Cytokine and Growth Factor Reviews 53 (2020) 25–32

Contents lists available at ScienceDirect

Cytokine and Growth Factor Reviews

journal homepage: www.elsevier.com/locate/cytogfr

The cytokine storm in COVID-19: An overview of the involvement of the T

chemokine/chemokine-receptor system
Francesca Coperchinia, Luca Chiovatoa,b, Laura Crocea,b, Flavia Magria,b, Mario Rotondia,b,*
a
Istituti Clinici Scientifici Maugeri IRCCS, Unit of Internal Medicine and Endocrinology, Laboratory for Endocrine Disruptors, 27100 Pavia, PV, Italy
b
Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, PV, Italy

ARTICLE INFO ABSTRACT

Keywords: In 2019–2020 a new coronavirus named SARS-CoV-2 was identified as the causative agent of a several acute
COVID-19 respiratory infection named COVID-19, which is causing a worldwide pandemic. There are still many unresolved
Coronavirus questions regarding the pathogenesis of this disease and especially the reasons underlying the extremely dif-
Chemokines ferent clinical course, ranging from asymptomatic forms to severe manifestations, including the Acute
CXCL10
Respiratory Distress Syndrome (ARDS). SARS-CoV-2 showed phylogenetic similarities to both SARS-CoV and
CXCL8
Cytokine storm
MERS-CoV viruses, and some of the clinical features are shared between COVID-19 and previously identified
beta-coronavirus infections. Available evidence indicate that the so called “cytokine storm” an uncontrolled
over-production of soluble markers of inflammation which, in turn, sustain an aberrant systemic inflammatory
response, is a major responsible for the occurrence of ARDS. Chemokines are low molecular weight proteins with
powerful chemoattractant activity which play a role in the immune cell recruitment during inflammation. This
review will be aimed at providing an overview of the current knowledge on the involvement of the chemokine/
chemokine-receptor system in the cytokine storm related to SARS-CoV-2 infection. Basic and clinical evidences
obtained from previous SARS and MERS epidemics and available data from COVID-19 will be taken into account.

1. Coronavirus: the past and the present especially in neonates, in the elderly, and in individuals with under-
lying illnesses.
Coronaviruses, a genus of the Coronaviridae family, are enveloped SARS-CoV, a novel coronavirus, was identified in 2002 as the pa-
viruses with a large plus-strand Ribonucleic Acid (RNA) genome [1]. thogenic agent of the Severe Acute Respiratory Syndrome (SARS) out-
The genomic RNA is 27–32 kb in size, capped and polyadenylated. break that occurred in in the Guangdong Province of China [2]. So far,
Coronaviruses were identified in several non-human species, including SARS is the most severe human disease caused by a coronavirus. Recent
rats, mice, chickens, cattle, turkeys, swine, cats, dogs, rabbits and evidence confirmed that the SARS-CoV virus originated from a muta-
horses. In these species, Coronavirus infection often causes devastating tion occurring in a non-human host, probably bats, gains the ability to
epizootics of respiratory or enteric diseases. Several coronaviruses, such affect humans. Luckily, the transmission of SARS-CoV was relatively
as HCoV-229E and HCoV−OC43, were identified since the mid-1960s. inefficient, since its spread occurred only through direct contact with
Prior to the SARS-CoV outbreak, coronaviruses were only thought to infected individuals, with negligible infectivity during incubation state.
cause mild, self-limiting respiratory infections in humans, commonly The outbreak was largely contained within households and healthcare
referred at as “colds”. These viruses are endemic among the human settings.
populations, causing 15–30 % of respiratory tract infections each year. A novel human Coronavirus, named Middle East Respiratory
Rarely, these viruses can cause lower respiratory tract infections, Syndrome-CoV (MERS-CoV), emerged in the Middle East in 2012 as the

Abbreviations: AP-1, activator protein-1; ARDS, acute respiratory distress syndrome; COVID-19, Coronavirus Disease 2019; CSF, colony-stimulating factors; DNA,
deoxyribonucleic acid; ICU, Intensive Care Units; IFN, interferon; IL-, interleukin; IRF, interferon regulatory transcription factor; LPS, lipopolysaccharide; MERS,
Middle East Respiratory Syndrome; MERS-CoV, Middle East Respiratory Syndrome Coronavirus; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B
cells; PBMCs, Peripheral Blood Mononuclear Cells; RNA, Ribonucleic Acid; SARS, Severe Acute Respiratory Syndrome; SARS-CoV, Severe Acute Respiratory
Syndrome Coronavirus; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TH1, T-helper-1; TNF, Tumor Necrosis Factor
⁎
Corresponding author at: Istituti Clinici Scientifici Maugeri IRCCS, Unit of Internal Medicine and Endocrinology, Laboratory for Endocrine Disruptors, Via S.
Maugeri 4, I-27100 Pavia, PV, Italy.
E-mail address: mario.rotondi@icsmaugeri.it (M. Rotondi).

