Experimental and Therapeutic Medicine

Spandidos Publications

Overview of the pathogenesis of COVID-19 (Review)

Chao Li, Qifang He, [...], and Jun Liu

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Abstract

At present, the pathogenesis of the novel coronavirus disease 2019 (COVID-19) has not been fully
elucidated. Clinical and experimental findings from studies investigating COVID-19 have suggested that
the immune-inflammatory response has a crucial role in severe acute respiratory syndrome coronavirus
2 (SARS-CoV-2) infection. The present article aimed to systematically review the available literature on
the pathogenesis of COVID-19. Severe COVID-19 is characterized by organ dysfunction,
hypercytokinemia and lymphopenia. It is assumed that the direct cytopathological damage of host cells
and the dysregulated immune response caused by SARS-CoV-2 may be the primary underlying
mechanisms of COVID-19. Based on the published literature, this review attempts to provide an
integrated view of the immunological mechanisms and the potential pathogenesis of COVID-19,
providing an in-depth summary of the host-pathogen interaction and host immune responses. It is of
great importance to elucidate the possible pathogenesis of COVID-19 to determine the direction of
future research.

Keywords: coronavirus disease 2019, severe acute respiratory syndrome coronavirus 2, pathogenesis,
immunity, cytokine storm

1. Introduction

The ongoing outbreak of the novel coronavirus disease 2019 (COVID-19) caused by severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2) may be a potentially once-in-a-century pandemic (1).
The crude mortality rate of COVID-19 is estimated at 3%; however, the mortality rate of critical patients
was at one point as high as 61.5% (2). No effective antiviral drugs specific for treating SARS-CoV-2
infection are currently available. Early identification of patients with severe COVID-19 and active organ
support remain the most efficient strategies for preventing its progression and improving clinical
outcomes (3). Additionally, strict preventative measures to lower the risk of further disease
transmission, including social distancing and self-isolation, were adopted quickly in a number of
countries, which had a profoundly negative impact on the physical and mental health and well-being of
individuals (4,5). Hence, there is strong concern regarding the pathogenesis of COVID-19 amongst
healthcare professionals due to its high infectivity and lethality.

At present, the pathogenic mechanisms of human COVID-19 remain to be fully elucidated. Recently,
accumulating evidence from clinical trials and experimental studies in vitro and in vivo have increased
our knowledge of the potential molecular mechanisms of COVID-19 (6-18). Additionally, previous work
with other highly pathogenic β-coronaviruses, such as SARS-CoV and Middle East respiratory syndrome
coronavirus (MERS-CoV) may provide insights that could improve our understanding of the underlying
mechanisms of COVID-19. SARS, MERS and COVID-19 share various clinical, laboratory and
histopathological characteristics (11). Similar to SARS and MERS, there are no significant distinguishing
clinical characteristics of COVID-19 and symptoms overlap largely with other severe acute lower
respiratory infections (19). SARS-CoV-2 has 75-80% genomic similarity to the SARS-CoV, and 50% to the
MERS-CoV (20,21). Moreover, SARS-CoV and SARS-CoV-2 attach to the same receptor, angiotensin-
converting enzyme 2 (ACE2), suggesting a similar tissue tropism and route of entry (8,22). A recent
autopsy study revealed that pathological changes in patients with COVID-19 are highly similar to
features observed in patients with SARS and MERS (23). Lymphopenia is a common event that can
predict pneumonia development and progression to respiratory failure in patients with SARS, MERS and
COVID-19 (6,24,25). More importantly, although SARS-CoV-2 infection and host immune patterns are
incompletely characterized, elevated plasma levels of TNF-α, IL-2, IL-7, IL-10, granulocyte colony
stimulating factor (G-CSF), interferon γ-induced protein 10 (IP10), monocyte chemoattractant protein-1
(MCP-1), macrophage inflammatory protein 1 α (MIP-1A) and C-reactive protein (CRP) may be markers
of severe status in the early stages of infection (6,24), suggesting that hypercytokinemia-related
immunopathology may serve a fundamental role in severe COVID-19. Although COVID-19, SARS and
MERS resemble each other clinically, in vitro studies have highlighted notable differences between these
viruses with respect to their growth characteristics, receptor utilization and host responses, suggesting
that their pathogenesis may also significantly differ. Additionally, dysregulation of the cholinergic anti-
inflammatory pathway may be involved in severe COVID-19. Of note, it is speculated that as the SARS-
CoV-2 virus replicates, cell and viral debris or virions may interact with the nicotinic acetylcholine
receptors, thus blocking the action of the cholinergic anti-inflammatory pathway (26-30).

