key: cord-0800297-vlse2pzs
authors: Keam, Synat; Megawati, Dewi; Patel, Shailesh Kumar; Tiwari, Ruchi; Dhama, Kuldeep; Harapan, Harapan
title: Immunopathology and immunotherapeutic strategies in severe acute respiratory syndrome coronavirus 2 infection
date: 2020-07-09
journal: Rev Med Virol
DOI: 10.1002/rmv.2123
sha: 687cff5e2c1813cefb86dff9b5c891776292191f
doc_id: 800297
cord_uid: vlse2pzs

The outbreak of coronavirus disease 2019 (COVID‐19) and pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), has become a major concern globally. As of 14 April 2020, more than 1.9 million COVID‐19 cases have been reported in 185 countries. Some patients with COVID‐19 develop severe clinical manifestations, while others show mild symptoms, suggesting that dysregulation of the host immune response contributes to disease progression and severity. In this review, we have summarized and discussed recent immunological studies focusing on the response of the host immune system and the immunopathology of SARS‐CoV‐2 infection as well as immunotherapeutic strategies for COVID‐19. Immune evasion by SARS‐CoV‐2, functional exhaustion of lymphocytes, and cytokine storm have been discussed as part of immunopathology mechanisms in SARS‐CoV‐2 infection. Some potential immunotherapeutic strategies to control the progression of COVID‐19, such as passive antibody therapy and use of interferon αβ and IL‐6 receptor (IL‐6R) inhibitor, have also been discussed. This may help us to understand the immune status of patients with COVID‐19, particularly those with severe clinical presentation, and form a basis for further immunotherapeutic investigations.

The outbreak of coronavirus disease 2019 (COVID-19) that started from the Hubei Province in China in December 2019 1 was declared as a Public Health Emergency of International Concern (PHEIC) by the World Health Organization (WHO) on 30 January 2020, 2 has now attained pandemic status affecting more than 200 countries. [3] [4] [5] The infection is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that shares 79.6% sequence identity to severe acute respiratory syndrome coronavirus (SARS-CoV). 6 As of 14 April 2020, based on COVID-19 Global Cases, 7 tail; and (c) small membrane protein (E), a highly hydrophobic protein. 15 S protein is trimeric and processed by host cellular proteases to form two functional subunits S1 and S2, which remain noncovalently bound in the prefusion conformation. 16 The S protein plays a major role in membrane fusion and viral entry into host cells through the cellular angiotensin-converting enzyme 2 (ACE2) receptor. Moreover, the receptor-binding domain (RBD) is located in the S1 subunit at the apex of the S protein of SARS-CoV. 17, 18 Although some risk factors, such as age and the presence of comorbidity, have been associated with disease severity and mortality of patients with COVID-19, 19 there is still a lack of understanding of the role of the immune system on disease severity and mortality rate.

An initial study suggested clear changes in immune responses during disease progression in a patient with COVID-19. 20 Therefore, dysregulated host-immune responses might be one of the important factors for the pathogenesis and disease severity of COVID-19. This review aims to collate the recent immunological studies from patients with COVID-19, which may give us an insight on (a) the interaction between the host immune system and the virus and (b) disease pathogenesis thereby, helping in developing effective immune-based therapies for SARS-CoV-2 infection.