https://doi.org/10.1016/j.cytogfr.2020.05.003
Received 6 May 2020; Accepted 7 May 2020
Available online 11 May 2020
1359-6101/ © 2020 Elsevier Ltd. All rights reserved.
F. Coperchini, et al. Cytokine and Growth Factor Reviews 53 (2020) 25–32

causative agent of a series of highly pathogenic respiratory tract in- infections [11]. Acute respiratory distress syndrome (ARDS) is a de-
fections in Saudi Arabia and other countries in the Middle East [3]. In vastating event, with an estimated mortality of approximately 40 %,
the early stages of the outbreak, a high mortality rate of ∼50 % was defined as the presence of bilateral lung infiltrates and severe hypox-
reported, but the outbreak did not accelerate through 2013 and by the emia. ARDS can occur in a variety of clinical situations, including
end of 2014 it was largely controlled. Also for this virus, a zoonotic pneumonia, sepsis, pancreatitis, blood transfusion. ARDS pathogenesis
origin is suspected, since dromedary camels may be its natural hosts. involves inflammatory injury to the alveolo–capillary membrane, which
In early December 2019, several pneumonia cases of unknown results in increased lung permeability and the exudation of protein-rich
origin were observed in Wuhan (China). The pathogen was identified as pulmonary edema fluid into the airspaces, leading in the end to re-
a novel enveloped RNA β coronavirus that was named severe acute spiratory insufficiency [12].
respiratory syndrome coronavirus 2 (SARS-CoV-2) [4]. The virus As shown by previous data in the literature, increased circulating
showed phylogenetic similarities to both SARS-CoV and MERS-CoV levels of pro-inflammatory cytokines (eg, Interferon γ, interleukin (IL-)
viruses. In view of its similarities to bat coronaviruses, it was postulated 1B, IL-6, IL-12) and chemokines (CXCL10, and CCL2) are associated
that bats could have been the primary hosts of SARS-CoV-2. This hy- with pulmonary inflammation and extensive lung involvement in SARS
pothesis suggested that the infection originated via transmission from patients, similarly to what happens in MERS-CoV infection [13]. As far
wild animals illegally sold in the Huanan Seafood Wholesale Market. as COVID 19 infection is concerned, Huang et al. recently reported that
On January, 30th, 2020, The World Health Organization (WHO) de- infected patients also show high levels of pro-inflammatory cytokines
clared coronavirus disease 2019 (COVID-19) a public health emergency and chemokines [4]. The demonstration of increased levels of IL-1B,
of international concern, and on March 11th, WHO Director General IFNγ, CXCL10, and CCL2 strongly pointed toward an activation of T-
referred to COVID-19 as a pandemic. As of May 5th, 2020, the number helper-1 (Th1) cell function. More importantly, the so called “cytokine
of confirmed cases of COVID-19 has exceeded 3 million worldwide, storm” emerged as a main factor driving a more severe clinical course.
with more than 250,000 COVID-19-related deaths. The epidemic has This concept originated from the observation that COVID-19 patients
put public health systems under severe strain both in western countries requiring ICU admission displayed higher concentrations of CXCL10,
and in the developing world. SARS-CoV-2 displays a more efficient CCL2 and TNFα as compared to those in which the infection was less
transmission pattern when compared with SARS-CoV and MERS-CoV severe and did not require an ICU admission. To further complicate the
[5], retaining a high transmission rate also in the asymptomatic in- issue, it should be highlighted that, in patients with SARS-Cov-2 in-
cubation period [6]. The clinical spectrum of COVID-19 syndrome fection, at difference from SARS-CoV infection, there is also an in-
varies remarkably, going from asymptomatic forms to acute bilateral creased secretion Th2-immune-oriented cytokines such as IL-4 and IL-
pneumonias requiring hospitalization. Common presenting symptoms 10, whose main effect is to suppress inflammation [14].
include fever, fatigue and dry cough, while laboratory tests often show Taken together, these data clearly indicate that, in SARS-CoV in-
lymphopenia and elevated lactate dehydrogenase levels. Chest com- fection, ARDS is the ultimate result of a cytokine storm. In this scenario,
puted tomographic scans show a typical pattern of bilateral patchy the release by immune effector cells of large amounts of pro-in-
