RT Journal Article SR Electronic T1 Mycobacterium tuberculosis genetic features associated with pulmonary tuberculosis severity JF bioRxiv FD Cold Spring Harbor Laboratory SP 2022.05.25.493361 DO 10.1101/2022.05.25.493361 A1 Charlotte Genestet A1 Guislaine Refrégier A1 Elisabeth Hodille A1 Rima Zein-Eddine A1 Adrien Le Meur A1 Fiona Hak A1 Alexia Barbry A1 Emilie Westeel A1 Jean-Luc Berland A1 Astrid Engelmann A1 Isabelle Verdier A1 Gérard Lina A1 Florence Ader A1 Stéphane Dray A1 Laurent Jacob A1 François Massol A1 Samuel Venner A1 Oana Dumitrescu A1 the Lyon TB study group YR 2022 UL http://biorxiv.org/content/early/2022/05/25/2022.05.25.493361.abstract AB Mycobacterium tuberculosis (Mtb) infections result in a wide spectrum of clinical presentations but without proven Mtb genetic determinants. Herein, 234 pulmonary tuberculosis (TB) patients were stratified according to TB disease severity and Mtb genetic features were explored using whole genome sequencing, including heterologous single nucleotide polymorphism (SNP) calling to explore micro-diversity. Clinical isolates from patients with mild TB carried mutations in genes associated with host-pathogen interaction, while those from patients with moderate/severe TB carried mutations associated with regulatory mechanisms. Genome-wide association study identified a SNP in the promoter of the gene coding for the virulence regulator EspR associated with moderate/severe disease. Structural equation modelling and model comparisons indicated that TB severity was associated with the detection of Mtb micro-diversity within clinical isolates and to the espR SNP. Taken together, these results provide a new insight to better understand TB pathophysiology and could provide new prognosis tool for pulmonary TB severity.Competing Interest StatementThe authors have declared no competing interest.