiple reddish macules/papules around the sandfly bite that quickly increase in size
and develop central ulceration
 Mucosal leishmaniasis: Manifestation: commonly affects the nasopharynx
(mucosal bleeding, nasal blockage)

Laboratory diagnosis

detecting amastigotes in a bone marrow, spleen, or lymph node biopsy

Treatment

Amphotericin B

Helminths-flatwormes
Cestodes-tapeworms
Taenia solium
General properties
Adult causes taeniasis and larvae cause cysticercosis. It has scolex (four suckers and circle of
hooks and gravid proglottids.

cycle
 Pigs and cattle are infected when they ingest either the eggs or proglottids in human 
stool. A six-hooked embryo (oncosphere) emerges from each egg in the pig’s
intestine. The embryos burrow into a blood vessel and are carried to skeletal muscle. 
 They develop into cysticerci in the muscle, where they remain until eaten by a
human. So the larvae (cysticerci) are found in the pig
Definitive host
→ ingested in poorly cooked pork → in small intestine, larvae mature and grow → adults
consist of scolex (head) and numerous proglottids (autonomous segments)→ scolex attaches
to intestinal wall, proglottids containing eggs passed in feces → worm consumes food
ingested by host  → malnutrition
Intermediate host
humans ingest eggs from infected feces (vs. larvae in pork) → eggs hatch into oncospheres
(embryo ) in small intestine→ oncospheres penetrate intestinal wall and travel to other tissues
especially in brain, skeletal muscle, and eye → there they encyst to form cysticerci
containing larvae,→ neurologic defects (seizures, focal symptoms) or blindness→ when
cysts die after several years, increased inflammation 

Clinical findings
 intestinal infection: asymptomatic; malnutrition, abdominal discomfort ( anorexia
and diarrhea can occur)
 tissue infection: cysticercosis (neurologic defects, blindness) 
o Infect the eye, brain, muscle, and lungs. The symptoms vary depending on the
location of the cysticerci, but can include meningioencephalitis, seizures, and
other neurologic manifestations. The cysticerci can become very large
especially in the brain, where they manifest as a space-occupying lesion
o  Cysticercosis in the eyes can appear as uveitis or retinitis, or the larvae can be
visualized floating in the vitreous. Subcutaneous nodules containing cysticerci
commonly occur. Cysts also are commonly found in skeletal muscle.

Laboratory diagnosis
Intestinal- proglottids, eggs in the stool; tissue infection- calcified cystecerci in muscle or
brain, eosinophilia in muscle.

Treatment
Adult tapeworm- praziquantel. Cysticercosis surgery praziquantel or albendazole

Diphyllobothrium latum
General properties
causes diphyllobothriasis. has two elongated sucking grooves by which the worm attaches to
the intestinal wall. intermediate hosts: freshwater copepod (Cyclops) and freshwater fish.
Treatment praziquantel

Clinical findings
 asymptomatic, but abdominal discomfort and diarrhea can occur.
  competition for vitamin B12 leads to a B12 deficiency, which can result in
megaloblastic anemi

echinococcus granulosus
General properties
unilocular hydatid cyst disease -echinococcosis.smallest tapeworms. Definitive hosts dogs,
intermediate-sheep, humans are accidental hosts. Treatment- albendazole

cycle
  Dogs contain the adult tapeworm in the intestines. worms in the dog’s intestine
liberate thousands of eggs
 Sheep ingest the eggs in dog feces. 
 The oncosphere embryos formed in the small intestine and migrate primarily to the
liver ,lungs, bones, and brain
 The embryos develop into large fluid-filled hydatid cysts which generates many
protoscoleces
 The life cycle is completed when the entrails (e.g., liver containing hydatid cysts) of
slaughtered sheep are eaten by dogs.
 Humans are accidental intermediate hosts 
 They ingest food contaminated with dog feces containing the eggs 
 Eggs hatch oncosphere embryos in human intestine
 Hydatid cysts form primarily in the liver, lung, brain, and bone
 The cyst acts as a space-occupying lesion, putting pressure on adjacent tissue
 if the cyst ruptures spontaneously or during trauma or surgical removal, life-
threatening anaphylactic shock can occur.
  Rupture of a cyst can also spread protoscoleces

Clinical findings
Many are asymptomatic, liver cysts may cause hepatic dysfunction, Cysts in the lungs can
destroy a bronchus, causing bloody sputum. Cerebral cysts can cause headache and focal
neurologic signs. Rupture of the cyst can cause fatal anaphylactic shock.

Laboratory diagnosis
mild eosinophilia, leukopenia or thrombocytopenia, liver function abnormalities. Diagnosis is
by serologic testing. by X-ray or CT to detect hydatid cysts.

Trematodes- flukes