Year : 2021 | Volume
: 10 | Issue : 1 | Page : 1--6
Immunology of coronavirus disease 2019 raises more questions than answers
Department of Basic Medical Sciences, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences; King Abdullah International Medical Research Centre, Ministry of National Guard-Health Affairs, Riyadh, Kingdom of Saudi Arabia
Department of Basic Medical Sciences, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh
Kingdom of Saudi Arabia
Coronavirus disease 2019 (COVID-19) pandemic is by far one of the biggest global health crises of this century. Unfortunately, up till now, there is no preventative vaccine and treatment strategies are disadvantaged by the ever-emerging viral mutations and the significantly high morbidity and fatality rate. Theoretically, the main hope to change this situation would be to develop novel, effective treatment and vaccine against COVID-19 based on the activation of T- and B-cells. An important part of this process understands the mechanisms of innate and acquired immunity to COVID-19. In this review article, a literature search was conducted using PubMed search engine looking at what has been published up to the 20th of July 2020 about the immunology of COVID-19. The aim is to collate all the evidence and highlight key features of what we know thus far about the immunity of COVID-19. This should hopefully deepen our understanding of the activated immune responses which will take us a step forward in the search for an effective COVID-19 vaccine.
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Nasr A. Immunology of coronavirus disease 2019 raises more questions than answers.Saudi J Health Sci 2021;10:1-6
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Nasr A. Immunology of coronavirus disease 2019 raises more questions than answers. Saudi J Health Sci [serial online] 2021 [cited 2021 Jun 13 ];10:1-6
Available from: https://www.saudijhealthsci.org/text.asp?2021/10/1/1/311954
In March 2020, the World Health Organization (WHO) declared coronavirus disease 2019 (COVID-19) a pandemic. COVID-19 is triggered by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease was first reported in Wuhan, Hubei, China, on the December 31, 2019.
As of the 9th of September 2020, the impact of COVID-19 in different parts of the world has reached about 27,486,960 confirmed infected cases and 894,983 deaths according to the WHO situation report. The aim of this review is to understand and describe the mechanisms activated within the immune system against SARS-CoV-2.
The following search strategies were undertaken in indexed only peer reviewed biomedical literature search engine such as (PubMed). In order to look at the biomedical literature available on the immunology of COVID-19, the following key words were used: COVID-19 AND immunology OR immunology of SARS-CoV-2 AND antibodies OR B-Cells OR cytokines. This yielded: 110 articles published in PubMed which were reviewed and full texts were selected from the relevant abstracts. Few of the articles were in foreign languages so the search engine was modified to pick up English articles only. This of course introduces an element of bias and may have limitations on the overall search, as we know that the pandemic originated in China and as such some of the articles will be written in different languages. Furthermore, reviewing the references within the articles expanded the literature search. The challenges with this search strategy were that any papers with the word cytokine or immunology were appearing in the search. On the flip side, once we filtered through the articles, it was easy to narrow it by date of publication, as we know that COVID-19 was first identified on the 31st of December 2019.
Throughout this article, the word COVID-19 and SARS-CoV-2 will be used interchangeably.
The pathogenesis of the SARS-CoV and SARS-CoV-2 is very similar, especially in the recognition interactions. The binding between the SARS-CoV-2 and lung cells is usually through the angiotensin-converting enzyme 2 (ACE-2) receptors expressed in the Type II pneumocytes in the lung cells. The binding triggers an inflammation cascade in the lower respiratory tract. When the SARS-CoV-2 spike (S) protein binds to the ACE-2 receptor, the complex is processed by type two trans-membrane protease (TMPRSS2) leading to cleavage of ACE-2 and activation of the S-protein., This is similar to the mechanism used by the influenza virus to enter into the target cell. The invasion mechanism suggests that, the cells in which ACE-2 and TMPRSS2 are simultaneously present; are most susceptible to entry by SARS-CoV.,, Early indications are that SARS-CoV-2 virus also requires ACE-2 and TMPRSS2 to enter cells.,, Virus cell interaction is one of the ways of producing a large amount of immune mediators.,, This is demonstrated in diagram one (1) sections A and B (mechanism of virus entry and replication).