shadows or ground glass opacity. A significant percentage of cases re- flammatory cytokines (IFNα, IFNγ, IL-1β, IL-6, IL-12, IL-18, IL-33,
quires admission to intensive-care-units (ICU) due to acute respiratory TNFα, TGFβ) and chemokines (CXCL10, CXCL8, CXCL9, CCL2, CCL3,
distress syndrome that requires mechanical ventilation support. A CCL5) precipitates and sustains the aberrant systemic inflammatory
subgroup of patients with severe COVID-19 can experience the so-called response [4,13,15,16]. The cytokine storm is readily followed by the
“cytokine storm syndrome”, characterized by a fulminant and fatal immune system “attacking” the body, which in turn will cause ARDS
hyper-cytokinemia associated with multi-organ failure. and multiple organ failure, the final result being death, at least in the
most severe cases of SARS-CoV-2 infection [11].
2. The cytokine storm induced by SARS-Cov-2 infection The cytokine storm, and the consequent ARDS, results from the
effects of a combination of many immune-active molecules. Interferons,
The term “cytokine storm” has become increasingly used not only interleukins, chemokines, Colony-stimulating factors and TNF-alpha
by Authors of scientific articles but also by popular media. It is likely represent the main components involved in the development of the
that the widespread use of this term is related with its rather immediate Cytokine storm and will be briefly overviewed.
meaning, which actually recalls the role of the immune system in - Interferons, a family of cytokines with a central role in virus-
producing an uncontrolled and generalized inflammatory response [7]. directed innate immunity binds specific receptors and result in the
It seems not casual that the term cytokine storm was first employed in expression of genes encoding protein with anti-viral or im-
describing the events modulating the onset of the graft-versus-host munomodulatory properties. This sequence of events supported the
disease [8], a condition characterized by an impressively powerful ac- therapeutic use of IFNs in some viral diseases such as chronic hepatitis,
tivation of the immune system. Cytokine storms characterize a wide but also in non-viral conditions including leukemia and lymphoma,
spectrum of infectious and non-infectious diseases, and since 2005, it melanoma and multiple sclerosis [17,18].
was associated to the avian H5N1 influenza virus infection [9]. Apart - Tumor necrosis factor α (TNFα) is a pyrogen cytokine released
from the immediate significance of the term cytokine storm, the bio- from immune cells in the acute phase of inflammation and infection. It
logical and clinical consequences of this immune system hyperactivity is a central cytokine in viral diseases and is associated with a number of
are by far less known, making it worthwhile to be briefly overviewed. chronic inflammatory and autoimmune diseases [19].
There are several similarities in the clinical features between - Colony-stimulating factors (CSF). These proteins are associated
COVID-19 and previously identified beta-coronavirus infections. Shared with inflammatory conditions and are components of an amplification
clinical findings include that most patients present with fever, dry cascade which ultimately increases cytokine production by macro-
cough, dyspnea, and bilateral ground-glass opacities on chest CT scans phages at sites of inflammation, This effect perpetuates the in-
[10]. However, the physiopathology of the mechanisms through which flammatory reaction [20].
SARS-CoV or MERS-CoV sustain high pathogenicity are yet to be - Interleukins are a family of cytokines involved in immune cells
completely unveiled. differentiation and activation. They mediate the traffic of immune cells
Since the first reports on COVID-19 disease, it appeared clear that to the site of the infection, induce the increase of the acute phase sig-
Acute respiratory distress syndrome (ARDS) accounted for a significant naling, activate epithelial cells and mediate the production of sec-
number of deaths among infected patients and that ARDS should be ondary cytokines [21]. Among them, Interleukin-6 (IL-6) deserves a
regarded as the hallmark immune-mediated clinical consequence in more extensive discussion in view of its involvement in the coronavirus-
SARS-CoV-2, similarly to what described for SARS-CoV and MERS-CoV induced cytokine storm. IL-6 is crucially involved in acute