As SARS-CoV-2 and SARS-CoV are similar, 6 it is suggested that the biochemical interactions are likely to be similar. Like SARS-CoV, SARS-CoV-2 enters the host cells through ACE-2 receptors on type II pneumocytes in the lungs. 6, 21, 22 After breaching the first line of immune defence, such as mucus and ciliated cells, the pathogen-associated molecular patterns (PAMPs) on the virus alert frontline innate immune cells such as monocytes, alveolar macrophages, natural killer (NK) cells, and neutrophils to the presence of the invading virus. 23 To mount the appropriate response, these innate immune cells express pattern recognition receptors (PRRs) such as toll-like receptors (TLRs), retinoic acidinducible gene I (RIG-I)-like receptors (RLRs), and nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) that recognize PAMPs. The interaction between PRR and PAMP induces phagocytosis and activates intracellular signaling pathways to stimulate the synthesis of proinflammatory cytokines, such as type I interferons (IFN-I, ie, IFNα/β) and type II interferons (IFN-II, ie, IFN-γ), and chemokines, such as CXCL-10 and CCL-2. 12,23,24 IFN-I inhibit viral replication via multiple mechanisms. 25 Infected cells with reduced major histocompatibility complex I (MHC-I) expression also activate NK cells to produce significant amounts of IFN-γ and induce apoptosis through cytotoxic granules and antibody-dependent cellular cytotoxicity (ADCC). 26, 27 In SARS-CoV infection, dendritic cells (DCs) and macrophages are the key players in innate immune responses as they possess the capacity to kill through phagocytosis and IFN release (ie, plasmacytoid DCs utilize TLR-7 to sense viral nucleic acid leading to IFN-I secretion to lyse the viruses). 24 More importantly, they are capable of presenting viral peptides to bridge to adaptive immune responses. 28 IFN-I, secreted by infected cells and innate immune cells, such as macrophages and DCs, is a potent cytokine in controlling viral infection and priming adaptive immune responses. 29 IFN-I blocks viral replication by inducing hundreds of interferon stimulated genes (ISGs),

including key components of the protein synthesis machinery, protein kinase R (PKR), and 2 0 -5 0 -oligoadenylate synthase (OAS)/RNAse L. 29 PKR halts general protein synthesis through phosphorylation of eukaryotic initiation factor 2 subunit-α (eIF2α) and OAS/RNase L degrades viral ssRNA, thereby effectively impairing viral replication. 25 The key role played by PKR and OAS/RNAse L in the innate immune responses to CoV is emphasized by MERS-CoV expressing protein NS4a to inhibit PKR activation 30 and NS4b to inhibit RNase L activation. 31 Moreover, IFN-I stimulates CD8 + T proliferation, promotes B cell activation, antibody production, and class switching (ie, IgM to IgG), 32 and activates NK cells and macrophages to clear the viruses. 33 The role of IFN in SARS-CoV-2 infection, including other innate immune components and responses, is shown in Figure 1A . Pretreatment of nonlymphatic cells with IFN-α before infection with SARS-CoV induces substantial gene expression for IFN induction, IFN-signaling pathways, and antiviral effector proteins. 34 An in vitro study shows that IFN-α can inhibit SARS-CoV as seen by the cytopathic effect, plaque assay, and immunoblot analysis. 35 SARS-CoV-2 is sensitive to IFN-I pretreatment. 36 In this study, Vero cells pretreated with recombinant IFN-I prior to infection with SARS-CoV-2 showed a significant reduction of SARS-CoV-2 replication-a 3 to 4 log drop in viral titer. 36 This suggests that IFN-I has antiviral potential for SARS-CoV-2; therefore, further clinical trials are required to evaluate this potential.

