key: cord-0783733-7vrqmrkj
authors: Li, Chung-Hsiang; Clair Chiou, Hsin-Ying; Lin, Ming-Hong; Kuo, Chang-Hung; Lin, Yu-Chih; Lin, Yi-Ching; Hung, Chih-Hsing; Kuo, Chao-Hung
title: Immunological Map in COVID-19
date: 2021-05-12
journal: J Microbiol Immunol Infect
DOI: 10.1016/j.jmii.2021.04.006
sha: b16a1f7773cb860d800b2131eb38b576af4fb35e
doc_id: 783733
cord_uid: 7vrqmrkj

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by SARS-CoV-2, a newly discovered coronavirus that exhibits many similarities with the severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) coronaviruses (SARS-CoV and MERS-CoV, respectively). The definite pathogenesis and immunological influences of SARS-CoV-2 have not been fully elucidated. Therefore, we constructed a brief summary comparison of SARS-CoV-2, SARS-CoV, and MERS-CoV infections regarding their immunological changes. In addition, we further investigated the immunological differences between severe and nonsevere COVID-19 cases, and we searched for possible immunological predictors of the patient outcome by reviewing case series studies to date. Possible immunological predictors of a poor outcome are leukocytosis, neutrophilia, lymphopenia (both CD4 and CD8 T cells), an increased neutrophil-to-lymphocyte ratio (NLR), and increased levels of pro-inflammatory cytokines (IL-6 and TNF-α), Th1 cytokines (IL-2 and IFN-γ), regulatory T cell cytokines (IL-10) and Th17 cytokines (IL-17). A more precise immunological map needs to be established, which may assist in diagnosing this disease and facilitate immunological precision medicine treatment.

of T cells, CD4+, and CD8+ cells in COVID-19 patients, suggesting that high TNF-, 1 IL-6, and IL-10 expression may negatively regulate T cell survival and proliferation. 20 2 Whether SARS-CoV-2 infections induce T cell apoptosis and contribute to lymphopenia 3 is still unknown. 4

On the other hand, T cells undergo functional exhaustion in COVID-19 patients, 5 which diminishes host antiviral activity. The inhibitory factor PD-1 was highly expressed 6 in T cells of COVID-19 patients compared to T cells of healthy controls. PD1+CD8+ T 7 cell levels were significantly increased in intensive care unit (ICU) patients compared 8 with those in non-ICU patients and healthy controls. 20 Several T cell functional 9 molecules, such as IFN and TNF in CD4+ T cells were lower in the severe group than 10 in the mild group. 21 The levels of granzyme B and perforin in CD8+ T cells were higher 11 in the severe group than in the mild group. 21 This finding indicates that SARS-CoV-2 12 damages the function of CD4+ T cells and promotes excessive activation and possibly 13 subsequent exhaustion of CD8+ T cells. Moreover, the levels of multifunctional CD4+ T 14 cells significantly decreased in the severe group, whereas the proportion of nonfunctional 15 subsets increased. The elevated exhaustion level and reduced functional diversity of T 16 cells may serve as a predictive marker for severe progression in COVID-19 patients. 21 In 17 both SARS-CoV and SARS-CoV-2 infection, the levels of multifunctional CD4+ T cells 18

were increased in severe cases compared with moderate cases. 21, 22 The reduced 19 functional diversity of T cells may be a unique immune response to SARS-CoV-2 1 infection compared to that of other coronaviruses. 2 3

In SARS-CoV and MERS-CoV infection, delayed or suppressed type I IFN induction in 5 host cells has been found to be an early important immunopathological feature, and this 6 phenomenon is also observed in SARS-CoV 2 infection. These coronaviruses employ 7 multiple strategies to interfere with the signaling leading to type I IFN production and/or the 8 signaling downstream of the interferon-α/β receptor (IFNAR). 1, 13 This dampening strategy is 9 closely associated with disease severity. 13 As a consequence, strategies to boost immune 10 responses (antisera or pegylated IFNα) at an early stage may be important. 11

For the development of an endogenous protective immune response in the incubation 12 and nonsevere stages, the host should be in good general health and have an appropriate 13 genetic background (e.g., HLA) that elicits specific antiviral immunity. However, when the 14 protective immune response is impaired, the virus will propagate, and massive destruction of 15 the affected tissues will occur, especially in organs that have high ACE2 expression, such as 16 the intestine and kidney. 17

A cytokine storm is a potentially fatal hyperrelease of inflammatory mediators and 18 cytokines in response to stimulation of T cells and macrophages by pathogens. An early 19 rapid increase in the serum levels of proinflammatory cytokines was also observed in 1 SARS-CoV and MERS-CoV infection, suggesting a potential similar cytokine 2 storm-mediated disease severity. 23 The T cell response in SARS-CoV infection was 3 extensively investigated, and the data show that strong T cell responses were correlated 4 significantly with increased neutralizing antibody levels, while higher serum Th2 5 cytokine levels (IL-4, IL-5, and IL-10) were detected in the fatal group. 22 In MERS-CoV 6 infection, an early rise in CD8+ T cells correlated with disease severity, and in the 7 convalescent phase, Th1 cells were dominant. 24 8