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inflammation due to its role in regulating the acute phase response the broncho-alveolar lavage fluid [44–46] of patients with ARDS. A
[21]. It is produced by almost all stromal cells and B lymphocytes, T direct role of CXCL8 in the progression of ARDS was proven in rabbit
lymphocytes, macrophages, monocytes, dendritic cells, mast cells and with acid-induced ARDS lead to a 10-fold increase in CXCL8 levels in
other non-lymphocytic cells, such as fibroblasts, endothelial cells, ker- the alveolar fluids. Of note, pre-treatment with an anti-CXCL8 antibody
atinocytes, glomerular Mesangial cells and tumor cells [22]. The pro- prevented the development of the typical acute lung injury [47].
duction of this cytokine is increased by IL-1β and tumor necrosis factor Although chemokines are crucially involved in the regulation and
(TNF- α) [23]. IL-6 may also be responsible for the activation of T maintenance of immune responses, their role in the onset of the cor-
helper 17 (TH17) cells in the dendritic cell-T cell interaction [24]. In onavirus-induced cytokine storm is still poorly investigated.
COVID-19 affected patients, a high TH17 cells activation could result
from a virus-driven increased production of IL-6 by the immune system. 3. Chemokines: small molecules with an important role in
IL-6 plays a key role in the pathogenesis of the cytokine storm owing to inflammatory diseases
its pleiotropic properties. Several studies showed that the serum levels
of IL-6 are increased in COVID-19 patients and that its circulating levels Chemokines are a family of low molecular weight proteins ex-
are positively related to disease severity [14,25,26]. For this reason, pressed, both constitutively and in an inducible manner, by several
high serum IL-6 levels were suggested as predictors for disease severity types of cells. Chemokines play an important role in the inflammatory
[27,28]. Indeed, in animal models of SARS-CoV infection, the inhibition response by attracting leukocytes to sites of infection. These small
of the transcription factor of IL-6 and, in turn of its production, was proteins also contribute to the homeostatic circulation of leukocytes
associated with reduced mortality [29]. through tissues [31]. At present, 50 chemokines and 20 chemokine
During the present COVID-19 pandemic, the use of Tocilizumab as a receptors have been recognized and classified. Chemokines are named
therapeutic agent was proposed. Tocilizumab is a humanized anti-IL-6 according to the most recent nomenclature, which classifies them ac-
receptor IgG1 monoclonal antibody used for the treatment of rheuma- cording to their chemical structure, the C, CC CXC and CX3C families
toid arthritis and other chronic inflammatory diseases [14]. By blocking [48]. The binding of chemokines to their receptors is responsible for
the IL-6-receptor interaction, Tocilizumab inhibits the IL-6-mediated their chemoattractant ability. The chemokine receptors belong to the
signal transduction. Although clinical data on the use of Tocilizumab in seven-transmembrane-spanning, G-protein-coupled receptors, which
COVID-19 patients derive from small series, some authors recommend are expressed primarily on leukocytes but also on other cells, e.g., en-
its use in critically ill COVID-19 patients with significantly elevated IL-6 dothelial cells [49]. The many functions of chemokines include the
levels [14]. control of cell proliferation and differentiation, the regulation of an-
-Chemokines are a large family of cytokines characterized by a giogenesis and immune and inflammatory responses, tumor growth and
powerful chemotactic effect. Chemokines metastasis [50–52]. Most recently, several studies investigated the in-
act as chemo-attractants in the migration of the immune system volvement of chemokines in coronavirus-related infective disease. It
cells, but they are also involved in several other processes including the emerged that specific chemokines could play a crucial role in the de-
development and function of innate and adaptive immune system, velopment of COVID-19-related symptoms, thus confirming what pre-
embryogenesis, and cancer metastasis [30,31]. They are promptly se- viously known for other types of coronaviruses, such as SARS and
creted by a variety of cells in response to viral or microbial infections MERS. [13,53]. These findings could be somehow expected in view of
[32]. the well-known role of chemokines in viral infections.
Chemokines act as powerful chemoattractants which recruit in-
flammatory cells to migrate from the intravascular space across the 3.1. The involvement of chemokines in viral infections
endothelium and epithelium into the inflammation site, according to a
chemokine gradient [33]. The role of one specific chemokine, CXCL10 Before addressing the specific relationship between chemokines and
(previously referred to as interferon-γ inducible protein of 10 kDa, or coronavirus infections, it is mandatory to briefly overview the general
IP-10), has been highlighted in ARDS in both experimental models and role of chemokines in viral infections and how viruses contrast the
in patients. actions of chemokines.
Indeed, in a mouse model of IL-2 –induced ARDS, an up-regulation Viruses are infectious agents of small size and simple composition
of the mouse CXCL10 analogue mob-1 mRNA was observed at initiation that can multiply only in living cells of animals, plants, or bacteria. All
of lung injury [34]. Several studies also showed that the intratracheal viruses contain a nucleic acid, either -DNA (deoxyribonucleic acid) or
injection of mob-1 in mice induced pulmonary migration of leukocytes -RNA (ribonucleic acid), and several proteins. Viruses should not even
in the alveolar space, with massive recruitment of neutrophils, espe- be considered organisms since they are not free-living (i.e., they require
cially monocytes. This event was rapidly followed by microvascular a host cell), thus viruses need to elude the host immune defense to
injury and pulmonary edema typical of ARDS [35,36]. CXCL10 sig- infect its cells in order to reproduce and survive. [54].
naling appears to be a critical factor for the onset of ARDS, as shown in The chemokine/chemokine receptor-related immune defenses are
mice models of ARDS induced by either acid aspiration or by viral in- the main obstacles to be by-passed by viruses. Some chemokines play a
fection (with influenza H5N1 virus). Briefly, Ichikawa et al., demon- direct anti-viral effect by inducing an array of phenomena that lead
strated that wild-type mice developing ARDS had increased levels of cells to determine an “anti-viral “state. These phenomena include ac-
CXCL10 mainly due to an increased secretion by infiltrating neu- tivation of apoptosis or direct killing of infected cells by activated im-
trophils, which induced an autocrine loop mechanism on the chemo- mune cells. Chemokines also recruit immune cells to the site of infec-
taxis of inflamed neutrophils, leading to fulminant pulmonary in- tion, which will fight against the intruder [55]. Viral infections are
flammation. On the contrary, CXCL10 and/or its receptor CXCR3 associated with enhanced expression of several chemokines, in parti-
knock-out mice showed decreased lung injury severity and increased cular the interferons-inducible ones. Interferons, which can be pro-
survival in response to both viral and non-viral lung injury [37]. duced by any mammalian cell, are involved in the rapid and efficient
Moreover, CXCL10 expression in the lung was significantly up-regu- host innate response against viruses. A powerful IFN response triggered
lated after induction of ARDS with Lipopolysaccharide (LPS) in a mouse by the first contact with a virus can slow down viral multiplication and
model of lung injury, and the neutralization of CXCL10 with anti- “buy time” for the organism to establish a more efficient adaptive im-
CXCL10 antibody lead to amelioration of lung injury [38]. mune response [56]. IFNs can stimulate surrounding cells to express
CXCL8 (also referred at as IL-8) is another chemokine considered as potent antiviral proteins including enzymes, transcription factors, cell
a potential prognostic bio-marker for ARDS clinical course [39]. Indeed, surface glycoproteins, cytokines and chemokines [57,58]. Moreover,
CXCL8 levels were found to be elevated both in plasma [40–43] and in they can inhibit cell proliferation, regulate apoptosis and modulate the