The B cell response of humoral immunity is essential for controlling viral infection and replication of extracellular viruses through antibody F I G U R E 1 Immune responses and immunotherapy strategy in SARS-CoV-2 infection. Immune response to SARS-CoV-2 involving innate and adaptive immunity. A1, SARS-CoV-2 enters the host cells by binding the receptor for angiotensin converting enzyme 2 (ACE2). The infected cells then release interferon type I (IFN-α/β); innate immune cells respond to the IFNs by establishing an antiviral state. In case of severe infection, the viruses are sensed by monocytes, tissue macrophages, and resident dendritic cells resulting in uncontrolled proinflammatory cytokine (IFN, TNF-α, IL-1β, and IL-6) production, leading to a phenomenon called the cytokine storm, which damages the host's respiratory epithelial cells. Exhausted natural killer cells with increased expression of the inhibitory receptor, NKG2A, are also seen in SARS-CoV-2. A2, In SARS-CoV-2 infection, increased antibody production and poor T cell responses are observed (A2). CD4+ T cell and CD8+ T cell numbers decrease, and the exhausted phenotype, which is characterized by a higher expression of inhibitory receptors, such programmed death receptor-1 (PD-1) and cytotoxic T lymphocyte associated antigen-4 (CTLA-4), is seen. Immunotherapy strategies for SARS-CoV-2 have been proposed. B1, Transferring convalescent sera with neutralizing antibodies from the recovered patients. The antibodies can directly bind to SARS-CoV-2 and prevent the virus from infecting new cells (neutralization), enhance phagocytosis (opsonization), recruit complement to lyse infected cells or neutralize the viruses, and promote NK cell mediated killing of infected cells through antibody dependent cellular cytotoxicity (ADCC). B2, IFN α/β bind to IFN receptors and induce an antiviral response by expressing several interferon stimulated genes (ISGs), such as PKR, OAS, and Mx. The protein product of ISGs controls viral infection. (B3) The IL-6R inhibitor (such as tocilizumab) binds to the membrane bound IL-6 receptor (mIL-6R) and soluble IL-6 receptor (soluble IL-6R). Binding of tocilizumab to IL-6R inhibits the IL-6 signaling pathway production. B cell activation is achieved through the crosslinking of two or more membrane immunoglobulins (Ig) to multiple antigenic molecules (epitopes or antigenic determinants). Moreover, T-cellmediated immune responses lead to the generation of antibody secreting plasma cells and memory B cells. 37, 38 Antibodies control viral infection through several mechanisms, including neutralization, opsonization, phagocytosis, activation of the classical complement pathway, and ADCC (an NK cell mediated apoptosis), and therefore prevent extracellular viruses from replicating and further infecting healthy cells. 37, 39, 40 A study has found an increase in the number of antibody-secreting cells (ASCs) during SARS-CoV-2 infection. 20 The median duration of detectable IgA and IgM is approximately 5 days (ranging from 2 to 6 days) and 14 days for IgG (ranging from 10 to 18 days) after the onset of symptoms. 41 Although no crossreactivity was observed between SARS-CoV-2 nucleocapsid protein and positive human plasma for coronaviruses NL63, 229E, OC43, and HKU1, there was a strong crossreactivity with SARS-CoV positive plasma. 41 The increased production of IgM and IgG in SARS-CoV-2 infection was detected in blood before the recovery of symptoms and persisted for at least 7 days after the full resolution of symptoms. 20 Analysis of serum samples collected 14 days or longer after the onset of COVID-19 symptoms revealed 94% and 88% seropositivity rate for IgG and IgM, respectively, against the SARS-CoV-2 internal nucleoprotein (NP) antigen. 42 For IgG and IgM against surface spike protein receptor binding domain (RBD), the seropositivity rates were higher, 100% and 94%, respectively. 42 The level of antibodies against NP and RBD correlated with their neutralizing activities. 42 Taken together, humoral responses were clearly activated with diverse isotypes of antibodies during SARS-CoV-2 infection ( Figure 1A ).

An increased IgG response with a higher titer of total immunoglobulins in the patients with severe COVID-19 resulted in worse outcome, which suggests the possible role of antibody-dependent enhancement (ADE) during SARS-CoV-2 infection. [43] [44] [45] However, how effective these antibodies are to neutralize extracellular viruses and to activate phagocytosis, classical complement pathway, and ADCC needs to be evaluated and further studies are warranted. In addition, impaired adaptive immune responses along with uncontrolled inflammatory innate responses were reported to be harmful, leading to local and systemic tissue damage. 45 However, one study found that the level of antibodies detected in patients with COVID-19 is associated with virus neutralization titer, 42 [46] [47] [48] ; however, some young healthy adults, 20-40 years of age, have also developed severe clinical manifestations that require their admittance to the intensive care unit (ICU) and a small proportion (0.1% to 0.2%) has been reported to have died. 49 This might suggest that the host immune responses in those groups were unable to control viral replication, leading to severe disease progression. The exact immunological reasons why some patients cannot deal with SARS-CoV-2 remain largely unknown.