It is difficult to elaborate the exact pathogenesis of COVID-19. A growing body of studies have suggested
the pivotal role of a dysregulated or exacerbated immune response against SARS-CoV-2, leading to an
intense inflammatory response (6,18). This dysregulated inflammatory response is systemic, but
primarily affects the lungs. The present review discusses and summarizes the possible pathogenesis of
SARS-CoV-2-mediated dysregulated immune responses and the possible pathogenetic mechanisms of
SARS-CoV-2-mediated dysregulated immune inflammatory responses (Fig. 1). Further virus and immune-
related research is urgently required to improve our understanding of the exact pathogenesis of COVID-
19, and ultimately lead to improvements in precise diagnosis, treatment and effective vaccine design to
manage COVID-19.

Figure 1

Figure 1

Hypothetical pathogenesis of COVID-19. Severe acute respiratory syndrome coronavirus 2 targets cells
through the S protein that binds to the ACE2 receptor, replicating and assembling in target cells before
being released extracellularly. Inflammatory ...

2. Overview of SARS-CoV-2

Coronaviruses (CoV) are a large family of enveloped single positive-strand RNA viruses, which include α,
β, γ and δ genera with varying degrees of pathogenicity and immunogenicity (31). Most CoVs only cause
self-limiting respiratory tract infections (32). By contrast, SARS-CoV, SARS-CoV-2 and MERS-CoV, belong
to the β-CoV genera, and may cause acute respiratory distress syndrome (ARDS) and extrapulmonary
manifestations, such as diarrhea, shock, severe renal and liver dysfunction, and multiple organ
dysfunction syndrome (MODS) (32).

The genomic structure of SARS-CoV-2 provides important information regarding the pathogenicity and
related virulent factors. The entire genome of SARS-CoV-2 has been sequenced, and has been
demonstrated to contain 29,903 nucleotides (21). The SARS-CoV-2 is genetically similar to SARS-CoV and
bat SARS-like coronaviruses. Chan et al (32) found that the genome of SARS-CoV-2 has 82% nucleotide
similarity with that of human SARS-CoV. Further genetic analysis confirmed that SARS-CoV-2 was ~79%
homologous to SARS-CoV and ~50% homologous to MERS-CoV (20).

Structural proteins, including spike (S), envelope (E), membrane (M) and nucleocapsid (N) proteins,
serve a crucial role in the pathogenesis of viruses, as well as virion assembly and structure (33). The S
glycoprotein has a very potent influence on viral tropism and pathogenic phenotype. It has been
confirmed that the S protein is the primary protein that mediates the binding of SARS-CoV-2 to the
receptor ACE2 of the host cells and causes membrane fusion, which serves a key role in viral entry into
cells (7,8). The S protein is the primary target of neutralizing antibodies (Abs) and the focus of treatment
and vaccine development. In SARS-CoV, the nucleocapsid (N) protein binds to viral RNA and participates
in viral replication, M protein serves an important role in stabilizing the viral structure, envelope
formation, as well as viral budding and release. The E protein has been demonstrated to be a virulence
domain that activates immunopathology in SARS-CoV infection (34). However, it is currently unclear
whether these structural proteins undergo similar functions in COVID-19.
It appears that SARS-CoV-2 may be less pathogenic than MERS-CoV and is closer to that of SARS-CoV.
The basic reproductive number ‘R0’ is defined as the number of additional individuals one case infects
during the course of their illness. The estimated average R0 for COVID-19 ranges between 2 and 6.47
(35-40). In comparison, the estimated average R0 for SARS was 2, and 1.3 for MERS (36). The mean serial
interval, in the epidemiology of infectious diseases, refers to the duration between symptom onset of a
secondary case and that of its primary case (37). A recent study reported that the mean serial interval
(the duration between symptom onset of a secondary case and that of its primary case) of COVID-19
was 3.96 days, considerably shorter than that for SARS (8.4 days) or MERS (14.6 days), suggesting that
SARS-CoV-2 spreads far more rapidly than SARS-CoV and MERS-CoV. SARS-CoV-2 appears to have higher
transmissibility (a higher R0) and a similar case fatality rate to that of SARS-CoV (40,41).

There are some differences in the viral load kinetics between SARS-CoV, MERS-CoV and SARS-CoV-2
infections (42). For the majority of patients with COVID-19, the peak viral load of SARS-CoV-2 is very high
at presentation, and declines steadily. By contrast, the viral load of SARS-CoV peaks at ~10 days, and
that of MERS-CoVin the second week after symptom onset (43). Of note, the peak viral load of SARS-
CoV-2 is positively correlated with age (43). High viral loads in the upper respiratory tract samples in
patients with COVID-19 are suggestive of a significant shedding of SARS-CoV-2 and a potentially high risk
of transmissibility during the first few days of clinical symptoms (44).