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F. Coperchini, et al. Cytokine and Growth Factor Reviews 53 (2020) 25–32

immune response [59]. Among interferons-induced molecules, the These findings prompted further in vitro studies aimed at in-
chemokine CXCL10 is currently regarded as a main player in the or- vestigating the relationship between SARS and the chemokine system.
ganism anti-viral response [60], and particularly in respiratory tract Spiegel et al., demonstrated that, in addition to its direct effect on
infections. Several studies demonstrated that CXCL10 levels, as eval- epithelial lung cells, SARS-CoV could also enter macrophages and
uated in serum, bronchial-alveolar washing fluid or nasal secretions, dendritic cells [72]. This appeared crucial as viral entrance in these
consistently correlate with the severity and duration of acute re- cells lead to an abortive infection (e.g. the virus enters the host-cell but
spiratory tract infection due to viral infections [60–62]. cannot successfully complete replication). Yet the virus elicited the
Also the chemokine CXCL8, is involved in inflammation and im- secretion of pro-inflammatory chemokines by dendritic and macro-
mune cell trafficking in the context of viral infections. CXCL8 plays a phages cells [73]. This finding was confirmed in vivo because the serum
major role in the initial control of respiratory tract infection due to its levels of a wide spectrum of cytokines and chemokines produced by
chemotactic activity for neutrophils and monocytes [63]. CXCL8 levels dendritic cells and macrophages were elevated in SARS-CoV infected
in the nasal washing fluid correlate with symptoms severity during patients [74]. Furthermore, the infection with SARS-CoV of human
acute respiratory tract infections [64]. Although in the majority of cases primary myeloid-derived dendritic cells was followed by an impaired
a strong chemokine action can efficiently contrast viral infections, some defensive IFNβ response, which was paralleled by a moderate up-reg-
viruses acquire the capacity of escaping this surveillance system. Fur- ulation of pro inflammatory cytokines (such as TNF-α and IL-6) and a
thermore, viruses can use the chemokine system network for their own much more significant up-regulation of inflammatory chemokines (such
favor by several strategies: as CXCL10, CCL3, CCL5, and CCL2) [75]. The authors suggested that
the lack of response to antiviral interferons in the presence of chemo-
- Some viruses “mimic” the components of the chemokine system by kine up-regulation could represent a further mechanism of immune
producing molecules that are very similar to chemokines and can evasion by SARS-CoV [73]. In line with this hypothesis, the direct ex-
interact with their receptor. These molecules generate an incon- posure of lung epithelial cells [76] or Peripheral Blood Mononuclear
gruous signal leading to a disorganized immune response to viruses Cells (PBMCs) [75] coming from SARS infected patients to viral pro-
[65]. teins (such as S-protein and N-protein) induced a prompt release of
- Inhibition of the interferon-induced anti-viral response. Several several chemokines, including CXCL8 and CXCL10. In vitro gene-ex-
viruses do impair the intracellular receptors devoted to pathogen pression studies also reported that PBMC from normal healthy donors
recognition, such as Toll like receptors and intracellular RNA sen- inoculated with SARS-CoV showed an early enhancement in the ex-
sors. [66] pression of several chemokines belonging both to the CC family (CCL4,
CCL20, CCL22, CCL25, CCL27, and their receptors CCR4, CCR7) and of
Taken together, the above data indicate that viruses can interfere the CXCL family (CXCL8 and IL-17) [77]. Additional data came from
with the chemokine/chemokine-receptors system using their own animal models of SARS-CoV infection. In mice infected with SARS-CoV,
properties to modify intracellular signaling with the final result to the clinical features of the syndrome showed an age-dependent increase
further disseminate the infection. in severity (similarly to what observed in humans), which was related
to an increased level of pro-inflammatory cytokines and chemokines,
4. Chemokines and Corona Virus: Lessons from the SARS and the paralleled by a reduction in T-cell responses [78]. Another study
MERS epidemics and available data from COVID-19 showed that in mice infected with SARS-CoV, robust virus replication
accompanied by delayed type I interferon secretion caused a rapidly
The strict relationship between Conaviruses infection and chemo- fatal pneumonia. This delayed Type I-interferon signaling promoted the
kines has been thoroughly investigated during both the SARS-CoV and accumulation of pathogenic inflammatory monocyte-macrophages,
the MERS-CoV epidemics, while some initial data are available re- with resulting increase in cytokine (IL-6) and chemokine (CCL2) lung
garding SARS-CoV-2 and its related syndrome, COVID-19. levels, vascular leakage, and impaired virus-specific T cell responses.
[79].
4.1. SARS-CoV These data suggest that coronaviruses, and in particular SARS-CoV,
have a peculiar ability to counteract the antiviral IFN response, pointing
Since the first reports of SARS, it seemed clear that the severe toward the fact that the severity of disease might be due to immune
clinical manifestations of the disease could not be ascribed only to the dysregulation, rather than to the level of viremia. This dysregulation
viral activity per se, but that an immune-mediated mechanism rather would be characterized by an insufficient type I interferon response
than a direct virus-induced damage would drive the clinical progression (too little and too late), paralleled by an aberrant pro-inflammatory
[67]. Indeed from the physio-pathology point of view, the most inter- chemokine secretion by alveolar macrophages, dendritic cells and
esting observation was the demonstration that viral titers seemed to pneumocytes [66,80].
paradoxically diminish during the most severe phase of the disease both In vitro data suggest that this class of viruses, and in particular SARS-
in humans and in several animal models [1]. Data coming from pa- CoV, uses several strategies to avoid Type I IFN response, both passive
tients’ series described during the 2003–2004 epidemics clearly sug- and active [56,59].
gested that complex alterations in the chemokine system were related
to the outcome of SARS-CoV infection (Fig. 1). - Passive mechanisms include the induction of double membrane
In vivo studies showed that several circulating chemokines (CXCL8, vesicles (DMV) at perinuclear sites within the cytoplasm where RNA
CCL2 and CXCL10) and inflammatory cytokines (IL-1, IL-6 and IL-12) synthesis takes place. This strategy may help to hide and protect
were elevated in patients with SARS-CoV [68,69]. CXCL10 was also RNA replication intermediates from being sensed by intracellular
considered an excellent prognostic marker for SARS disease progression RNA-sensors, thus avoiding the activation of the IFN cascade
[70,71]. In particular, Jiang et al. showed that CXCL 10 serum levels [81,82].
were significantly increased during the early stage of SARS, and re- - Active mechanisms include a direct action of viral proteins on
mained elevated until resolution. Moreover, persistently elevated transcription factors and intracellular signaling molecules that reg-
CXCL10 serum levels during follow-up were predictive of a worse ulate the IFN cascade. In particular, the SARS-CoV protein ORF6 is
outcome of the infection [71] able to inhibit the action of interferon regulatory transcription

