MIMS' PATHOGENESIS

OF INFECTIOTJS
DISEASE

SIXTH EDITION
ANtHoNv A. NasH
Roprnr G. Darzm
J. Ross Frrzcrnaro

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E[SE/IER
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 Contents

k'cfrce vii Summary 92

Bibliography 92

1. General Principles 5. The Spread of Microbes Through

Eil{ioenphy 7 the Body
Direct Spread 96
2. Attachment to and Entry Microbial Factors Promoting Spread 9?
of Microorganisms into the Body Spread Ma Lymphatics 97
Inrroduction 9 Spread Ma the Blood 99
Adhesion/Entry: Some General Considerations 14 Spread Via Other Pathways 1.15
The Skin 15 Bibliography ll7
Respiratory Tiact l7
Gastrointestinal Tiact 20 6. The Immune Response to Infection
Oro,pharynx 30 Antibody Response 126
Urinogenital Tiact 32 T,Cell.Mediated Immune Response 133
Conjtrnctiva 34 NK Cells 1,35
The Normal Microbiota 35 Macrophages, Neutrophils and Mast Cells 136
Exit of Microorganisms from the Body 40 Complement and Related Defence
Bibliography 48 Molecules 139
Conclusions Conceming the Immune Response
3. Early Stages of Infection After to Microorganisms 143
Pathogen Entry Bibliography 144
Growth in Epithelial Cells 5l
Intracellular Microorganisms and Spread Through 7. Microbial Strategies in Relation
the Body 54 to the Immune Response
Subepithelial Invasion 56 Induction of Immunological Tolerance 146
Nutritional Requirements of Invading Microbes 63 Immunosuppression 150
Bibliography 64 Absence of a Suitable Thrget for the Immune
Response I54
4. Encounter of Microbes with Microbial Presence in Bodily Sites Inaccessible
Phagocytic Cells to the Immune Response L55
Cell Biology of Phagocytosis 69 Induction of Inappropriate Antibqrlr,--
Phagocytosis in Polymorphonuclear Leucocytes 70 and T.Cell Responses 156
in Macrophages 75
-
Phagocytosis Antibodies Mopped up by Soluble
Microbiai Strategy in Relation to Phagocytes 77 Microbial Antigens 158
Growth in the Phagocytic Cell 86 Local Interference with Immune Forces 159
Killing the Phagocyte 88 Reduced Interferon Induction or
Entry into the Host Cell Other than by Responsiveness 162
Phagocytosis 89 Antigenic Variation 163
Consequences ofDefects in the Phagocytic Cell 90 Bibliography 169
vl CONTENTS

8. Mechanisms of Cell and Tissue Damage Persistent lnfection Without Shedding 268
Infection with No Cell or Tissue Damage 176 Significance for the Individual of Persistent
Direct Damage by Microorganisms L77 Infectioru 7.70

Microbial Toxins 179 Conclusions 271

Indirect Damage via In{lammation 209 Bibliography Z7l
Indirect Damage via the Immune Response
(lmmunopathology) 210 11. Host and Microbial Factors
Other Indirect Mechanisms of Damage ZZ0
Influencing Susceptibility
Diarrhoea 223
Genetic Factors in the Microorganism 274
Bibliography 230 Genetic Factors in the Host 279
Suess and Hormonal Factors 286
9. Recovery from Infection Other Factors 289
Immunological Factors in Recovery 233 Bibliography 289
Inflammation 242
Complement 243
Interferons 245 12. Vaccines and How They \7ork
Multimechanistic Recovery: An Example 247 Introduction 291
Temperature 249 General Principles 293
Tissue Repair 250 Complications and Side Effects of Vaccines 299
Resistance to Re,lnfection 253 Reverse Vaccinology 301
Bibliography 255 Bibliography 302