3. Pathogenesis of COVID-19

The pathogenic phases of COVID-19 remain incompletely understood. Previous studies have proposed
SARS may consist of three phases: Viral replication, immune hyperactivity and pulmonary destruction
(45). The clinical phases of COVID-19 have been recently proposed: Viremia phase, acute phase and
recovery phase (14). It is generally hypothesized that the course of infection goes through the following
stages (33,45-48): Viral invasion and replication, dysregulated immune response, multiple organ damage
and recovery. Firstly, the virus enters the host cells, where it replicates, assembles and is released
extracellularly to target cells, and this directly causes the damage and destruction of parenchymal cells
such as alveolar epithelial cells. At the same time, a large number of pathogen associated molecular
pattern (PAMP) and damage associated molecular pattern (DAMP) molecules are released to stimulate
the innate immune response, induce inflammatory cell infiltration, release large quantities of cytokines,
chemokines, proteases and free radicals, causing ARDS, sepsis and MODS. It has been observed that the
pathological findings of COVID-19-induced pneumonia appear to resemble those seen in SARS-CoV and
MERS-CoV infection including bilateral acute changes with diffuse alveolar damage and vascular
congestion, patchy inflammatory cellular infiltration, intra-alveolar edema, hemorrhage, proteinaceous
exudate, denudation and reactive hyperplasia of pneumocytes, as well as the presence of
multinucleated giant cells, but hyaline membrane formation was is not prominent observed (49,50).
After the initial critical stage, the inflammatory response is gradually resolved, the damaged organ
gradually recovers, and some of the damaged organs enter fibrosis and chronic stage, such as chronic
critical illness, persistent inflammation, immunosuppression and catabolism syndrome.

It is speculated that the major pathological alterations that take place in the vital organs during COVID-
19 may be caused directly by the cytopathic effect mediated by SARS-CoV-2, and indirectly as a result of
the harmful immune responses induced by SARS-CoV-2, but the relative importance of each of these
requires further study. There is some evidence supporting the more important role of an abnormal
immune response (rather than a direct viral cytopathic effect) in the effects of COVID-19. It has been
observed that patients with COVID-19 had the highest viral load during the early stage (43). The timeline
of COVID-19 infection showed that the median time from onset of symptoms to first hospital admission
was 7 days, 9 days till ARDS, and 10.5 days till ICU (24). The association of worsening clinical progression
with declining viral loads (42) and the onset of an immunological response, plus the presence of
significantly elevated cytokines levels suggested that severe lung damage was largely
immunopathological in nature (6,24,42,44).

SARS-CoV-2 invades host cells It is widely accepted that human CoV transmissibility and pathogenesis
primarily depends on the interactions between the virus and specific host cells (46,51). Receptor
recognition and entry is the first step of viral infection and is the key determinant of tissue tropism.
Enhanced binding affinity between SARS-CoV-2 and ACE2 has been proposed to correlate with elevated
virus transmissibility and disease severity in humans (7,52). CoV entry into host cells is a multi-step
process involving several distinct domains in the S protein that mediates viral attachment to the target
cell surface, receptor engagement, protease processing and membrane fusion. Subsequently, the viral
genome is released into the cytoplasm, and the virus replicates within the host cells (53). Notably, three
CoV (human CoV-NL63, SARS-CoV and SARS-CoV-2) that bind to the same receptor (ACE2) cause
diseases of varying severity, indicating that there may be other pathogenic factors underlying the
differences between these three coronaviruses (54). It has been demonstrated that the overall ACE2-
binding mode of the SARS-CoV-2 S receptor-binding domain (RBD) is nearly identical to that of the SARS-
CoV RBD, but SARS-CoV-2 RBD takes a more compact conformation, which enhances its ACE2-binding
affinity (8,9). Walls et al (7) showed that the RBD of SARS-CoV-2 S protein and SARS-CoV S protein bind
with similar affinities to human ACE2 to enter cells. However, another study observed that SARS-CoV-2
and ACE2 have an affinity that is 10-20 times that of SARS-CoV, which may be related to the higher
transmissibility seen in SARS-CoV-2(55).