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Fig. 1. Schematic representation of the

“Cytokine storm” development after SARS-
CoV-2 infection. The presence of SARS-CoV-2
in the lung induces an uncontrolled generalized
immune response. Several immune cells (like
T-lymphocytes, macrophages and dendritic
cells) sustain the impressive secretion of cyto-
kines and chemokines ultimately leading to
acute respiratory distress syndrome.

factor-3 (IRF-3), a transcription factor of the IFN genes [83,84]. was up-regulated to a greater extent by MERS-CoV infection as com-
pared with SARS-CoV. At difference, CCL2 and CXCL10 were more
The fact that SARS-CoV infection would upregulate the transcrip- strongly up-regulated by SARS-CoV than MERS-CoV [92]. In addition,
tion of CXCL10, while significantly down-regulating IFNs signaling, in dendritic cells infected with MERS-CoV, a significant down-regula-
could seem paradoxical. However, transcriptional enhancement of tion of IFN response paralleled by a striking elevation of CXCL10 was
CXCL10 could be due to a direct effect on the Nuclear Factor kappa- observed [93]. A strong induction of CXCL10 secretion was observed
light-chain-enhancer of activated B cells (NF-kB) [85] triggered by also in monocyte-derived macrophages infected with MERS-CoV
SARS-CoV [86], even if other Authors did not confirm this early ob- [94,95]. Interesting data come also from an experimental mouse model
servation [87]. Similarly, the up-regulation of the CXCL8 gene expres- of MERS-CoV infection, in which a significant increase in CXCL8 ex-
sion, could be due to a direct effect of the virus at the cellular level. pression was observed in lung and brain tissue after infection with
Indeed, intestinal and lung cells lines infected by SARS-CoV, promptly MERS-CoV [96].
increase their secretion of CXCL8 [88]. This observation would fit with
the notion that the expression of CXCL8 is dependent on the tran- 4.3. SARS-CoV-2 and COVID-19 syndrome
scription factor Activator protein 1 (AP-1), which was shown to be
strongly up-regulated by SARS-CoV [86,89]. Data regarding the relationship between COVID-19 and chemokine
dysregulation are still scanty, but are increasingly being reported.
4.2. MERS-CoV Although preliminary, the available data provided by both clinical and
in vitro studies suggest possible similarities between what was observed
During the MERS-CoV epidemics, several studies were aimed at after SARS-Cov and MERS-Cov infection. Overall, an increased pro-
understanding the pathogenic mechanisms underlying the severe and duction of pro-inflammatory chemokines (mainly CXCL10 and CXCL8)
often fatal pneumonia were performed. Available data suggest that seems to characterize also COVID-19 infection.
MERS-CoV infection shares some immunological aspects of SARS-CoV There are few in vitro studies regarding SARS-CoV-2 infection pub-
infection, in terms of involvement of the chemokine system. First, an lished so far. The results of a study comparing SARS-CoV-2 and SARS-
increase in the serum levels of CXCL10 when compared to controls was CoV viruses behavior in the lung tissue should be overviewed. Briefly,
observed also in MERS-CoV patients. More importantly, a persistent the inoculation of the two viruses in ex vivo human lung tissue explants
CXCL10 increase was associated with disease severity [90]. showed that SARS-CoV-2 was more capable, as compared with SARS-
In this regard, the case of two paradigmatic patients diagnosed with CoV, in both infecting and replicating in human lung. Furthermore,
MERS-Cov is worth noting. One had a fatal outcome and experienced an SARS-CoV-2 infection was less able to trigger the expression of any
impaired IFN response together with a relevant increase in serum IFNs, suggesting that SARS-CoV and SARS-CoV-2 might differ in their
CXCL10 levels. The other one, with a favorable outcome, displayed an ability to modulate the production of pro-inflammatory cytokines and
up-regulation of IFNs and IRF3 and a less pronounced increase of serum chemokines. As an example, it could be worth highlighting that SARS-
CXCL10 levels [91]. CoV infection upregulated 11 out of the 13 pro-inflammatory factors
In vitro studies also support the relevance of chemokines in MERS- evaluated, while SARS-CoV-2 upregulated only five of them, (namely,
CoV patients. A 2013 study evaluated the expression of several che- CXCL10, IL6, CCL2, CXCL1, CXCL5). Interestingly, CXCL8 transcription
mokines and cytokines in cell lysates of polarized airway epithelial cells was up-regulated only by SARS-CoV, but not SARS-CoV-2 infection,
infected with MERS-CoV or SARS-CoV. The results showed that CXCL8 while the opposite was observed for CXCL10 [97].