Cytokine storms also play an important role in fatal COVID-19. Forty-one 9 hospitalized patients with high levels of proinflammatory cytokines, including IL-2, IL-7, 10 IL-10, interferon gamma-induced protein 10 (IP-10), MCP-1, MIP-1α, and TNF-α, were 11 observed in severe COVID-19 cases; these findings are in line with SARS and MERS in 12 the presence of lymphopenia. 23 Cytokine storms can initiate viral sepsis and inflam-13 matory-induced lung injury, which leads to other complications, including pneumonitis, 14 acute respiratory distress syndrome, respiratory failure, shock, organ failure, and poten-15 tially death. 15, 23 Further autopsy or biopsy studies are necessary to understand additional 16 details. 17 18

We performed a literature review in PubMed of confirmed COVID-19 case series to 1 investigate the relationship between immune reactions and disease severity in COVID-19 2 patients (Table 3) . 10, 23, 25-30 Compared to nonsevere cases, severe COVID-19 cases had a 3 significant increase in leukocyte and neutrophil counts; on the other hand, decreased total 4 lymphocyte (both CD4+ and CD8+ T cell) and NK cell and normal or decreased B cell and 5 eosinophil counts were also found. Elevated levels of proinflammatory cytokines (IL-6 and 6 TNF-α), Th1 cytokines (IL-2 and IFN-γ), regulatory T cell cytokines (IL-10), and Th17 7 cytokines (IL-17) were also observed. Th2 cytokines (IL-4) elevation may be noted 8 occasionally. In conclusion, these findings suggest that Th1 and Th17 responses have an 9 important role in COVID-19 severity. 10

In Th17 responses, increased IL-17 secretion can further induce the production of 11 proinflammatory cytokines IL-1β, IL-6, and TNF-α, with chemokines. Furthermore, 12 proinflammatory cytokines such as IL-1β and TNF-α could promote the Th17 response in 13 turn. Th17 cells can promote eosinophil production and recruitment into the lungs to induce 14 lung allergic disease. Furthermore, studies have demonstrated that IL-6 is essential in SARS 15 lung pathology; therefore, this finding could explain the important role of the Th17 response 16 in COVID-19 lung disease. 31 17 Zhou P reported a clinical analysis of 99 cases in Wuhan that showed increased total 18 neutrophils, reduced total lymphocytes, increased serum IL-6, and increased C-reactive 19 protein (CRP). 32 In severe or lethal cases of SARS-CoV or MERS-CoV infection, 1 increased neutrophil and monocyte-macrophage influx have been consistently observed. 2

Another report also revealed significantly increased total neutrophils and decreased total 3 lymphocytes in patients receiving ICU care compared to those in patients receiving 4 non-ICU care; furthermore, increased neutrophil and decreased lymphocyte counts also 5 correlate with disease severity and death. 33 Since lymphocytopenia is often seen in 6 severe COVID-19 patients, the severe and fatal cases caused by SARS-CoV-2 infection 7 may be mediated by leukocytes other than T cells. Furthermore, the 8 neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-C-reactive protein ratio (LCR) 9

are established inflammation markers that reflect the systemic inflammatory response, 10 and both tests are available in almost all hospital laboratories. NLR values increased 11 significantly in severe COVID-19 patients, while LCR values decreased significantly. 12

Increased NLR values and decreased LCR levels may indicate a poor prognosis. 23, 27 13 A recent review of antibody mediated immunity to coronaviruses revealed that a slower 14 antibody response may be associated with more severe disease in MERS-CoV and 15 SARS-CoV-2 infections. 34 In addition, the median time to detect different antibodies was 16 shortest for SARS-CoV-2, followed by SARS-CoV, and the longest time was seen for 17 MERS-CoV infection. 34 These findings could partially explain the differences in the disease 18 severity among these three coronaviruses. Therefore, a delayed antibody response may be 19 considered a risk factor for a poor prognosis. 1 2

During the worldwide SARS-CoV-2 pandemic, multisystem inflammatory syndrome 4 was first diagnosed as hyperinflammatory shock. MIS-C shares partially similar symptoms 5 but is distinct from typical Kawasaki disease. A systemic review of 953 MIS-C cases 6 worldwide showed that MIS-C has a higher median age of onset than typical KD. MIS-C is 7 distinct from KD, with a higher rate of shock, intensive care treatment, coronary dilatation, 8 aneurysm formation, and mortality rates. 35 9 MIS-C presents with more systemic inflammation (higher leukocyte counts and CRP), 10 more frequent lymphocytopenia with thrombocytopenia, and higher myocardial injury 11 markers including troponin I, BNP (B-type natriuretic peptide), and coagulopathy (D-dimers), 12 than typical KD. 35 The immunological characteristics of MIS-C are similar to those of KD, 13 including elevated IL-6 and CXCL-10 levels, which contribute to most cytokine storms. 36 14 However, significantly elevated IL-17A was only observed in KD but not MIS-C. 36 The length of each color bar is correlated with the influence degree of each infection. Figure  8 1C: The viral influences of MERS-CoV, SARS-CoV, and SARS-CoV-2 on organ system. The 9 length of each color bar is correlated with the influence degree of each infection. Figure 1D : 

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 (Table 3) NA: data not currently available J o u r n a l P r e -p r o o f