Innate Immune Response
The innate immune response triggers a signaling cascade that starts with the recognition of pathogen-associated molecular patterns. These are molecules which are associated with viral infections and act as ligands for host pattern recognition receptors such as toll-like receptors (TLR). For double-stranded ribo-nucleic acid viruses in the lungs such as the common cold, influenza, SARS-CoV, Middle East respiratory syndrome-CoV, and SARS-CoV-2, TLRs are activated, in particular TLR-3, TLR-4 and TLR-5 (reviewed by Li et al., 2020). Different TLRs are able to initiate innate immune responses by using adapter proteins such as myeloid differentiation factor 88, toll/interleukin-1 receptor (TIR)-domain-containing adapter-inducing interferon-β (TRIF), TIR domain-containing adapter protein as well as TRIF-related-adaptor molecule., The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ƙB) plays an important role in regulating the immune response to COVID-19 infection. NF-ƙB pathway will promote the production of proinflammatory cytokines such as interleukin-1 β (IL-1 β) and interferons (IFNs). In general, TLR-5 promotes the productions of IFN-β cytokines and activation of type I IFN responses,, which offer a possible opportunity to re-establish anti-viral immune defences that are decreased during COVID-19 infection. SARS-CoV-2 infection is a rapidly replicating virus with large amplification of the virus in respiratory epithelial cells, which initiates the acute inflammatory respiratory symptoms. Inflammation is usually mediated by pro-inflammatory cytokines such as (IL-1, IL-6, TNF, and IL-8). In general, IL-1 cytokine occurs after the binding of SARS-CoV-2 to the TLR receptor which forms a complex that activates a complement component cascade. Viral encoded proteins help the virus escape detection by the complement system and activate the antiviral response. The pro-inflammatory properties of the complement component C3a and C5a are able to initiate inflammatory cell recruitment and neutrophil activation (this is schematically demonstrated in [Diagram 1] section C [innate immunity]). Activation of inflammasome is usually associated with the generation of caspase-1, which results in the formation of IL-1 and IL-6 cytokines that induce the signs and symptoms of inflammation such as fever and pain. As such, blockade of C3a and C5a has the potential to treat acute lung injury.[INLINE:1]
The complement component C3b will activate the opsonization mechanism through the macrophages and neutrophils. The activated complement component 5 (C5b) and other complement proteins (C6, C7, C8, and the cell membrane-binding protein C9) bind together to initiate the final processing of the membrane attack complex. SARS-CoV-2 infection activates the complement pathway where its signaling contributes to the disease process. Complement activation in patients with COVID-19 can be a novel therapeutic target through neutrophil activation and the inflammation that eventually leads to endothelial damage. On the other hand, a recent study showed that complement inhibition can be a new target in treating COVID-19 with systemic thrombosis. Activation or inhibition of complement is still debatable in the clinical outcome of COVID-19 patients.
Adaptive Immune Response
When a virus attacks a cell, the antigen presenting cells (APC) process and present the viral particles in the form of antigenic peptides or epitopes expressed over major histocompatibility complex (MHC). The APC includes dendritic cells, macrophages, and B-cells. If these antigenic particles are presented over MHC Class I, they will recognize, bind, and activate cluster of differentiation (CD) 8+ (also known as cytotoxic T-lymphocytes [CTL]). If the antigenic particles are presented over MHC Class II, they will activate CD4+ cells also known as T-helper cells (Th). The Th cells will in turn be divided into different subsets depending on which cytokines are being released by them. In COVID-19, the virus gets recognized by the APC which present its viral peptides over MHC to be recognized by T-cells (Th0). Th0 will produce TH1 cells that will release IL-1, IL-12, transforming growth factor (TGF)-α, and IFN-γ cytokines, which will active CD8+ (CTL). In COVID-19, CD8+ cells kill the infected viral cells by mechanisms mediated by perforin/granzymes that eventually activate the caspase pathways, which lead to cell death. Th0 will also produce Th2 cells which will release IL-4, IL-5, TGF-β1, IL-6, and IL10., These cytokines will activate the B-cells to help them differentiate into (i) plasma cells (effector cells) to release antibodies such as IgM, IgG, and IgA specific against COVID (ii) Memory B-cells which play a role in the prevention of infection following exposure to the antigen again. This is demonstrated in diagram one (1) section D (adaptive immunity).