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The potential involvement of the chemokine system during SARS- Declarations of interest
CoV-2 infection was already evident from the first COVID-19 series
described by Chinese physicians in early January 2020. It was reported None.
that several pro-inflammatory cytochines and chemokines, including
CXCL10, CXCL8, CCL2, TNFα and IFNγ were higher in the plasma of Funding
COVID-19 patients as compared to healthy controls. More importantly,
among infected patients, CXCL10, CCL2 and TNFα circulating con- This paper was not supported by any grant or funding.
centrations (but not those of IFNγ) were found to be significantly higher
in patients requiring admission to Intensive Care Units as compared to CRediT authorship contribution statement
patients experiencing a less severe clinical course [4].
Chen et al., recently characterized the immunological features of Francesca Coperchini: Conceptualization, Methodology, Writing -
COVID-19 patients with different severity of the disease. Briefly, the 11 original draft. Luca Chiovato: Supervision. Laura Croce: Writing -
patients with severe disease displayed significantly higher serum levels original draft. Flavia Magri: Writing - review & editing. Mario
of IL-6, IL-10, and TNF-α and lower absolute numbers of T lympho- Rotondi: Conceptualization, Writing - review & editing, Supervision.
cytes, CD4 + T cells, and CD8 + T cells as compared with the 10 pa-
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Severe acute respiratory syndrome coronavirus open reading frame (ORF) 3b, ORF Luca Chiovato obtained his M.D. degree at the University
6, and nucleocapsid proteins function as interferon antagonists, J. Virol. 81 (2) of Pisa in 1976. He completed his postgraduate Degree in
(2007) 548–557. Internal Medicine in 1982 and obtained his PhD in
[85] T.H. Leung, A. Hoffmann, D. Baltimore, One nucleotide in a kappaB site can de- Endocrine and Metabolic Sciences at University of Florence
termine cofactor specificity for NF-kappaB dimers, Cell 118 (4) (2004) 453–464. in 1988. At present his position is: Full Professor of
[86] J. Cinatl, G. Hoever, B. Morgenstern, W. Preiser, J.U. Vogel, W.K. Hofmann, Endocrinology at University of Pavia, director of the
G. Bauer, M. Michaelis, H.F. Rabenau, H.W. Doerr, Infection of cultured intestinal Internal Medicine and Therapeutics department of the
epithelial cells with severe acute respiratory syndrome coronavirus, Cell. Mol. Life University of Pavia, Director of the Laboratory for
Sci. 61 (16) (2004) 2100–2112. Endocrine Disruptors and Director of the Head Unit of
[87] M. Frieman, M. Heise, R. Baric, SARS coronavirus and innate immunity, Virus Res. Internal Medicine and Endocrinology, ICS Maugeri SpA
133 (1) (2008) 101–112. –I.R.C.C.S, Pavia. His main research fields are: endocrine
[88] M. Spiegel, F. Weber, Inhibition of cytokine gene expression and induction of autoimmunity; thyroid diseases, genetics and clinics of
chemokine genes in non-lymphatic cells infected with SARS coronavirus, Virol. J. 3 obesity; endocrine disruptors.
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[89] R. He, A. Leeson, A. Andonov, Y. Li, N. Bastien, J. Cao, C. Osiowy, F. Dobie, T. Cutts,
M. Ballantine, X. Li, Activation of AP-1 signal transduction pathway by SARS cor-
Laura Croce: obtained her M.D. degree at the University of
onavirus nucleocapsid protein, Biochem. Biophys. Res. Commun. 311 (4) (2003)
Pavia in 2013. She completed her postgraduate Degree in
870–876.
Endocrinology and Metabolism in 2018 at the University of
[90] E.S. Kim, P.G. Choe, W.B. Park, H.S. Oh, E.J. Kim, E.Y. Nam, S.H. Na, M. Kim,
Pavia. At present she is attending the PhD Couse in
K.H. Song, J.H. Bang, S.W. Park, H.B. Kim, N.J. Kim, M.D. Oh, Clinical progression
Experimental Medicine at the University of Pavia and she is
and cytokine profiles of middle east respiratory syndrome coronavirus infection, J.
Researcher at the Unit of Endocrinology of ICS Maugeri SpA
Korean Med. Sci. 31 (11) (2016) 1717–1725.
– I.R.C.C.S, Pavia. Her Research fields are: clinics of thyroid
[91] E. Faure, J. Poissy, A. Goffard, C. Fournier, E. Kipnis, M. Titecat, P. Bortolotti,
disease, role of chemokines in autoimmune endocrine dis-
