The Immunopathobiology of SARS-CoV-2 Infection

Abstract

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to coronavirus disease 2019 (COVID-19). Virus-specific immunity controls infection, transmission and disease severity. With respect to disease severity, a spectrum of clinical outcomes occur associated with age, genetics, comorbidities and immune responses in an infected person. Dysfunctions in innate and adaptive immunity commonly follow viral infection. These are heralded by altered innate mononuclear phagocyte differentiation, activation, intracellular killing and adaptive memory, effector, and regulatory T cell responses. All of such affect viral clearance and the progression of end-organ disease. Failures to produce effective controlled antiviral immunity leads to life-threatening end-organ disease that is typified by the acute respiratory distress syndrome. The most effective means to contain SARS-CoV-2 infection is by vaccination. While an arsenal of immunomodulators were developed for control of viral infection and subsequent COVID-19 disease, further research is required to enable therapeutic implementation.

Keywords: ACE2; COVID-19 vaccines; SARS-CoV-2; cytokine storm; immunity; mutant viral variants.

Figure 1.

Virus infection induces host immune responses. Schematic representation of the genomic and sub-genomic organization of SARS‐CoV-2. During the viral replication cycle, SARS‐CoV‐2 first binds to the ACE2 receptor, which engages TMPRSS2 for entry into an epithelial host cell. Following entry of the genomic RNA into cell cytoplasm, the two large open reading frames (ORFs) 1ab are translated into a viral transcriptase complex (phosphatase activity and RNA‐dependent RNA polymerase (RdRp) and a helicase). Replication of the genome involves the synthesis of a full‐length negative‐strand RNA and serves as a template for full‐length genomic RNA. After translation, structural proteins are localized to the golgi intracellular membranes and the endoplasmic reticulum golgi intermediate compartment where budding occurs. New virions that are assembled with full genome RNA are released from the cell by exocytic vesicles. Oligomerization and activation of NLRP3 inflammasome are illustrated through different pathways. MAVs serve to recognize pathogen-associated DNA/RNA which transcend a signal. Calcium potassium imbalance contributes to inflammasome activation. PAMPs and DAMPS, produce active IL-1β, IL-18, and N-Gasdermin D. These engage the innate and adaptive immune systems(figure originally made in house by authors).

Figure 2.

Viral induction of macrophage signaling pathways. SARS-CoV-2 infection of lung epithelial cells leads to induction of expression of CCL2 and CCL7 chemokines, which in turn, affect the release of a cascade of pro-inflammatory factors that include, but are not limited to, alveolar macrophage TNF-α and IL-6. This occurs in parallel with neutrophil chemoattractants, CXCL1 and CXCL2. CCL2 and CCL7 significantly increases the infiltration of leukocytes (macrophages and lymphocytes) with neutrophil accumulation. This leads to activation of macrophages and facilitates cell entry into alveoli through a leaky endothelium. In tandem, type I IFN responses are operative from alveolar epithelial cells leading to activation of the JAK-STAT pathway. This process increases transcription and translation of interferon-stimulated genes and additional inflammatory agents. NLRP3 inflammasome, formed due to infection, converts Pro IL-1β and Pro IL18 into IL-1β and IL-18, respectively, which work in autocrine fashion in both lymphocytes and macrophages. The cytokine GM-CSF further engages the JAK-STAT pathway serving to amplify the release of inflammatory molecules through the GMC receptor, and also by causing lymphocyte release of IFN-γ, TNF-α from activated NK cells and T cells. Phagocytosis of SARS-CoV-2 and oxidative stress causes signaling by TLR2, TLR4 to further drive synthesis of inflammatory molecules via NF-κB mediated protein kinase B signaling. Antibody bound SARS-CoV-2 also adds to this cascade by binding to Fc receptor binding and ITAM and spleen tyrosine kinase-based signaling (figure originally made in house by authors).

Figure 3.

SARS-CoV-2 immunity. Following SARS‐CoV‐2 infection of epithelial cells, lysis and epithelial damage is one pathway. Another is in presentation of viral antigens from antigen presenting DCs or macrophages to CD8+T cells. The resultant mobilization of cytotoxic CD8+ T cells can recognize viral antigens on neighboring cells with the release of perforin and granzymes. This causes infected epithelial cells to undergo apoptosis. DCs can also present the viral antigens to CD4+ T cells and induce cell differentiation to memory Th1, Th17, and memory T follicular helper cells. These latter cells facilitate B cells differentiation into plasma cells promoting the production of IgM, IgA, and IgG isotype virus‐specific antibodies. Tissue macrophages may also present viral antigens to mobilize CD4+T cell immune responses. (figure originally made in house by authors and concept adopted from these references (Jansen et al. ; Azkur et al. 2020).

Figure 4.

Characteristics of novel variants of SARS-CoV-2. Genetic mutations in SARS-CoV-2 (origin: Wuhan City, China) are generating novel viral variants, such as the three popular strains - B.1.1.7 United Kingdom (UK), B.1.351 South Africa (SA), and P.1 Brazil. The mutation can change many attributes including transmission rates and severity of disease. The reduction in neutralization capacity due to mutation could affect the current vaccination strategy (CDC 2021). The B.1.351 and P.1 variants (also known as 501Y.V2 and 501Y.V3) that have emerged in South Africa and Brazil, respectively, has additional mutations in the RBD at positions E484 and K417. Viral variants with the triple combination of N501Y, E484K and K417N/T have significantly reduced susceptibility to vaccine-induced and convalescent sera (Cele et al. ; Gupta 2021). (*) = detected in some but not all sequences. Introduction of the mutation that encodes the E484K substitution in the B.1.1.7 led to a more-substantial loss of neutralizing activity by vaccine-elicited antibodies (Collier et al. ; Wise 2021) (figure originally made in house by authors).