The characteristic distribution of SARS-CoV-2 and ACE2 may contribute to revealing the pathogenic
mechanisms of COVID-19. SARS-CoV-2 viral RNA can be detected in respiratory secretions, peripheral
blood, urine and stool specimens of some patients with COVID-19, which coincides with various
transmission pathways in SARS-CoV-2 infection (56). Virions in the blood that are released from the
primary target (for example the lung) may circulate and infect host cells in the remote secondary organs
and tissues.
On the other hand, ACE2 is expressed in the lungs, heart, renal system and gastrointestinal tract, of
which it is abundantly present in the epithelia of the human lungs and small intestines (57-59). These
observations may indicate that ACE2 serves an important role in extrapulmonary manifestations of
COVID-19, such as gastrointestinal symptoms (57,60,61). It is noteworthy that gut-lung crosstalk may be
involved in the pathogenesis of COVID-19; however, the potential efficacy of probiotics as one of the
novel therapeutic approaches of COVID-19 requires further exploration (62). In addition, ACE2 is widely
expressed in the vascular endothelial cells and smooth muscle cells in all organs, which may cause
extensive vascular endothelial cell injury and this may be the molecular basis by which multiple organ
lesions are formed in COVID-19-infected patients (59,63). Cardiac injury has been reported in 7-23% of
patients with COVID-19, which is associated with a higher mortality (64). A more recent study showed
that patients with basic heart failure disease showed increased ACE2 expression, suggesting that cardiac
cells with high expression of ACE2 may act as the target cells of SARS-CoV-2(65).

Direct cytopathic effect of SARS-CoV-2 After entering the host cells, the virus can replicate and survive
within the target cells. It is speculated that the life cycle of SARS-CoV-2 may be similar to other single
positive-strand RNA coronaviruses to a certain extent (33,66,67). After replication is complete, new virus
particles are assembled in the endoplasmic reticulum, after which they are released outside of the cell.
At the same time, target cells lyse or form syncytia and other lesions occur. SARS-CoV-2 may induce a
substantial cytopathic effect on host cells, thus early effective antiviral treatment may reduce the risk of
progression, and thereby mortality (68). It is unclear whether SARS-CoV-2 interferes with target cells in
other ways to cause host cell damage or apoptosis, including mitochondrial damage, endoplasmic
reticulum stress, intracellular environment alterations (such as pH changes) or enzyme dysfunction.

In view of the expression of ACE2 in immune cells, including monocytes/macrophages and lymphocytes
(59), it is unclear whether SARS-CoV-2 can directly infect certain immune cells to cause immune cell
damage. More importantly, immune cells may migrate within the body. Therefore, the SARS-CoV-2-
infected immune cells may allow the virus to disseminate systemically. Pathological studies using COVID-
19 models have shown that the common type of damage caused by SARS-CoV-2 infection also occurs in
the immune system, and spleen and lymphoid atrophy have been shown to be associated with marked
cytokine activation, suggesting that SARS-CoV-2 might directly damage immune cells (6,24,25,69).

Initiation of the innate immune response The innate immune response, which uses various pattern
recognition receptors (PRRs) to recognize and respond to viruses, is an important barrier to viral
infection (70). The intensity of the host immune and inflammatory responses are closely related to the
type of invading virus, the viral load, and the age and immune status of the host (71). In general, host
innate immune cells are stimulated to produce antiviral and proinflammatory cytokines and chemokines
to eliminate the invading viruses (71,72).
PAMP-PRR pathway The viral RNA that is present within the infected cells is detected by various PRRs in
the immune cells, which leads to the secretion of type I interferons (IFNs), proinflammatory cytokines
and chemokines (70,73). Previous studies have demonstrated that key components of the innate
immune signaling pathways serve important roles as protective factors against SARS-CoV disease,
including STAT1 and myeloid differentiation primary response protein MyD88(74). Gralinski et al (75)
identified an adaptor protein (TIR domain-containing adapter molecule 2) in the toll-like receptor
signaling pathway that may be involved in the development of SARS. The IFN response, a key
component of antiviral innate immunity, is initiated by retinoic acid-inducible gene-I-like receptor-
mediated recognition of viral replicative intermediates in the cytosol (73). However, Channappanavar et
al (76) showed that robust SARS-CoV replication and delayed IFN-I signaling promotes severe SARS, as
IFN-I could promote the accumulation of pathogenic macrophages, thus causing lung immunopathology
and vascular leakage. In this regard, the specific pathogenic PAMPs of SARS-CoV-2 and the
corresponding PRRs and signaling pathways remain to be systemically identified.

