Naveen Vankadari

Conference 2023 Live Talk

Talk title

Genetics of the human TMPRSS2 regulates COVID-19 infection and Arbidol as a potential drug in COVID-19 patient viral clearance

Authors and Affiliations

Naveen Vankadari1, Mitnala Sasikala2, Xuemin Fang3, Lu Tian4, Subbu S Latha5, Ke Wang6, Peng Peng7, Nageshwar D Reddy2

1. Faculty of Medicine and Dentistry, University of Melbourne, Melbourne, VIC, Australia 2. Institute of Translational Research, AIG Hospital, Hyderabad, Telengana, India 3. Graduate School of Health Innovation, Kanagawa University of Human Services, Kawasaki, Kanagawa, Japan 4. Department of Biomedical Data Science, Stanford University, California, CA, USA 5. Center for Innovation in Molecular and Pharmaceutical Sciences, Dr. Reddy’s Institute, Hyderabad, Telengana, India 6. Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Wuhan City, Hubei Province, China 7. Wuhan Institute , Wuhan Pulmonary Hospital, Wuhan City, Hubei Province, China

Abstract

Background

Mortality due to COVID-19 caused by SARS-CoV-2 infection varies among populations. Functional relevance of genetic variations in ACE2 and TMPRSS2, two crucial host factors for viral entry, might explain some of this variation. Determining how SARS-CoV-2 enters cells by processing its spike-glycoprotein has significant ramifications for the development of potential treatments and in understanding the disease progression.

Methods

We recruited 510 COVID-19 patients and retrieved DNA from 520 controls from a repository. Associations between variants in ACE2 and TMPRSS2 with disease severity were identified by whole exome sequencing (WES, n = 20) and targeted genotyping (n = 1010). Molecular dynamic simulations (MDS) were performed to explore functional relevance of the variants. Cleavage of spike glycoprotein by wild and variant TMPRSS2 was determined in HEK293T cells. Potential effects of confounders on the association between genotype and disease severity were tested. Similarly the another cohort study objective is to evaluate the treatment efficacy of Arbidol, together with the concurrent drugs Oseltamivir and Lopinavir/Ritonavir on mortality and lesion absorption based on chest CT scan.

Results

WES identified deleterious variant in TMPRSS2 (V160M). The minor allele frequency (MAF) was 0·27 in controls, 0·31 in asymptomatic, 0·21 in mild-to-moderately affected and 0·19 in severely affected COVID-19 patients. No confounding effect of diabetes and hypertension were observed on the risk of developing severe COVID-19 disease with respect to genotype. MDS revealed decreased stability of TMPRSS2 with 160 M variant. Spike glycoprotein cleavage by TMPRSS2 reduced ~2·4-fold in cells expressing 160 M variant. With respect to Arbidol, according to a chest CT scan, Arbidol showed great promise, was linked to lower cohort mortality, decreased lesion absorption, and reduced mortality (P=02023), and its efficacy was increased when combined with oseltamivir.

Conclusions

These findings provide insight into the potential treatments for viral infection as well as to the process by which host or human genetic changes influence viral infection in different geographic locations.