During SARS-CoV infection, the virus employs strategies to block IFN production. 50, 51 In this context, the production of IFN-I induced by polyinosinic:polycytidylic acid (poly I:C) or Sendai virus was suppressed by the nucleocapsid (N) protein of the SARS-CoV. 50 The SARS-CoV membrane protein also inhibits the formation of the TRAF3·TANK·TBK1/IKK-ϵ complex, leading to decreased interferon regulatory factor (IRF)3/IRF7 transcription factor and hence reduces IFN production. 51 The TRAF3·TANK·TBK1/IKK-ϵ complex is required 

Lymphocytes such as T cells (CD4 + and CD8 + T cells) and NK cells are important for viral clearance. 55 whereas cytotoxic T cells may directly kill the virus. 63, 68 The SARS-CoV-2 is reported to attack respiratory epithelial cells followed by spread to other cells. Moreover, the virus infects peripheral leucocytes and lymphocytes particularly T cells. 69 The damage caused by SARS-CoV-2 to lymphocytes including T cells leads to lymphopenia and predisposes the individuals to secondary bacterial infections and increased severity of the disease. 69 The increase in proinflammatory and decrease in anti-inflammatory cytokines may indicate the T-cellmediated response against SARS-CoV-2, resulting in cytokine storm associated hyperinflammation and subsequent severe pneumonia in COVID-19. [67] [68] [69] The increased levels of proinflammatory cytokines may result in shock and severe tissue damage in heart, kidney, and liver along with respiratory and multiple organ failure. 45 The severe and fatal cases of COVID-19 are characterized by lymphopenia and sustained inflammation. 66 A recent study has found a significant decrease of total T lymphocytes, CD8 + T cells, and NK cells in patients with COVID-19 and this reduction was more prominent among those with severe disease compared with those with a mild one. 70 Moreover, NK cells become exhausted during SARS-CoV-2 infection, characterized by increased expression of inhibitory receptor, NKG2A (NK group 2 member A), 70 which induces NK cell exhaustion in chronic viral infection ( Figure 1A ). In patients with COVID-19, significant decrease of CD107a + NK, IFN-γ + NK, IL-2 + NK, TNF-α + NK, and granzyme B + NK cells has also been observed, most likely due to the overexpression of NKG2A. 70 A study confirmed that the number of NK and CD8+ T cells was restored when the expression of NKG2A was reduced among COVID-19 survivors after treatment. 70 IFN-γ from CD4 + T cells is required to activate macrophages as potent killers of intracellular pathogens through the Th1 pathway;

IFN-γ is also required for robust CD8 + T cell responses. 71 TNF-α, secreted by CD4 + T cells also has direct antiviral effects, resulting in reduced viral replication. 72 In patients with SARS-CoV-2, there was a significant reduction of IFN-γ + CD4 + T cells and TNF-α + CD4 + T cells in those with severe disease compared with those with a mild clinical manifestation. 73 Moreover, the level of coinhibitory receptors, such as programmed death receptor-1 (PD-1), cytotoxic T lymphocyte associ- T cells) were below the normal range. 75 In addition, an analysis of the blood sample from a patient with COVID-19 found increased follicular

T cells. 20 Taken together, the evidence suggests that the number of lymphocytes, such as NK cells and T cells, in patients with COVID-19 decreased and were exhausted with increased expression of inhibitory receptors such as NKG2A, PD-1, and CTLA-4 ( Figure 1A) . Apart from the increase in the expression of inhibitory receptors, reduction of activation and proliferation capacities of lymphocytes may also be associated with low costimulatory receptor expression (CD28) and reduced growth cytokines, such as IL-2. 75 The characteristics of impaired lymphocyte responses in SARS-CoV-2 infection, which may contribute to disease progression, are presented in Table 1 .

The COVID-19 associated deaths in severe forms were mostly attributed to respiratory failure 68, 69 probably caused by lethal pneumonia following hyperinflammation. 64, 68, 69 The cytokine storm, dysregulated and uncontrolled release of proinflammatory cytokines, inducing systemic immune responses and inflammation, can lead to severe clinical manifestations, such as sepsis and multiple organ failure. 76 Ref.