L. Martinez, S. Dubucquoi, R. Dessein, P. Gosset, D. Mathieu, B. Guery, Distinct
orders and thyroid cancer, endocrine disruptors, obesity.
immune response in two MERS-CoV-infected patients: can we go from bench to
bedside? PLoS One 9 (2) (2014) e88716.
[92] C. Lau, K. Anitole, C. Hodes, D. Lai, A. Pfahles-Hutchens, J. Seed, Perfluoroalkyl
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[93] H. Chu, J. Zhou, B.H. Wong, C. Li, Z.S. Cheng, X. Lin, V.K. Poon, T. Sun, C.C. Lau,
J.F. Chan, K.K. To, K.H. Chan, L. Lu, B.J. Zheng, K.Y. Yuen, Productive replication Flavia Magri obtained his M.D. degree at the University of
of Middle East respiratory syndrome coronavirus in monocyte-derived dendritic Pavia in 1987. She completed her postgraduate Degree in
cells modulates innate immune response, Virology 454-455 (2014) 197–205. Endocrinology in 1990 and in Internal Medicine in 1995.
[94] J. Zhou, H. Chu, C. Li, B.H. Wong, Z.S. Cheng, V.K. Poon, T. Sun, C.C. Lau, She obtained her PhD in Internal Medicine and Medical
K.K. Wong, J.Y. Chan, J.F. Chan, K.K. To, K.H. Chan, B.J. Zheng, K.Y. Yuen, Active Therapy at University of Pavia in 2000. At present her po-
replication of Middle East respiratory syndrome coronavirus and aberrant induction sition is: Associate Professor in Endocrinology at University
of inflammatory cytokines and chemokines in human macrophages: implications for of Pavia. She works at the Unit of Internal Medicine and
pathogenesis, J. Infect. Dis. 209 (9) (2014) 1331–1342. Endocrinology, ICS Maugeri SpA – I.R.C.C.S, Pavia. Her
[95] C.T. Tseng, L.A. Perrone, H. Zhu, S. Makino, C.J. Peters, Severe acute respiratory main research fields are: physiopathology and clinics of
syndrome and the innate immune responses: modulation of effector cell function thyroid diseases, thyroid cancer and thyroid diseases in
without productive infection, J. Immunol. 174 (12) (2005) 7977–7985. pregnancy
[96] X.Y. Hao, Q. Lv, F.D. Li, Y.F. Xu, H. Gao, The characteristics of hDPP4 transgenic
mice subjected to aerosol MERS coronavirus infection via an animal nose-only ex-
posure device, Animal Model Exp. Med. 2 (4) (2019) 269–281.
[97] H. Chu, J.F. Chan, Y. Wang, T.T. Yuen, Y. Chai, Y. Hou, H. Shuai, D. Yang, B. Hu,
X. Huang, X. Zhang, J.P. Cai, J. Zhou, S. Yuan, K.H. Kok, K.K. To, I.H. Chan, Mario Rotondi obtained his M.D. degree at the University
A.J. Zhang, K.Y. Sit, W.K. Au, K.Y. Yuen, Comparative replication and immune of Naples in 1992. He completed his postgraduate Degree in
activation profiles of SARS-CoV-2 and SARS-CoV in human lungs: an ex vivo study Endocrinology and Metabolism at the University of Naples
with implications for the pathogenesis of COVID-19, Clin. Infect. Dis. (2020). in 1998 and obtained his PhD in Endocrine and Metabolic
[98] G. Chen, D. Wu, W. Guo, Y. Cao, D. Huang, H. Wang, T. Wang, X. Zhang, H. Chen, Sciences at University of Naples in 2003 with a project fo-
H. Yu, M. Zhang, S. Wu, J. Song, T. Chen, M. Han, S. Li, X. Luo, J. Zhao, Q. Ning, cused on the role of chemokines in Graves’disease. At pre-
Clinical and immunological features of severe and moderate coronavirus disease sent his position is: Associate Professor in Endocrinology at
2019, J. Clin. Invest. 130 (5) (2020) 2620–2629. University of Pavia, Director of the School of Postgraduate
[99] Y. Xiong, Y. Liu, L. Cao, D. Wang, M. Guo, A. Jiang, D. Guo, W. Hu, J. Yang, Z. Tang, Endocrinology and Metabolism, University of Pavia. He
H. Wu, Y. Lin, M. Zhang, Q. Zhang, M. Shi, Y. Zhou, K. Lan, Y. Chen, Transcriptomic works at the Laboratory for Endocrine Disruptors and at the
characteristics of bronchoalveolar lavage fluid and peripheral blood mononuclear Unit of Internal Medicine and Endocrinology, ICS Maugeri
cells in COVID-19 patients, Emerg. Microbes Infect. 9 (1) (2020) 761–770. SpA – I.R.C.C.S, Pavia. His main research fields are: phy-
[100] F. Wang, H. Hou, Y. Luo, G. Tang, S. Wu, M. Huang, W. Liu, Y. Zhu, Q. Lin, L. Mao, siopathology and clinics of thyroid diseases, in particular
M. Fang, H. Zhang, Z. Sun, The laboratory tests and host immunity of COVID-19 thyroid autoimmunity; role of chemokines in autoimmune endocrine disorders, thyroid
patients with different severity of illness, JCI Insight (2020). cancer and kidney transplantation.

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