Immunological co-ordination between gut and lungs in SARS-CoV-2 infection

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved into a major pandemic called coronavirus disease 2019 (COVID-19) that has created unprecedented global health emergencies, and emerged as a serious threat due to its strong ability for human-to-human transmission. The reports indicate the ability of SARS-CoV-2 to affect almost any organ due to the presence of a receptor known as angiotensin converting enzyme 2 (ACE2) across the body. ACE2 receptor is majorly expressed in the brush border of gut enterocytes along with the ciliated cells and alveolar epithelial type II cells in the lungs. The amino acid transport function of ACE2 has been linked to gut microbial ecology in gastrointestinal (GI) tract, thereby suggesting that COVID-19 may, to some level, be linked to the enteric microbiota. The significant number of COVID-19 patients shows extra-pulmonary symptoms in the GI tract. Many subsequent studies revealed viral RNA of SARS-CoV-2 in fecal samples of COVID-19 patients. This presents a new challenge in the diagnosis and control of COVID-19 infection with a caution for proper sanitation and hygiene. Here, we aim to discuss the immunological co-ordination between gut and lungs that facilitates SARS-CoV-2 to infect and multiply in the inflammatory bowel disease (IBD) and non-IBD patients.

Keywords: ACE2; COVID-19; Gastrointestinal tract; Gut–lung axis; Inflammatory bowel disease; SARS-CoV-2.

Fig. 1

Graphical representation of gut microbiota alterations and COVID-19-associated mortality rate among various age groups. Source: Ahlawat et al., 2020; Novel, 2020.

Fig. 2

Representation of a probable “gut-lung axis” in SARS-CoV-2 caused COVID-19 disease. Inhalation of SARS-CoV-2-laden-droplets expelled from an infected person leads to binding of SARS-CoV-2 to angiotensin converting enzyme 2 (ACE2) and other receptors for entry to host cells. The hyperactive host immune system releases inflammatory mediators leading to “cytokine storm”. Increased inflammatory mediators lead to lung hyper-permeability such that the virus along with the inflammatory mediators via circulation migrates to intestine and binds highly expressed ACE2 receptors on the enterocytes. SARS-CoV-2 reduces the expression of ACE2 receptors and affects the microbial composition and host immune system. The inflammatory mediators disrupt the intestinal permeability leading to the leakage of gut microbes and associated metabolites into circulation. The leaked microbes and products via circulation migrate to organs including lungs and produce abnormalities. “Microbial dysbiosis” is also suspected due to the observation of diarrhea as a main GI symptom in patients with the COVID-19 disease. Inset: Human organs that express ACE2 receptor with the representation of the organs where SARS-CoV-2 reach have been reported previously. : ACE2 receptor, : TMPRSS2 receptor, : neutrophils, : lymphocytes, : mucus, and : inflammatory mediators. *ACE2 and TMPRSS2 are expressed in the brush border of host cells. In figure, the localisation of ACE2 and TMPRSS2 outside of the gut or lungs instead of in brush border contact is just for easy representation to the readers.

Fig. 3

Representation of various immunomodulatory drugs that are proposed to treat the SARS-CoV-2 caused COVID-19 disease, and their action mechanism.