10. Failure to Eliminate Microbe Appendix 305

Latency 259
Persistent Infection with Shedding 264
Conclusions 313
Epidemiological Significance of Persistent Infection Glossary 317
with Shedding 267 Index 323
 Preface

h has been 12 years since the fifth edition The sixth edition maintains the standards
d lhis book was published. In that time, and unique style of earlier editions despite
re have witnessed a revolution in the tech- the absence of Professor Mims whose vision
rlngies underpinning studies of the patho- was paramount in bringing pathogenesis to
SE Eis of infectious disease. In the fifth a wider audience. In particular, we have
cdilioru 30 bacterial genomes had been com- endeavoured to use accessible language and
pleted. We now have access to thousands of simple but colourful diagrams to convey
rrrqpleted pathogen genomes and those of the mechanisms of pathogenesis to students
Eumy mammaliaru avian and piscine 'hosf of infectious disease.
species. This has led to new ways of explor-
mg how pathogen and host interact and Tony Nash
how they evolve. In turn the new insights Bob Dalziel
gained into pathogenesis are leading to Ross Fitzgerald
improvements in diagnostics, vaccines and
therapeutics.
 General Principles
When writing a book about infectious diseases, it is important to define exactly
what
ffG mean in using the term in order to provide a context fbr the information to come. In
ry biological terms,.the relationship between two distinct but associated organisms
cnr be classified as parasitic, where one benefits at the expense of the other, or ,1ii.,fioti.
itmutualistic), where both benefit. There is another commbnly used category calied com-
nrqrsalism, whereby the organisms co-exist without damage io
either org"anism. It is often
difficult to use this category with confidence, because ur,lppu.".tly co"mmensal associa-
tixr often proves on closer examination to be really parasitic-or symbiotic.
The classification system can be applied to the isiociation between microorganisms
and
rertebrates. Generalised infections such as measles, fuberculosis or typhoii
are clearly
examples of parasitism. On the other hand, the microbiota inhabiti"g ih" rumen
of cows
a the caecum of rabbits, enjopang food and shelter and at the samJ time supplying the
hct with food derived from the utilisation of cellulose, are clearly symbiotic. iri Jaaitior,,
recent and on-going research is revealing the great variety of ways by which
resident bac-
contributing to the normal function of their host ipecies. For example, the bacteria
Tfu-l."
that live on human skin may at first be considered as commensals. They eijoy
rrr"itu. u1a
food (sebum, sweat, etc.) but are normally harmless. If the skin ,rrfr." is examined
by
the scanning electron microscope, the bacteria, such as Staphytococcus epideiiiiii u"a
Proprionibacterium acnes, are seen in small colonies scattered over a moon-iike
landscape.
The colonies contain several hundred individualsl and the bacteria adhere to
the epitheiial
squames that form the cornified skin surface, and extend between the squame,
ur,'d do*o
the mouths of the hair.follicles-and glands onto the skin surface. They can be reduced
in
numbers, but never eliminated, by scrubbing and washing, and are most numerous
in
more moist regions such as the armpit, groyne and perineuir. The dryness
of the stratum
corneum makes the skin an unsuitable environmentlor most bacteria, and merely
occlud-
ing and thus hydrating an area with polythene sheeting leads to a large increase in
the
number of bacteria. The secretions of apocrine sweat glarids are metaboliled by
skin bacte-
ria, and odoriferous amines and other substances such as lGandrostene steroids are
llhe average size of these colonies is determined by counting the total number of bacteria
recovered by
scmbbing and comparing this with the number of foci of bacterial growth obtained
from velvet pad
replicas. The sterile pad is applied firmly to the skin, then removeJand
apptied to the bacterial growth
plate.

Mim' Patlageresis of Infectitus Dise6e,

DOL http://dr.doi.org/1}.10l6ts978-0.t2,39?I88.3.00001.9
@ 2015 Elsevier Lrd. All righrs resewed.
2 1. GENERALPRINCIPLES

produced,- giving the body a characteristic smell that modern man, at least, finds unpleas-
ant'z Deodorants, containing aluminium salts to inhibit sweating, and often antiseptics to
inhibit bacterial growttr, are therefore often applied to the apocrine gland areas in tire axil-
lae. However, body smells have been of great significance in the social and sexual life of
humans and mammals in general. Not all body smells are produced by bacteria, and skin
glands may secrete substances known as pheromones that are themselves odoriferous but
some skin bacteria do contribute to body smells and could for this reason be classified as
symbiotic rather than parasitic. There is also evidence that harmless skin bacteria inhibit
the colonisation and growth of more pathogenic bacteria, again indicating benefit to the
host and a symbiotic classification for these bacteria.
A microbe's ability to multiply is obviously of paramount importance; indeed, we call a
microbe dead or nonviable if it cannot replicate.3 The ability to spread from host to host is
of equal importance. Spread can be horizontal in a species, whereby one individual infects
another by contact, or via insect vectors (Figure 1.1). Alternatively, spread can be 'vertical'
in a species, with parents infecting offspring via sperm, ovum, the placenta, the milk, or
by contact. Clearly if a microbe does not spread from one individuaf to another it will die
with the individual and cannot persist in nature. The crucial significance of the ability of a