Macrophages are crucial components of innate immunity and potential mediators of immunopathology
(77). Moreover, macrophages are the main target cells for SARS-CoV replication (78). MERS-CoV and
SARS-CoV can easily infect and robustly replicate in human macrophages and dendritic cells, inducing
the aberrant production of proinflammatory cytokines and chemokines (77,79,80). In SARS-CoV
infection, viroporin 3a has also been shown to induce the activation of nucleotide oligomerization
domain-like receptor protein 3 inflammasome and the secretion of IL-1β in macrophages, suggesting
that PAMP-PRR signaling in macrophages may result in the release of proinflammatory cytokines in
COVID-19(15).

DAMP-PRR pathway Following cellular injury and necrosis, endogenous DAMPs can be released, such as
DNA, RNA, ATP, heat shock proteins, high mobility group protein B1 and the extracellular matrix, which
could be recognized and activated by corresponding PRRs, and promote the release of cytokines and
chemokines, and this may further aggravate the inflammatory response and tissue damage, forming a
vicious cycle (81). It is speculated that both DAMPs and PAMPs may also contribute to the systemic
dysregulation of the innate immune response and may be involved in the development of MODS in
COVID-19. After SARS-CoV-2 activates PRRs, it may induce the antiviral innate immune response, and
also lead to cell damage and organ dysfunction.

Adaptive immune response Antigen-presenting cells present antigen peptides to T and B cells for
recognition, thereby inducing cellular and humoral immunity. Ni et al (82) characterized SARS-CoV-2-
specific humoral and cellular immunity in recovered patients with Covid-19. Both T cells and B cells were
detected in newly discharged patients (82). In addition, Spearmen's correlation showed that the
neutralizing antibody titers were significantly positively correlated with the numbers of NP-specific T
cells (82). These findings suggested both B and T cells participate in immune-mediated protection to
viral infection.
Cellular immune response The role of T cells and its subsets in resisting COVID-19 remains unclear.
Previous studies have confirmed that the S protein of SARS-CoV is the primary antigen protein that
induces the host immune response, and serves an important role in activating cytotoxic T cell responses
and causing humoral immune responses. Xu et al (23) found that the proportions of circulating CD4+ and
CD8+ T cells were substantially decreased in patients infected with COVID-19, but their status was
hyperactivated. In addition, there is an increased percentage of highly proinflammatory T helper 17
(Th17) cells and high numbers of cytotoxic CD8+ T cells, indicating that the overactivation of T cells may
partly account for the severe inflammatory response (23). However, the disease is more severe when
lymphocytopenia is present in COVID-19, suggesting that the T cell response may be necessary for SARS-
CoV-2 clearance. Diao et al (83) observed that in addition to a reduction in the number of T cells,
surviving T cells are functionally exhausted in COVID-19. In addition, T cell subpopulation differentiation
and functional imbalance are key factors in the development of some inflammatory diseases. Therefore,
an imbalance in the ratio of Th1/Th2 and Th17/regulatory T cells in COVID-19 may be a research topic
that requires further study.

Humoral immune response The host humoral response against SARS-CoV-2 comprises specific IgA, IgM
and IgG responses. Most patients with COVID-19 have a specific Ab response ≥10 days following the
onset of symptoms (41). In a recent study of 82 confirmed and 58 probable COVID-19 cases, the specific
IgM and IgA Abs were detected on day 5 (IQR 3-6), while IgG was detected on day 14 (IQR 10-18) after
symptom onset (84). However, the persistence of neutralizing Abs for SARS-CoV-2 requires further
study.

Antiviral neutralizing Abs play a pivotal role in viral clearance. The S protein RBD is specific for SARS-CoV-
2 and may be the direct target for neutralizing Abs (43). Tian et al (17) assessed the cross-reactivity of
anti-SARS-CoV Abs with SARS-CoV-2 S protein. This previous study revealed that the epitope of CR3022,
a SARS-CoV-specific human monoclonal Ab, which does not overlap with the ACE2 binding site, could
bind potently with SARS-CoV-2 RBD. Most recently, the neutralizing Ab from three convalescent SARS
patients was reported to reduce SARS-CoV-2-driven cell entry, although with lower efficiency compared
with SARS-CoV, suggesting that Ab responses raised against SARS-CoV S protein during infection or
vaccination could at least partially protect against SARS-CoV-2 infection (22). It has also been suggested
that convalescent plasma in patients with COVID-19 might be useful as a potential therapy (85). On the
other hand, Ab-dependent cell-mediated cytotoxicity may also be involved in cellular damage and organ
injury (15). The Fc receptor-mediated Ab-dependent enhancement of SARS-CoV-2 infection may
additionally lead to inflammatory responses (15).

