A Dual-Route Perspective of SARS-CoV-2 Infection: Lung- vs. Gut-specific Effects of ACE-2 Deficiency

Abstract

SARS-CoV-2, primarily considered a respiratory virus, is increasingly recognized as having gastrointestinal aspects based on its presence in the gastrointestinal (GI) tract and feces. SARS-CoV-2 uses as a receptor angiotensin-converting enzyme 2 (ACE-2), a critical member of the renin-angiotensin-aldosterone system (RAAS) involved in the regulation of blood pressure and fluid system. In addition to the systemic endocrine functions, RAAS components are also involved in intracrine and organ-specific local functions. The angiotensin-converting enzyme 2 (ACE-2) is a key component of RAAS and a receptor for SARS-CoV-2. It is expressed in many tissues with gastrointestinal (GI) tract ACE-2 levels far exceeding those in the respiratory tract. SARS-CoV-2 binding to its receptor results in a deficiency of ACE-2 activity in endocrine, intracrine, and local lung and GI tract ACE-2. The local ACE-2 has different organ-specific functions, including hypertension-independent activities; dysregulations of these functions may contribute to multiorgan COVID-19 pathology, its severity, long-term effects, and mortality. We review supporting evidence from this standpoint. Notably, COVID-19 comorbidities involving hypertension, obesity, heart disease, kidney disease, and diabetes are associated with gastrointestinal problems and display ACE-2 deficits. While RAAS inhibitors target both endocrine and intracrine ACE-2 activity, the deficit of the local ACE-2 activity in the lungs and more so in the gut have not been targeted. Consequently, the therapeutic approach to COVID-19 should be carefully reconsidered. Ongoing clinical trials testing oral probiotic bound ACE-2 delivery are promising.

Keywords: ACE-2 receptor; COVID-19; RAAS inhibitors; gastrointestinal infection; microbiota.

FIGURE 1

Respiratory vs. gastrointestinal aspects of Sars-CoV-2 infection. The respiratory and gastrointestinal nature of SARS-CoV-2 infection is compared in terms of the relative distribution of ACE-2 receptors, viral entry, presence of viral particles, symptoms, gut microbiota, and inflammation. The critical involvement of gut microbiota dysbiosis that determines the risk and the severity of COVID-19 is present in several comorbidities such as cardiovascular disease, chronic kidney disease (CKD), diabetes mellitus type 2 (DMT2), hypertension, and pulmonary arterial hypertension.

FIGURE 2

SARS-CoV-2 infection and local ACE-2 deficiency in lungs vs. the gut. Panel (A). Proteins involved in SARS-CoV-2 infection. Angiotensin cleaving enzyme 2 (ACE-2) functions as SARS-CoV-2 receptor, expressed more abundantly in the gut than lungs. A membrane-anchored metalloproteinase 17 (ADAM17) is involved in shedding sACE-2 from membranes, may be involved in activation of SARS-CoV-2 spike (S) protein. Furin, a membrane-bound protease activates SARS-CoV-2 by cleaving S-protein at the specific furin-like cleavage site (FCS). Trypsin increases SARS-CoV2 fusogenic capacity in the gut. Human airway trypsin-like protease (HAT) increases viral fusogenic activity in the lungs but is less efficient than trypsin. Membrane-bound transmembrane serine protease 2 (TMPRSS2) is involved in S-protein priming. Panel (B). Effect of local ACE-2 deficiency in lungs vs. the gut. ACE-2, functions as a chaperone for the neutral amino-acid transporter B⁰AT1 in the gut; B⁰AT1 is not expressed in the lungs. ACE-2 deficiency in the gut results in down-regulation of ACE-2/B⁰AT1 complexes and decreased intestinal uptake of neutral amino acids such as glutamine and tryptophan, critical to T-cell functions thus contributing to inflammation; decreased tryptophan transport interferes with glucose homeostasis. ACE-2 interacts with DABK/bradykinin receptor B1 (BKB1R) and plays a critical role in regulating inflammation via ACE-2/DABK/BKB1R axis; ACE-2 deficiency contributes to increased inflammation in lungs and the gut. ACE-2 interacts with the MAS oncogene (Mas) receptor which activates glucose transport via ACE-2/Ang-(1–7)/Mas axis; ACE-2 deficiency blocks glucose transport in the gut (Ferreira et al., 2010; Stadnicki, 2011; Richard et al., 2017).