Horizontal spread
(e.9. polio, influenza, typhoid)

tr
fr

<-- Vertical spread

E
*t
(e.9. leukaemia viruses, congenital rubella,
G
Second
commensal bacteria)
!#
generation H
!.tr
FIGURE 1.1 Vertical and horizontal transmission of infection. Ltr
I.T

2The
smell of feet encased in shoes and socks is characteristic, and in many European languages it is
ltl
referred to as cheese-like. Between the toes lives Breaibacterium Eidermidls, which converts l-methionine to
r]I
methane thiol, a gas that contributes to the smell. A very similar bacterium is added to cheeses such as
Brie to enhance odour and flavour. r{
3sterilisation is the killing
of all forms of microbial life, and appropriately the word means making barren,
or devoid of offspring.
::
L

MIMS' PATHOGENESIS OF INFECTIOUS DISEASE

 1, GENERALPRINCIPLES 3

r-sube b spread can be illustrated by comparing the horizontal spread of respiratory

d ggnllv transmitted infections (STIs). An infected individual can transmit influenza
,q[ fu €orllmon cold to a score of others in the course of an innocent hour in a crowded
r@" An STI also must spread progressively from person to person if it is to maintain
ffi fo nature, but even the most energetic lover could not transmit a venereal infection
m sdr a scale. A chain of horizontal infection in this case, however, requires a chain of
w4 contact between individuals. If those infected at a given time never had sexual con-
mn rith more than one member of the opposite sex, the total incidence could double in a
flff*;rne and when the infected people died the causative microbe would be eliminated. In
ffirr rr-ords, STIs must be transmitted to more than one member of the opposite sex if
ffiry are to persist and flourish. The greater the degree of sexual promiscuity, the greater
dhsmrmber of sex partners, the more successful such infections can be. Further discussion
dsns are included in the next chapter.
Only a tiny proportion of the microorganisms associated with humans have the poten-
tnl to give rire to pathological changes or cause disease. Vast numbers of bacteria live
Urrrtessty in the mouth and intestines, on the teeth and skin, and most of the 150 or so
rirus€s that infect humans cause no detectable illness in most infected individuals, in spite
c{ cell and tissue invasion. This is to be expected because, from an evolutionary point of
$ieh', successful microbes must survive, multiply, and leave viable descendants. A suc-
.""sfuI parasitic microbe lives on or in the individual host, multiplies, spreads to fresh
irdividuals, and thus maintains itself in nature (Table 1.1).
A zuccessful parasitic microbe, like all successful parasites, will obtain what it requires for
proliferation from the infected host without causing much damage. If an infection is debilitat-
irg o. even lethal, there will be a reduction in numbers of the host species and thus in the
r,rr-be.s of the microorganism. Thus, although a small number of microbial pathogens cause
disease in a majority of those infected (so-called true pathogens), most are comparatively

TABLE 1.1 Obligatory Steps for Infectious Microorganisms

Step Phenomenon Requirement Chapter

1.Attachment + entry into lnfection (entry) Evade host's natural protective and 2
body cleansing mechanisms

2. Local or general spread Local events, spread Evade immediate local defences and 3,5
in the body the natural barriers to spread

3. Multiplication Multiplication Multiply; many offspring will die in host

ot en route to fresh host

4. Evasion of host defences Microbial answer to Evade phagocytic and immune defences long 4,6,7
host defences enough for full cycle in host to be completed

5. Shedding (exit) from Transmission Leave body at site and on a scale that 2
body ensures spread to fresh host

6. Cause damage in host Pathology, disease Not strictly necessary but often occursu 8

lSome damage may be ineviiable if efficient shedding is to occur (e.g. common cold, diarrhoea, skin vesicles)'