Hypercytokinemia and organ damage COVID-19 can cause both pulmonary and systemic inflammation,
leading to MODS in high risk patients (86). Organ dysfunction is the key diagnostic criterion for severe or
critical SARS-CoV-2 pneumonia (87,88). The most frequent organ dysfunction in patients with severe and
critical COVID-19 includes ARDS, shock, acute myocardial injury, liver injury, kidney injury and MODS
(2,25,86,88-90). The most frequent type of organ dysfunction in patients with severe and critical COVID-
19 admitted to the ICU includes ARDS (61.1%), arrhythmia (44.4%), shock (30.6%), myocardial injury
(22.2%) and acute kidney injury (8.3%) (82). Another clinical trial indicated that the majority of critically
ill patients with COVID-19 had organ function injury, including ARDS (67%), acute kidney injury (29%),
liver dysfunction (29%) and cardiac injury (23%), and 71% of these patients required mechanical
ventilation (2). It is generally assumed that the fundamental pathophysiology of critical COVID-19 is
severe ARDS (2).

The involvement of multiple organs may be related to the direct damage of target cells by SARS-CoV-2
and improper host responses, such as the immune-inflammatory response (Fig. 1). The effects of the
host immune response are a double-edged sword, both protecting the host (immunity) by clearing the
infection, and harming the host by inducing tissue and cell damage, resulting in immunopathology and
worse clinical outcomes (91). In other words, cytokines and chemokines released from activated
immune cells not only participate in the antiviral immune response, but can also cause cell damage and
organ dysfunction. The optimal objective is to achieve a careful balance in the immune response, which
could eliminate the virus, whilst avoiding inflammatory-mediated organ injury.

Hypercytokinemiais an uncontrolled host inflammatory state that is characterized by fulminant MOD

and elevated proinflammatory cytokine responses (92). Hypercytokinemia serves a key role in
pathogenic inflammation both in severe SARS and COVID-19 (11,92-96). The cytokines and chemokines
found in MERS-CoV-infected cells share a similar expression profile to SARS-CoV-infected cells (56).
Several studies from humans who succumbed to highly pathogenic human CoV infections, such as SARS
and MERS, have also suggested that a dysregulated immune response and immunopathology occurred,
resulting in excessive inflammation and lethal consequences during human CoV infections (92,95).
Macrophages in the lung tissue are proposed to be the primary inducer of hypercytokinemiaand
underlie the pathogenesis of MERS and SARS (54). In serum from patients with COVID-19 with a poor
outcome, there was a significant increase in CRP, IL-2, IL-7, IL-10, G-CSF, IP10, MCP-1, MIP-1A and TNF-α,
characterized as hypercytokinemia (24). Chen et al (6) also demonstrated elevated cytokine levels (IL-6,
IL-10 and TNF-α) in severe COVID-19. A recent study reported that COVID-19 is associated with an
elevated cytokine profile that is similar to that observed in secondary hemophagocytic
lymphohistiocytosis (97). Findings from autopsies and serum of patients with COVID-19 suggest a crucial
immune-inflammatory implication in the progression to ARDS and MODS (23). ARDS caused by SARS-
CoV-2 infection seems to primarily result from exaggerated and uncontrollable inflammation initiated by
viral replication. High levels of proinflammatory cytokines may lead to tissue damage in the heart, liver,
kidney and the central nervous system, causing sepsis, shock or multiple organ failure (92). The detailed
expression profile of the cytokine and chemokine responses in COVID-19 requires further investigation
and comparison with that in MERS and SARS.

Acquired immune-induced proinflammatory reactions (including Th17 and cytotoxic T lymphocyte

accumulation) may also serve an important role in tissue damage caused by hypercytokinemia (23). This
exacerbated detrimental inflammatory response towards invading viruses is termed sepsis (98). It is
suggested that appropriate immunomodulatory treatments according to the changes of patients'
immune status may be the key breakthrough in treatment. Most recently, preliminary data have shown
that dexamethasone resulted in lower 28-day mortality amongst patients hospitalized with COVID-19
who were receiving respiratory support (99). In addition, proteolytic enzymes (such as elastase,
collagenase, cathepsin and matrix metalloproteinase) released at the site of inflammation may also
mediate tissue and organ damage (100). Oxidative stress (such as increased reactive oxygen species and
reactive nitrogen species) is an important pathway that contributes to numerous inflammatory
pathological processes, including in patients infected with COVID-19. The oxidative damage imposed on
host tissues via polymorphonuclear cells and macrophage activation may lead to tissue damage and
organ dysfunction (101-103). Considering the harmful effects of oxidative stress in COVID-19,
antioxidant therapies using bioactive compounds, as well as encouraging healthy lifestyles as a potential
treatment is an attractive and practical strategy that warrants further study in the treatment of COVID-
19 (103-106).