When a cell becomes infected with the COVID-19 virus, it presents the viral antigenic peptides over MHC Class I. The same mechanism will occur in the CTL cells as in the adaptive immune response. In certain cases, COVID-19-infected viral cells lead to down regulation of the presentation of MHC Class I over the infected cell membrane. This allows the virus to evade the immune system. In this situation, the natural killer (NK) cells take over the immune defence mechanisms to kill the viral infected cells. NK cells often kill cells that do not present the MHC class I over their cell membrane. As such, NK cells are able to recognize self-cells that contain MHC Class1 and kill other cells that do not have it such as viral-infected cells.
In order to understand the cross-regulation of the Th1 and Th2 subsets, we need to review the feedback loop mechanisms that take place. Macrophage activation induces the production of IL-12, which promotes the production of Th1 which in turn produce IFN-γ. IFN-γ has two main functions. First, it directly inhibits the production of Th2 cells. Second, it inhibits the proliferation of the Th2 cell subset and antagonises B-cell activating effects of IL-4.
IFN-γ favors the development of Th1 through a positive feedback loop whereby more macrophages are activated and thus more IL-12 is produced leading to more production of Th1.
When the SARS CoV-2 infects the human cell, the inflammatory cascade and adaptive immune responses of the host cells are initiated by APCs such as dendritic cells, macrophage and B-lymphocyte cells (B-cells). Within this view, the crucial roles of APCs in processing and presenting viral-antigenic peptides over MHC Class I and II molecules for CD8+ and the CD4+ T-lymphocyte (T-cells). In a severe infection with COVID-19 which is associated with pneumonia and concomitant acute respiratory distress syndrome, the macrophages play an important role by producing the higher levels of numerous pro-inflammatory cytokines including IL-1 β, IL-6, TNF-α, and IL-8, These inflammatory cytokines promote the interaction of T-cells with the APC to exhibit two actions: First, presenting the viral antigen peptide to CD4+ T-helper (Th0) cells. In general, there are two common types of Th cells, namely Th1 and Th2.
As schematically demonstrated in section D of Diagram one (1), Th1 stimulates CTL also known as CD8+ cells, which normally target foreign antigens of any cells. Accordingly, CTL cells play a vital role in the process of clearance and killing of virally-infected cells which are normally expressed on MHC-I. In adaptive immunity, SARS-CoV-2 activates B-cells and plasma cells to produce SARS-CoV-2-IgG antibodies. Infected cell-gG antibody complex can be recognized by the high-affinity Fc gamma receptor-IIIa (CD16) of NK cells. These NK cells induce phagocytes and degradation of the infected cells in an antibody-dependent cell-mediated cytotoxicity.
The increase in the numbers of CD8+ T and Th17 cells indicates over-activation of T-cells which is believed to be the major cause of the severe immune injury. The normal incubation period of SARS-CoV-2 in the susceptible individual is between 1 and 14 days with an overall average rate of 3–7 days., The highest source of infection is contact with COVID-19 patients without personal protective equipment. Recently, Liu et al. have shown that there is a significant increase in circulatory levels of IL-6, IL-10, IL-2, and IL-4 with a parallel decrease in CD8+, CD4+, and B-cells (cytokine storm) in 40 COVID-19 Chinese patients. Thirteen patients exhibited severe symptoms while the other 27 patients had mild symptoms. Accordingly some other authors have suggested that the use of anti-inflammatory drugs in those patients could be useful in controlling the cytokine storm.
T-regulatory cells (Treg) are known as “suppressor T-cells,” which are part of the CD4+ Th cells subpopulation. In general, Treg can play an important role in suppressing the immune system by secreting IL-10 and TGF-β cytokines, which in turn reduce the inflammatory response. Furthermore, TGF-β contributes in the tissue repair process.
Tregs can suppress many of the immune cells such as (CTL, Th cells, monocytes, NK cells, as well as B-cells)., Tregs can delay the proliferation of CTL cells and Th cells through decreasing the secretion of IL-2 cytokines (which gives T-cells the survival signal), inhibiting APC maturation and eliminating effector cells through secreting cytokines., These findings could help the prevention of progression to severe disease. A recent review by Liu et al., 2020 suggested that induction of immunosuppressive Treg cells helps to decrease lung inflammation due to viral infections.