MIMS' PATHOGENESIS OF INFECTIOUS DISEASE

 S:n
&*
4 1. GENERAL PRINCIPLES

harmless, causing either no disease, or disease in only a small proportion of those infected.
Polioviruses, for instance, are transmitted by the faeial-oral route and cause a subclinical
intestinal infection under normal circumstances. But in an occasional host the virus invades ;nt
dFI
,1":"igrl nervous system and causes meningitis, sometimes paralysis, and very occasionally dfrq
death. This particular site of multiplication is irrelevant from fhe virus point of view, because
growth in the central nervous system is quite unnecessary for transmiision to the next host.
hm!
nhd
Well-established infectious agents have therefore generally reached a state of balanced patho-
genicity in the host and cause the smallest amount of damage compatible with the need to FM
,D&
enter, multiply, and be discharged from the body.
The importance of balanced pathogenicity is strikingly illustrated in the case of the nat-
@@ir
ural evolution of myxomatosis in the Australian rabbit-. After the first successful introduc-
mElh *
ffit
tion of the virus in 1950 more than 99Vo ol infected rabbits died, but subsequently new - ,fr
strains of virus appeared that were less lethal. The less lethal strains of virus were there-
fore selected during the evolution of the virus in the rabbit population, because they
ftnum r
oEWtu
persisted longer and were therefore more successful parasites, the genetics of the rabbit dlt@
population also changed, because those that were genelically more su-sceptible to the infec-
tion were eliminated. Rabies, a virus infection of the central nervous system, seems to con-
tux
tradict, but in fact exemplifies, this principle. Infection is classically acquired from the bite
Arduu
of a rabid animal and the disease in man is almost always fatal,Lt the virus has shown
ad*
rtuflS il
no signs of becoming less virulent. Man, however, is an unnatural host for rabies virus, m4eard
and it is maintained in a less pathogenic fashion in animals such as vampire bats and
u[m@ tl
skunks. In these animals, there is a relatively harmless infection and the virus is shed for
long periods in the saliva, which is the vehicle of transmission from individual to individ-
pEfu
ms* in
ual. Rabies is thus maintained in the natural host species without serious consequences.
But bites can infect the individuals of other species,laccidentally' from the virus point of
h@f m
hfut
view, and the infection is a serious and lethal one in these unnatural hosts.
The g:l
Although successful parasites cannot afford to become too pathogenic, some degree of
tissue damage may be necessary for the effective shedding of microJrganisms to th! exte-
3fr
rior, as for instance in the flow of infected fluids from the nose in the coilunon cold or
spsed i
from,the alimentary canal in infectious diarrhoea. Otherwise there is ideally very little tis-
{rffi
Ths_'rh
sue damage, a minimal inflammatory or immune response, and a few miciobiai parasites
achieve the supreme,success of causing zero damage and failing to be recognised as para-
drrr" r
$F'fEr4
sites by the host. Different microbes show varying degrees of atiainment of this ideal state
nmisdi
of parasitism.
The concept of balanced pathogenicity is helpful in understanding infectious diseases,
but many infections have not yet had time to reach this ideal state.-In the first place, as *Tx'eir
each microorganism evolves, occasional virulent variants emerge and cause extensive dis- +'agra I
ease and death before disappearing after ali susceptible individuals have been infected, or rtu!|
before settling down to a more balanced pathogenicity. Secondly, a microbe recently intro- ilurfu
duced into a host (e.g. human immunodeficiency virus (HIV) ln humans) ,r,ry ,rot hur" Germq
had time to settle down into this ideal state. Thirdlp some of the microbes responsible for nsd b
serious human diseases had appeared originally in one part of the world, wheie there had irleryt c
been a weeding out of genetically susceptible individuais and a move in the direction of a =,an.
ir
more balanced pathogenicity. Subsequent spread of the microorganism to a new continent l ll"I{ r
i€ss- il,
has resulted in the infection of a different human population in ivhom the disease is much
hats ur

MIMS' PATHOGENESIS OF INFECTIOUS DISEASE

 1. GENERAL PRINCIPLES 5

6or severe because of greater genetic susceptibility. Examples include tuberculosis