Immunosuppression It has been observed that lymphopenia (defective acquired immunity) is a common
feature in patients with COVID-19, and it is related to disease severity and mortality (10,87,88,107).
Immunosuppression may lead to difficulty in removing the virus or secondary infections. Hospital-
acquired secondary infection is frequent in patients with severe COVID-19 (5-15.5%) (2,24,108). A recent
meta-analysis (109), including 3,448 patients from 28 studies, showed that secondary bacterial infection
was identified in 14.3% of patients with COVID-19. Moreover, it has been suggested that
immunocompromised patients may have a higher viral load of SARS-CoV-2, prolonged viral shedding and
impaired Ab responses (10,43). Liang et al (110) found that patients with cancer may be more
susceptible to infection with SARS-CoV-2 than healthy individuals, and had a worse prognosis, as their
immune systems were suppressed by the effects of the tumors and anticancer treatment.

The reason for significant lymphopenia in patients with severe COVID-19 remains unclear. It is
speculated that the underlying mechanisms of lymphopenia may include hemopoietic tissue depression,
as well as direct invasion by viral particles, which damages the lymphocytes and results in its destruction
(2). It has been postulated that SARS-CoV-2 may directly infect T cells and lead to T cell depletion (79).
Pathological studies on biopsy tissues from patients with COVID-19 have revealed that the cell damage
caused by SARS-CoV-2 infection often occurs in the immune system (50). Furthermore, it is hypothesized
that the underlying mechanism includes increased apoptosis or necrosis of immune cells (2), and
lymphocyte recruitment and sequestration in the infection sites or lymphoid tissues (lymphocyte
redistribution). However, these speculations require experimental confirmation. In addition, several
other factors may also contribute to the development of immune suppression, such as a reduction in the
number or function of antigen presenting cells, increased anti-inflammatory cytokines (such as IL-10 and
TGF-β), neuroendocrine responses (such as glucocorticoids), elevated regulatory T cells and myeloid-
derived suppressor cells (111). Of note, lymphopenia and hypercytokinemia were observed in patients
with critical SARS-CoV in 2003, Swine flu in 2009, and COVID-19 in 2019, which may indicate that there is
a particular dysregulated immunological phenotype associated with significantly elevated severity (25).
Renin-angiotensin system in COVID-19 ACE2 is an important component of the renin-angiotensin-
aldosterone system, which converts angiotensin II into angiotensin 1-7 and angiotensin I into
angiotensin 1-9(112). Notably, in addition to mediating viral entry, the SARS-CoV S protein also has
effects on the downregulated expression of ACE2, leading to aggravated lung injury (33). These results
have led to the hypothesis that the binding of SARS-CoV-2 S protein is a virulence factor for COVID-19
outside of its role in viral attachment and entry.

Our previous data and other studies have demonstrated that angiotensin II is involved in the
pathophysiological processes of pulmonary inflammation, pulmonary edema, pulmonary fibrosis and
parenchymal cell apoptosis in a lipopolysaccharide-induced ARDS animal model (Fig. 2) (113-117).
Blocking the angiotensin II receptor may inhibit the function of mature lung dendritic cells, reducing
lipopolysaccharide-induced ARDS (118), and thus guide the development of potentially beneficial drugs.

Figure 2

Figure 2

Schematic diagram of the proposed role of angiotensin II and ACE2 in the development of ARDS.
Angiotensin II may be involved in the pathophysiological processes of pulmonary inflammation,
pulmonary edema, pulmonary fibrosis and parenchymal cell apoptosis ...

4. Recovery of immune homeostasis and repair of organ damage

There are distinct long-term outcomes observed in patients with COVID-19, including recovery, organ
fibrosis and dysfunction, chronic critical illness or persistent inflammation, immunosuppression and
catabolism syndrome, and possibly even death. A retrospective study of 1,591 consecutive patients with
COVID-19 referred to ICU for admission in Italy revealed that 58% of patients were still in the ICU, 16%
patients were discharged, and 26% succumbed to the disease whilst in ICU (119). The long-term
prognosis of patients with COVID-19 depends on a variety of factors, including whether the virus is
cleared in time, and whether the inflammatory response subsides and inflammatory cells and cytokines
are cleared. During the recovery of COVID-19, the number of CD4+ T cells, CD8+ T cells, B cells and NK
cells, and the markers of CD8+ T cell exhaustion may gradually normalize. Additionally, SARS-CoV-2-
specific Abs can be identified. Long-term prognosis also depends on the regeneration and repair of
parenchymal cells in damaged organ tissues. Pulmonary fibrosis appears frequently in COVID-19,
including in patients who survived the infection (23,120,121). However, at present it is unknown
whether patients with COVID-19 will develop chronic critical illnesses or persistent inflammation-
immunosuppression and catabolism syndrome. There are a number of problems that require solving
even after the patient clears the acute phase. For example, how can chronic critical illness, persistent
inflammation, immunosuppression and catabolism syndrome be avoided? What are the roles and
mechanisms of specialized pro-resolving mediators in COVID-19? These gaps in our knowledge urgently
require further investigation in order to contribute to an improved understanding of the pathogenesis of
COVID-19.

