key: cord-0929789-nstzmthf
authors: Luan, Junwen; Ren, Yongwen; Gao, Shan; Zhang, Leiliang
title: High level of defensin alpha 5 in intestine may explain the low incidence of diarrhoea in COVID-19 patients
date: 2021-11-25
journal: Eur J Gastroenterol Hepatol
DOI: 10.1097/meg.0000000000001941
sha: c83b05450ab64ef3fdbfb3fce93d75139d1b36bf
doc_id: 929789
cord_uid: nstzmthf

nan

Corona virus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome corona virus 2 (SARS-CoV-2). Gastrointestinal symptoms have been described in COVID-19 patients [1] . However, the incidence rate of diarrhoea in COVID-19 patients is low [2] . The underlying mechanism remained inconclusive.

SARS-CoV-2 binds to its receptor angiotensin I converting enzyme 2 (ACE2), and then exploits transmembrane serine protease 2 (TMPRSS2) protease for S protein priming [3] . Furin activity may be critical for exposing the receptor-binding domain and fusion domain of SARS-CoV-2 S protein [3] . Defensin alpha 5 (DEFA5) plays an inhibitory role for SARS-CoV-2 entry by shielding ACE2 [4] . In this study, we aimed to explain the low incidence of diarrhoea by analyzing the expression of SARS-CoV-2 entry factors in human intestine.

Single-cell RNA sequencing (scRNA-Seq) data from human intestine based on scRNA-Seq data (GEO accession no. GSE125970) [5] were analyzed. Using the unsupervised graph-based clustering, we clustered the intestine tissues according to their corresponding marker gene expression profiles. The expression of ACE2, TMPRSS2, furin and DEFA5 was analyzed.

To better understand whether intestine supports SARS-CoV-2 infection, we evaluated the expression of ACE2, TMPRSS2, furin and DEFA5 in 14 537 individual cells derived from human intestine based on the scRNA-Seq data (GEO accession no. GSE125970) [5] . We identified 14 distinct cell clusters in intestine tissues (Fig. 1a) . ACE2 was primarily expressed in small intestine enterocyte progenitor cell and small intestine enterocyte (Fig. 1b,  c) . TMPRSS2 and furin were universally expressed in human intestine cells, leading to the dilemma that SARS-CoV-2 was unable to infect intestine. DEFA5 was reported to strongly inhibit the entry of SARS-CoV-2 by shielding ACE2. Interestingly, we found that high levels of DEFA5 were present in ACE2-expressing cells (small intestine enterocyte progenitor cell and small intestine enterocyte) (Fig. 1b, c) . Thus, DEFA5 in human intestine could reduce the entry of SARS-CoV-2, which partially explains the low incidence of diarrhoea in COVID-19 patients.

In this study, we evaluated the expression of SARS-CoV-2 entry factors in human intestine. scRNA-seq data indicated that ACE2, TMPRSS2 and furin were expressed in both small intestine enterocyte progenitor cell and small intestine enterocyte, indicating that SARS-CoV-2 might exploit ACE2, TMPRSS2 and furin for virus entry in the intestine and cause diarrhoea. However, the diarrhoea in COVID-19 was uncommon [2] . DEFA5 associated with ACE2 and blocked the ACE2-S interaction [4] . Low incidence of diarrhoea might be due to the high expression levels of antiviral factor DEFA5 in ACE2-expressing cells. Based on the current findings, we proposed that human intestine might be less vulnerable to attack by SARS-CoV-2 and that the incidence of diarrhoea may be low in COVID-19 patients. 

SARS-CoV-2 induced diarrhoea as onset symptom in patient with COVID-19

Manifestations and prognosis of gastrointestinal and liver involvement in patients with COVID-19: a systematic review and meta-analysis

Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein

Human intestinal defensin 5 inhibits SARS-CoV-2 invasion by cloaking ACE2

Single-cell transcriptome analysis reveals differential nutrient absorption functions in human intestine

There are no conflicts of interest.