ilp.tlng from resistant Europeans to susceptible Africans or North American Indians,
d ydlow fever spreading from Africans to Europeans. Finally, there are a number of
ffiorganisms that have not evolved towards a less pathogenic form in man because the
thian host is clearly irrelevant for the survival of the microorganism. Microorganisms of
ilhb sort, such as those causing rabies (see above), scrub typhus, plague, leptospirosis and
Frroacosis, have some other regular host species which is responsible, often together with
r rthropod vector, for their maintenance in nature.* The pathogenicity for man is of no
@equence to the microorganism. Several human infections that are spillovers from ani-
mk; domesticated by man also come into this category, including brucellosis, Q fever,
,d+uax, and livestock-associated meticillin-resistant Staphylococcus aureus (MRSA) infec-
ffi6s. As humans colonise every corner of the earttr, they encounter an occasional microbe
&ur an exotic animal that causes, quite 'accidentally' from the point of view of the micro-
a3anisms, a serious or lethal human disease. Examples include Lassa fever and Marburg
Oise"s" from African rodents and monkeys, respectively.s
On the other hand, a microorganism from one animal can adapt to a new species.
Advances in DNA sequencing and phylogenetic analyses are revealing much about the
er"olutionary history of pathogens. Measles, which could not have existed and maintained
itself in humans in the Palaeolithic era, probably arose at a later stage from the closely
related rinderpest virus that infects cattle. New human influenza viruses continue to arise
from birds, and the virus of the acquired immunodeficiency syndrome (AIDS), the modern
pestilence, seems to have arisen from a very similar virus infecting monkeys and chimpan-
zees in Africa. In addition, livestock strains of S. aureus most likely originated in humans
but jumped into animal hosts since domestication occurred several thousand years ago.
Microorganisms multiply exceedingly rapidly in comparison to their vertebrate hosts.
The generation time of an average bacterium is an hour or less, as compared with about
20 years for the human host. Consequently, microorganisms evolve with extraordinary
speed in comparison with their vertebrate hosts. Vertebrates, throughout their hundreds
of millions of years of evolution, have been continuously exposed to microbial infections.
They have developed highly efficient recognition (early warning) systems for foreign inva-
ders, and effective inflammatory and immune responses to restrain their growth and
spread, and to eliminate them from the body. If these responses were completely effective,
microbial infections would be few in number and all would be terminated rapidly;

aThese infections are called zoonoses.

sl-assa fever is a sometimes lethal infection of man caused by an arenavirus. The virus is maintained in
certain rodents in West Africa as a harmlebs persistent infection, and man is only occasionally infected.
Another serious infectious disease occurred in 1,967 in a small number of laboratory workers in Marburg,
Germany, who had handled tissues from vervet monkeys recently imported from Africa. The Marburg
agent is a virus and has since reappeared to cause fatal infections in Zaire and the Sudan, but nothing is
known of its natural history. Monkeys are not natural hosts and are probably accidentally infected, like
man. Since 1976,Ebola virus, related to Marburg, has caused dramatic local outbreaks inZaire and Sudan.
ln 2014 a major outbreak of Ebola resulted in the deaths of thousands of people in West Africa. Like Lassa
fever, it can spread from person to person via infected blood, but its natural host is unknown. However,
bats are a likely reservoir.

