SARS-CoV-2 and immune-microbiome interactions: Lessons from respiratory viral infections

Abstract

By the beginning of 2020, infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had rapidly evolved into an emergent worldwide pandemic, an outbreak whose unprecedented consequences highlighted many existing flaws within public healthcare systems across the world. While coronavirus disease 2019 (COVID-19) is bestowed with a broad spectrum of clinical manifestations, involving the vital organs, the respiratory system transpires as the main route of entry for SARS-CoV-2, with the lungs being its primary target. Of those infected, up to 20% require hospitalization on account of severity, while the majority of patients are either asymptomatic or exhibit mild symptoms. Exacerbation in the disease severity and complications of COVID-19 infection have been associated with multiple comorbidities, including hypertension, diabetes mellitus, cardiovascular disorders, cancer, and chronic lung disease. Interestingly, a recent body of evidence indicated the pulmonary and gut microbiomes as potential modulators for altering the course of COVID-19, potentially via the microbiome-immune system axis. While the relative concordance between microbes and immunity has yet to be fully elucidated with regards to COVID-19, we present an overview of our current understanding of COVID-19-microbiome-immune cross talk and discuss the potential contributions of microbiome-related immunity to SARS-CoV-2 pathogenesis and COVID-19 disease progression.

Keywords: COVID-19; Gut microbiome; Immunity; Respiratory tract microbiome; SARS-CoV-2.

Figure 1

Flow-chart of the inclusion/exclusion criteria and search strategy used in this study.

Figure 2

Lung microbiome changes in COVID-19. (1) SARS-CoV-2 infects target cells in the lung by engaging ACE2r and TMPRSS2 followed by (2) intracellular viral replication and localized inflammation (3) accompanied by the activation of immune cells (4) further adding to the inflammatory microenvironment via cytokine release. (5) Localized IFN-γ release contributes to microbiome dysbiosis characterized by increased populations of Bacteroides and Enterobacteriaceae which in turn (6) lead to increased mucus production and decreased mucociliary clearance. Collectively, these features increase the risk of secondary infections and the development of ARDS. Abbreviations: ACE2r, angiotensin-converting enzyme 2 receptor; ARDS, acute respiratory distress syndrome; Ly, lymphocyte; PMN, polymorphonuclear neutrophils; RBC, red blood cell; TMPRSS2, transmembrane protease serine protease 2; Type-II P, type-II pneumocyte.

Figure 3

Gut-lung Cross-talk. (1) The ingestion of dietary fibers is followed by (2) fermentation by anaerobic intestinal commensals that leads to the increased (3) production of SCFAs that are absorbed and transported through the blood circulation to the lungs. (4) In the intestinal micro-environment SCFAs induce an anti-inflammatory cytokine response that promotes Treg formation in the local LN. (5) Immune suppressive lymphocytes migrate to the pulmonary lymphatics maintaining cross-talk between the gut and the lung. Abbreviations: CM, colonic macrophage; DC, dendritic cell; Foxp3, forkhead box P3; LN, Lymph node; M, macrophage; SCFAs, short chain fatty acids; Treg, regulatory T cell.

Figure 4

Gut microbiome changes in COVID-19. (1) SARS-CoV-2 infects gut epithelial cells via ACE2/TMPRSS2 receptors, (2) triggering local inflammatory response and stimulating cytokine release along with (3) antigen presentation and the activation of immune responses. (4) Anti-viral immunity leads to the effective clearance of the viral infection or (5) sustained infection leads to the over-activation of the immune system. The pro-inflammatory cytokine (6) IFNα acts locally to augment opportunistic pathogens and suppress commensals. (7) Microbial dysbiosis prompts a reduction in SCFAs and (8) an upregulation of ACE2 receptor expression. The magnitude of these responses may contribute to systemic inflammation. Abbreviations: ACE2r, angiotensin-converting enzyme 2 receptor; DC, dendritic cell; M, macrophages; NK, natural killer; PMN, polymorphonuclear neutrophils; SCFAs, short chain fatty acids; Teff, effector T cells; TMPRSS2, transmembrane protease serine protease 2; Treg, regulatory T cell.