Of note, patients with COVID-19 can relapse or become reinfected. Relapse in patients with COVID-19
refers to the reappearance of symptoms in survivors due to the persistence of the SARS-CoV-2 at
immunologically segregated body sites. Reinfection refers to survivors being susceptible to acquiring
new infections after recovery. Patients reinfected with a strain determined to be of a different genotype
or subtype than the previous strain they were originally infected with can easily be identified using
genotyping assays. Elsayed et al (122) reported that there were 11 cases of relapse for COVID-19 at the
time of study. The reason for this is currently unknown, but it may involve factors such as age and
immune status of the host, the presence of underlying lung disease, and the severity of SARS-CoV2
infection, all of which could affect the elimination of the virus (122). It is noteworthy to speculate that
an inflammatory rebound triggered by an inappropriate immune response could constitute a probable
explanation of the recurrence of clinical symptoms (123).

5. Conclusions

In summary, the pathogenic mechanisms of COVID-19 as a novel severe respiratory infectious disease
are not yet fully determined, which is largely due to the novelty this disease. Although a number of
crucial questions remain unanswered at present, it is obvious that we are only beginning to understand
the pathogenic mechanisms of COVID-19. The present review discussed the pathogenesis of COVID-19.
It is assumed that SARS-CoV-2 dysregulates the immune inflammatory response in a manner similar to
SARS-CoV and MERS-CoV infections. Severe COVID-19 is characterized by organ dysfunction,
hypercytokinemia and lymphopenia. Immune dysfunction in patients with COVID-19, including
lymphopenia, decreased numbers of CD4+ T cells and abnormal cytokine levels, is a common feature
and may be a crucial factor associated with disease severity and worse outcomes (6,117). The direct
damage and lysis of host target cells by the virus and the inappropriate innate and acquired immune
responses of the host may be the key pathogenic mechanisms underlying the severity of SARS-CoV-2.
The molecular determinants that may account for the important differences in pathogenesis between
the highly pathogenic human coronaviruses (SARS-CoV, MERS-CoV and SARS-CoV-2) are currently
unknown. Further in-depth studies on the pathogenesis of COVID-19 will be crucial for devising novel
treatment strategies and designing effective vaccines for this highly fatal emerging infectious disease. As
our knowledge of the pathogenesis improves, a more reasonable approach to therapeutic treatments
and vaccine development can be designed in order to combat this novel and fatal illness.

Acknowledgements

Not applicable.
Funding Statement

Funding: The Fifth Program of the ‘333’ Project of Jiangsu Province (grant no. BRA2016070), Scientific
and Technological Development Project of Suzhou (grant no. SS201874).

Availability of data and materials

Not applicable.

Authors' contributions

JL conceived the subject of the review. CL and QH drafted the manuscript, and JL and HQ revised the
manuscript. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Article information

Exp Ther Med. 2021 Sep; 22(3): 1011.

Published online 2021 Jul 15. doi: 10.3892/etm.2021.10444

PMCID: PMC8311250

PMID: 34345293
Chao Li,1 Qifang He,1 Hebu Qian,2 and Jun Liu1

1Department of Critical Care Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University,
Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu 215001, P.R. China

2Department of Critical Care Medicine, Suzhou Ninth People's Hospital, The Affiliated Wujiang Hospital
of Nantong University, Suzhou, Jiangsu 215001, P.R. China

Correspondence to: Professor Jun Liu, Department of Critical Care Medicine, The Affiliated Suzhou
Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical
University, 16 West Baita Road, Suzhou, Jiangsu 215001, P.R. China nc.anis@dhpnujuil

Received 2020 Sep 10; Accepted 2021 Jan 21.

Copyright : © Li et al.

This is an open access article distributed under the terms of the Creative Commons Attribution-
NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the
original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Articles from Experimental and Therapeutic Medicine are provided here courtesy of Spandidos
Publications

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