From the Role of Microbiota in Gut-Lung Axis to SARS-CoV-2 Pathogenesis

Abstract

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is responsible for the outbreak of a new viral respiratory infection. It has been demonstrated that the microbiota has a crucial role in establishing immune responses against respiratory infections, which are controlled by a bidirectional cross-talk, known as the "gut-lung axis." The effects of microbiota on antiviral immune responses, including dendritic cell (DC) function and lymphocyte homing in the gut-lung axis, have been reported in the recent literature. Additionally, the gut microbiota composition affects (and is affected by) the expression of angiotensin-converting enzyme-2 (ACE2), which is the main receptor for SARS-CoV-2 and contributes to regulate inflammation. Several studies demonstrated an altered microbiota composition in patients infected with SARS-CoV-2, compared to healthy individuals. Furthermore, it has been shown that vaccine efficacy against viral respiratory infection is influenced by probiotics pretreatment. Therefore, the importance of the gut microbiota composition in the lung immune system and ACE2 expression could be valuable to provide optimal therapeutic approaches for SARS-CoV-2 and to preserve the symbiotic relationship of the microbiota with the host.

Figure 1

Relationship between the gut microbiota and lung immunity: the interaction between the intestinal commensal bacteria and establishing of lung immunity is mediated by various factors, including PAMPs, PRRs, SCFAs, intestinal integrity, and immune cells of the lamina propria. In a normal state, DCs are continuously sampled from the lumen through M-cell activity, extension of dendrites, and the gut barrier function, which determine bacterial/PAMP translocation. After DC sampling, these cells migrate to GALT and then MLN to regulate differentiation and homing of lymphocytes (T and B cells) depending on the released certain cytokines in respect to gut microbiota composition. The activated T and B cells are distributed in the lungs via circulation. Also, the levels of CCL20 and CCL17, which are produced by the lungs after microbial exposure, contribute to imprinting of T cell subsets, based on the cognate CCRs. Furthermore, SCFAs can penetrate into the bone marrow and influence lung immunity by affecting MDP differentiation to inflammatory or anti-inflammatory immune cells. Inflammatory macrophages and DCs in the lungs are derived from CDPs and Ly6C⁺ inflammatory monocytes. Alternatively, activated macrophages (AAMs) are anti-inflammatory immune lung cells, derived from Ly6C⁻ patrolling monocytes subtypes.

Figure 2

The function of two arms of renin-angiotensin-aldosterone system (RAAS) axis: the RAAS consists of two pathways including (i) ACE/Ang II/AT1R: in the pathway, Ang II which cleaved from Ang I by ACE activity, interacts with AT1R to induce vasoconstriction, inflammation, and fibrosis. (ii) ACE2-Ang1-7-MasR: in the pathway Ang 1-7 negatively regulate RAAS through promotion of vasodilation, anti-inflammatory and antifibrotic effects by interaction with MasR. Ang 1-7 are produced from cleavage of Ang II by ACE2 or metabolized of inactivated Ang 1-9 (cleaved from Ang I by ACE2) by ACE. The balance between two arms determines healthy state. In COVID-19 infection, ACE2, main receptor to SARS-CoV-2 entrance, is significantly decreased which results to inhibition of protective function of ACE2-Ang1-7-MasR arm. In opposite, the increased level of ACE2 resulted from ACEI and ARB medication in diabetic and hypertensive patients is considered as a double-edged sword which has been raised a big question: which aspects of increased ACE2 could be dominated during COVID-19 infection? increased susceptibility to viral infection or protective potential in RAAS system.