Cellular and Humoral Immune Responses in Covid-19 and Immunotherapeutic Approaches

Abstract

Coronavirus disease 2019 (Covid-19), caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can range in severity from asymptomatic to severe/critical disease. SARS-CoV-2 uses angiotensin-converting enzyme 2 to infect cells leading to a strong inflammatory response, which is most profound in patients who progress to severe Covid-19. Recent studies have begun to unravel some of the differences in the innate and adaptive immune response to SARS-CoV-2 in patients with different degrees of disease severity. These studies have attributed the severe form of Covid-19 to a dysfunctional innate immune response, such as a delayed and/or deficient type I interferon response, coupled with an exaggerated and/or a dysfunctional adaptive immunity. Differences in T-cell (including CD4⁺ T-cells, CD8⁺ T-cells, T follicular helper cells, γδ-T-cells, and regulatory T-cells) and B-cell (transitional cells, double-negative 2 cells, antibody-secreting cells) responses have been identified in patients with severe disease compared to mild cases. Moreover, differences in the kinetic/titer of neutralizing antibody responses have been described in severe disease, which may be confounded by antibody-dependent enhancement. Importantly, the presence of preexisting autoantibodies against type I interferon has been described as a major cause of severe/critical disease. Additionally, priorVaccine and multiple vaccine exposure, trained innate immunity, cross-reactive immunity, and serological immune imprinting may all contribute towards disease severity and outcome. Several therapeutic and preventative approaches have been under intense investigations; these include vaccines (three of which have passed Phase 3 clinical trials), therapeutic antibodies, and immunosuppressants.

Keywords:

• SARS-CoV-2
• inflammation
• immune regulation
• neutralizing antibodies
• cytokines
• autoantibodies
• type I interferon

Abbreviations

ACE2, angiotensin-converting enzyme 2; ADE, antibody-dependent enhancement; Auto-Abs, autoantibodies; ASC, antibody-secreting cell; BCG, bacilli Calmette–Guérin; CD, cluster of differentiation; Covid-19, coronavirus disease 2019; CRP, C-reactive protein; DAMPs, damage-associated molecular patterns; DNA, deoxyribonucleic acid; FcR, Fc receptor; FccRIIb, Fcc receptor IIb; GM-CSF, granulocyte macrophage-colony stimulating factor; HLA-DR, human leukocyte antigen DR isotype; TCR, T-cell receptor; Treg, regulatory T-cells; TRAF, TNF-receptor-associated factor; ICU, intensive care unit; IFN, interferon; IFNAR, interferon-α/β receptor; IFN-γ, interferon-γ; IL, interleukin; IgG, immunoglobulin G; IgM, immunoglobulin M; IP-10, interferon-γ-induced protein 10; IRF-3, interferon regulatory factor 3; MCP-1, monocyte chemoattractant protein-1; MERS-CoV, middle east respiratory syndrome coronavirus; MIP1α, macrophage inflammatory protein 1α; mRNA, messenger ribonucleic acid; NET, neutrophil extracellular trap; NF-κB, nuclear factor kappa B; NK, natural killer; PAMPs, pathogen-associated molecular patterns; PF4, plasma platelet factor 4; PD-1, programmed cell death protein 1; pDC, plasmacytoid dendritic cell; PRR, pattern-recognition receptor; RANTES, regulated on activation, normal T-cell expressed and secreted; rh, recombinant human; RBD, receptor-binding domain; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; STAT1, signal transducer and activator of transcription 1; TFH, T follicular helper; Th1, T-helper 1; TLR, Toll-like receptor; TNF, tumor necrosis factor; TIM-3, T-cell immunoglobulin and mucin domain-3.

Acknowledgments

This work was supported by a grant (CORONAPROP10) from the Kuwait Foundation for the Advancement of Sciences (KFAS).

Disclosure

The authors report no conflicts of interest in this work.