SARS-CoV-2 infectivity can be modulated through bacterial grooming of the glycocalyx
Authors: Martino Cameron , Kellman Benjamin P. , Sandoval Daniel R. , Clausen Thomas Mandel , Cooper Robert , Benjdia Alhosna , Soualmia Feryel , Clark Alex E. , Garretson Aaron F. , Marotz Clarisse A. , Song Se Jin , Wandro Stephen , Zaramela Livia S. , Salido Rodolfo A. , Zhu Qiyun , Armingol Erick , Vázquez-Baeza Yoshiki , McDonald Daniel , Sorrentino James T. , Taylor Bryn , Belda-Ferre Pedro , Das Promi , Ali Farhana , Liang Chenguang , Zhang Yujie , Schifanella Luca , Covizzi Alice , Lai Alessia , Riva Agostino , Basting Christopher , Broedlow Courtney Ann , Havulinna Aki S. , Jousilahti Pekka , Estaki Mehrbod , Kosciolek Tomasz , Kuplicki Rayus , Victor Teresa A. , Paulus Martin P. , Savage Kristen E. , Benbow Jennifer L. , Spielfogel Emma S. , Anderson Cheryl A. M. , Martinez Maria Elena , Lacey James V. , Huang Shi , Haiminen Niina , Parida Laxmi , Kim Ho-Cheol , Gilbert Jack A. , Sweeney Daniel A. , Allard Sarah M. , Swafford Austin D. , Cheng Susan , Inoyue Michael , Niiranen Teemu , Jain Mohit , Salomaa Veikko , Zengler Karsten , Klatt Nichole R. , Hasty Jeff , Berteau Olivier , Carlin Aaron F. , Esko Jeffrey D. , Lewis Nathan E. , Knight Rob 
Published: February 2025

The gastrointestinal (GI) tract is a site of replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and GI symptoms are often reported by patients. SARS-CoV-2 cell entry depends upon heparan sulfate (HS) proteoglycans, which commensal bacteria that bathe the human mucosa are known to modify. To explore human gut HS-modifying bacterial abundances and how their presence may impact SARS-CoV-2 infection, we developed a task-based analysis of proteoglycan degradation on large-scale shotgun metagenomic data. We observed that gut bacteria with high predicted catabolic capacity for HS differ by age and sex, factors associated with coronavirus disease 2019 (COVID-19) severity, and directly by disease severity during/after infection, but do not vary between subjects with COVID-19 comorbidities or by diet. Gut commensal bacterial HS-modifying enzymes reduce spike protein binding and infection of authentic SARS-CoV-2, suggesting that bacterial grooming of the GI mucosa may impact viral susceptibility.

IMPORTANCE

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019, can infect the gastrointestinal (GI) tract, and individuals who exhibit GI symptoms often have more severe disease. The GI tract’s glycocalyx, a component of the mucosa covering the large intestine, plays a key role in viral entry by binding SARS-CoV-2’s spike protein via heparan sulfate (HS). Here, using metabolic task analysis of multiple large microbiome sequencing data sets of the human gut microbiome, we identify a key commensal human intestinal bacteria capable of grooming glycocalyx HS and modulating SARS-CoV-2 infectivity
in vitro
. Moreover, we engineered the common probiotic
Escherichia coli
Nissle 1917 (EcN) to effectively block SARS-CoV-2 binding and infection of human cell cultures. Understanding these microbial interactions could lead to better risk assessments and novel therapies targeting viral entry mechanisms.