Humoral Immune Responses to Coronavirus Infection
During SARS-CoV-2, the humoral immune responses are also active. The complexes of monoclonal antibodies (mAbs) collaborate with each other to target different antigenic domains on the glycoprotein viral envelope. After infection, the induced neutralising antibodies act directly against the surface spike of the S1 protein and both IgM and IgG can be detected within 7 days after infection. Although IgM is usually produced earlier than IgG, IgG antibodies circulate for longer periods than IgM and IgA antibodies which are associated with the viral load and neutralizing activity., It has been demonstrated that activation of CD8+ T-cells is detrimental during the early stages of the infection. However, humoral immunity is essential at decreasing the levels of infections over longer periods of time., The protective immunity against COVID-19 is very challenging and there are no clear results describing the sensitization of the specific spike protein or from interactions of immunoglobulin. Although a recent long-term prospective cohort study has shown that the antibody titres to SARS CoV can be detected in patients for 12 years' post infection, over 70% of the study patients had extremely low titres. Furthermore, the 3-year postinfection antibodies titer were very limited for virus neutralisation, with little or no ability to protect a person from reinfection. Given the genetic similarity between the SARS-CoV-2 and SARS-CoV. One can postulate that a similar pattern of antibody titre might occur with SARS-CoV-2. As, these findings are scientifically not confirmed, studies are needed to reveal the role of antibodies in the adaptive immune responses post SARS-CoV-2. Up till now, the data obtained from this literature review describe more than 20 types of mAbs, the majority of which are human or humanized antibodies.
A recent study among the Spanish population suggested that the seroprevalence data detected antibodies for symptomatic COVID-19 patients, however the surveillance of asymptomatic patients demonstrated very low seroprevalence compared to symptomatic patients. In addition to that, most of the studied Spanish individuals were seronegative to SARS-CoV-2 infection. This finding may be difficult to be interpreted at this time. However, we can speculate that cellular immunity (mainly CTL cells) plays an important role against SARS-CoV-2 infection, which was not evaluated in those studies. CTL cells might have played a role in protecting the individuals against SARS-CoV-2 reinfection. A recent study in Switzerland shows that the seroprevalence can provide information related to the exposure but not immunity. Based on this, it is still largely undetermined if those patients are protected by other immune mechanisms (i.e., cellular immunity). However, currently available data suggest that immunity after SARS-CoV-2 infection is very similar to that observed in cold coronaviruses infection which is characterized by being insufficient and temporary lasting from several few months to years.
Memory B cells, usually play an important role during the COVID-19 re-infection, by secreting pathogen-specific associated receptors related to antigen binding sites and upregulation of transcription factor T-bet associated with the proliferation and differentiation of memory B cells to plasma cells for secreting specific antibody such as IgG. Reactivation of the memory CD4+ T-cells expressing the transcription factor T-bet help and activate memory B cells and secrete cytokines (including IFNγ) to activate innate cells On the other hand, the CD8+ memory T-cells can directly kill virus-infected cells through the perforin/granzymes (cytotoxic molecules). Recent findings demonstrated that the virus-specific memory lymphocyte population enhances the immune response to clear the virus and prevent disease by reducing the chance of transmission.
A previous study suggested that the memory B-cells isolate from a patient who had recovered from SARS-CoV infection had developed into mAbs. Those antibodies have demonstrated high viral neutralizing activity, both in vitro and in vivo. A recent study compared serum antibody memory B-cell responses to SARS-CoV-2 spike proteins among donors using a series of binding and functional assays. The result suggested that memory B-cells confer weak evidence of preexisting SARS-CoV-2 cross-reactive serum antibodies in prepandemic donors. However, there was stronger evidence of preexisting memory B-cells cross-reactive that were activated on subsequent infection with SARS-CoV-2. It follows that determining preexisting immunity to endemic coronaviruses could potentially be considered to evaluate antibody responses against SARS-CoV-2. Nevertheless, more studies are needed to determine the role of B-cells in COVID-19.
Taken together, the immune system plays an important role in COVID-19 infection at various stages including nonspecific (innate) and specific (acquired) immunity against SARS-CoV-2 infections. The immunology of COVID-19 is still not well understood and needs more in-depth analysis to understand the intricate underlying mechanisms and to take us a step forward toward vaccine and anti-viral medication development.
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