MMS' PATHOGENESIS OF INFECTIOUS DISEASE

 6 1. GENERAL PRNCIPLES

microorganisms would not be allowed to persist in the body for long

periods. But micro-
organisms, faced with the antimicrobial defences of the host species, hurre
evolved and
developed a variety of characteristics that enable them to bylpass'o, orrur.o^"
thur"
defences' In any case, the normal commensal microbiota is tolerated
b;.;;iififorms
$itical functions required for the general health and well-being of the host. The defences
are not infallible, and the rapid rate of evolution of microorganisms
ensures that they are
always many steps ahead. If there are possible ways rou"nd the established
defences,
microorganisms are likely to have discovered and taken advantage of them.
Successful
microorganisms, indeed, owe their success to this ability to adapt"and evolve,
weak points in the host defences. The ways in which the"phagocytic and immune"*ploitirg
defences
are overcome are described in Chapters 4and 7.
It is the virulence and pathogenicity of microorganisms, their ability to kill and damage
the host, that makes them important io the physicLn or veterinarian. If none
of the micro-
organisms associated. with any dimage, and none was notably beneficial, they
.man -did
yrou]d be interesting but relatively-unimportant objects. In fact, they have been responsibl-e
for the great pestilences of history, have it times determined the co.rrse of history,
and con-
tinue today, in spite of vaccines and antibiotics, as major causes of disease (see
table A.1).
Also, because of their rapid rate of evolution and the constanfly changing
circumstances of
human
!fe, they continue to present threats of future pestilences. hipoitantly, pathogens
constantly 're-invenf themselves through evolution in order to counteract human
efforts at
control such as antibiotic treatment. In fact the emergence of bacterial resistance
to virfually
all classes of antibiotics.is o1e of the greatest current-threats to man's capacity to
treat infec-
tious diseases' Overall, it is the purpose of this book to describe and disc^uss
tire mechanisms
of infection and the characteristici that make microorganisms pathogenic. In addition
to
understanding the role of commensal microbiota in the liealth hoJt, thiJis
the central signifi-
cant core of microbiology as applied to medicine.
.
L-ft9 last 12 years since the previous edition of this book, dramatic advances in molec-
ular biological techniques have 6een made resulting in broai new insights into
our under-
standing of the biology of microbes and how thef impact on our livis. We now
have a
vastly more detailed of host pathogen interactions at the cellular, genetic
and biochemical levels -understanding
based on our ability to manipulate microbial and host genJtics in
order to understand the critical interactions and responses involved. By sucfi means
a
great deal of biochemical information can be obtained about the microbial
determinants
involved in mediating differentaspects of the complex infection process.
But the most dramatic developments in re"eni years have come in DNA sequencing
technologies. New and_emerging methods can produce vast amounts of
sequence infor-
m3t1on rapidly and relativgly inexpensively. This has resulted in many
t'frorsa1,a, of
whole-genome sequences for bacteriil and pirasite pathogens and severai
hundred high-
er organisms (vertebrates and invertebrates) bec-oming available in the pu6lic
DNA -order
sequence databases' In addition, metagenomic studies" which qualitativeli,
and
quantitatively examine the microbial content-within biological samples
are info'rming
our understanding of. microbial diversity in different ecolJgical niches. In the
current
'post-genomic' era as it has come to be known, generating ,e"qr"r."
information is rela-
tively facile. It is the mining of the data and Ihe assigim"trt of functional
relevance
which is the bottle-neck in terms of biological un"derstanding. New sequencing

MIMS PATHOGENESIS OFINFECTIOUS DISEASE

 BIBLIOGRAPHY ?
5 als6 allow examination of genome-wide gene expression, building
on previ-
ipomic approaches, such as microarrays.
ftmrt advances made in DNA sequencing technology have resulted in large
complex
resdr as the human Senome requiring only a mattir of days to completJ
Nowihat
mres_of the major domestic livestock species have been completed, ihe opportuniiy
stdy the genome-wide interactions between pathogen and host genomes.
$macting mRNAs from bacteria grown in culture rrid frorn the slme organism from
mlnaion site (or grown in conditions which mimic infection conditions), i"t is possible
rffi which geie(s) are expressed or repressed in the *"Hil;:fJ?;:;ffiIr|:
lhftr*rs which are essential for survival during infection and which thus may reiresent
ffi ilEapeutic targets. Similar studies can ilso be carried out in cetts infeJtea by
'ecb allowing the host cell response to these pathogens to be dissected. In addition to
mo&m analysis, are resulting in very enhanced views of the
way fy #rricl -i.rob", .urr"
&ne Overall we are in a very exciting time with tremendous
'h 6e biology of infectious diseases. Considering that we ,.u pbtential for understand-
ilro in an age *fr"" tfr"
for treating bacterial infections are fast
reducing due to the increase"in antibiotic
"t,htt
urdstance, and that the threat-of emerging viral pathogens is very apparent, we
h qu improved understanding of ifueitious diseasi to design ritional waysmust uti-
for their
dol.
In order to facilitate an understanding of infectious disease it is possible to distinguish
&fuent phases of the 'pathogenic cyclej, including an appreciation for the bacterial,
host
d mvironmental factors which contribute to infeJtious diruuru and the outcome of infec-
lirL In addition to the bacterial virulence determinants involved, an understanii"j of 1,"
Lds phagocytic and immune defences is important, and these are briefly set"out in
Chapters 4,6 and 9. There are additional chapters on resistance and recov".y rro*
irrr".-
tixr, persistent infection, and the prevention of infection by vaccines

Bibliography
Burne! F'M', White, D.O., 7972. The Natural History of Infectious Disease, fourth
ed. Cambridge University
Press, Cambridge, U.K.
Human Microbiome project consortium,20L2. Structure, function and diversity
of the healthy human microbiome.
Nature 485 (7 402), 207 -214.
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