Increase [70] NKG2A + NK cells Increase [70] NKG2A + CD8 + T cells Increase [70] PD-1 Increase [73] CTLA-4 Increase [73] TIGIT Increase [73] Total T lymphocytes Decrease Decrease [70] CD8 + T cells Decrease Decrease [70] Total NK cells Decrease Decrease [70] CD107a + NK cells Decrease [70] IFN-γ + NK cells Decrease [70] IL-2 + NK cells Decrease [70] TNF-α + NK cells Decrease [70] Granzyme B + NK cells Decrease [70] IFN-γ + CD4 + T cells Decrease [73] TNF-α + CD4 + T cells Decrease [73] Helper T cells (CD3 + CD4 + T cells)

Decrease [75] Cytotoxic T cells (CD28 + CD8 + T cells)

Decrease [75] SARS-CoV. 77 Increased neutrophilic and monocytic inflammatory responses and cytokines, such as IL-1β, are the main characteristics of the cytokine storm. 78, 79 Acute lung injury is a common repercussion of the cytokine storm and is mostly associated with infection in the lungs and other organs. 77 The clinical signs associated with SARS-CoV-2 infection are fever, dry cough, sneezing, chest pain, and pneumonia along with ground glass opacities and bilaterally consolidated lungs on computed tomography (CT) scan. 68 95 Later, a larger study involving 80 patients was done to test the efficacy of convalescent plasma of patients with SARS. 96 The study highlighted that earlier administration of convalescent plasma (before day 14) was more effective and more likely to give a good outcome than administration after day 14, consistent with the concept of viremia peaks in the first week of infection. 96 During the current COVID-19 outbreak in China, administration of convalescent plasma has reported a reduction in viral load and morbidity of patients. 93, 97 The mechanism of how passive antibody therapy works is given in brief in Figure 1 .

According to the latest data, approximately 20% of patients have recovered from COVID-19 worldwide (COVID-19 Global Cases). 7

Neutralizing antibodies can be prepared from pooled convalescent plasma or monoclonal antibodies can be developed by immortalizing B-cell repertoires of convalescent plasma. 98 To increase efficacy, several factors, including the timing of plasma administration, antibody titer of the administered plasma, and screening of convalescent plasma for blood borne pathogens, need to be considered. 93 To provide a timely response to the COVID-19 pandemic, the US Food and Drug Administration (FDA) has approved convalescent sera to be delivered to patients seriously ill with COVID-19, under the emergency investigational new drug protocol. 99 The eligibility of the donor and the recipient has been extensively described. 99 The FDA has stipulated that convalescent sera must only be collected from individuals who have recovered, with complete resolution of symptoms at least 14 days prior to donation and with a SARS-CoV-2 neutralizing antibody titer greater than 1:320. 99 In addition, not only can convalescent plasma serve as a safe therapy for patients critically ill with COVID-19, such neutralizing antibodies also have the potential to be used as short prophylactic molecules for those at a high risk for COVID-19, including health-care providers and vulnerable individuals with comorbidities.

IFNs limit the spread of viral infection through induction of interferon stimulated genes (ISGs) that encode cytokines and antiviral proteins ( Figure 1 ). 100 These antiviral proteins exhibit antiviral effects both directly, by inhibiting viral replication, and indirectly, by stimulating the adaptive immune system. 100 

Emerging evidence shows that patients with COVID-19 exhibit the cytokine storm syndrome, characterized by the release of a high level of proinflammatory cytokines, including a marked elevation of IL-6. 85, 112, 113 The increased level of IL-6 was reported to be a reliable indicator of poor outcome in COVID-19 patients with severe forms of the disease. 45 A high level of inflammatory cytokines is associated with pulmonary inflammation and severe lung damage. 114 Treatment of hyperinflammation using existing, approved therapies that are readily available would benefit patients with severe COVID-19. Blocking the IL-6 receptor, using the relatively safe tocilizumab, has shown therapeutic benefit against inflammatory disease and rheumatoid arthritis. 115 Tocilizumab, a humanized monoclonal antibody, competitively binds both membrane-bound and soluble IL-6 receptors, thus preventing IL-6 from binding to its receptor ( Figure 1 ). 116 Inhibition of the IL-6 signaling cascade leads to a decrease in circulating immune cells. 116 Moreover, a clinical trial (ChiCTR2000029765) using tocilizumab was reported to be effective in quick control of fever along with improvement in respiratory function in patients with severe form of COVID-19. 45 K.D., S.K.P., and R.T. acknowledge their respective institute/university.

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The authors declare no competing interests.

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