Mycobacterium tuberculosis genetic features associated with pulmonary tuberculosis severity

Charlotte Genestet (1, 2, 3) , Guislaine Refrégier (4, 5) , Elisabeth Hodille (1, 3, 2) , Rima Zein-Eddine (4, 5) , Adrien Le Meur (4, 5) , Fiona Hak (4, 5) , Alexia Barbry (1, 3, 2) , Emilie Westeel (6, 7) , Jean-Luc Berland (6, 7) , Astrid Engelmann (8) , Isabelle Verdier (8) , Gérard Lina (1, 3, 2, 9) , Florence Ader (1, 3, 2) , Stéphane Dray (10) , Laurent Jacob (10) , François Massol (11, 12, 13) , Samuel Venner (10) , Oana Dumitrescu (1, 3, 2, 9)

1 CIRI - Centre International de Recherche en Infectiologie
2 HCL - Hospices Civils de Lyon
3 IAI - Institut des Agents Infectieux [Lyon]
4 ESE - Ecologie Systématique et Evolution
5 I2BC - Institut de Biologie Intégrative de la Cellule
6 Laboratoire des Pathogènes Emergents
7 Fondation Mérieux
8 CHBBF - Centre Hospitalier Fleyriat [Bourg en Bresse]
9 UCBL - Université Claude Bernard Lyon 1
10 LBBE - Laboratoire de Biométrie et Biologie Evolutive - UMR 5558
11 CIIL - Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204
12 Evo-Eco-Paléo (EEP) - Évolution, Écologie et Paléontologie (Evo-Eco-Paleo) - UMR 8198
13 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]

Objective: Mycobacterium tuberculosis (Mtb) infections result in a wide spectrum of clinical presentations but without proven Mtb genetic determinants. Herein, we hypothesised that genetic features of Mtb clinical isolates, such as specific polymorphisms or micro-diversity, may be linked to tuberculosis (TB) severity. Methods: 234 pulmonary TB patients (including 193 drug-susceptible and 14 mono-resistant cases diagnosed between 2017 and 2020 and 27 multidrug-resistant cases diagnosed between 2010 and 2020) 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. Finally, we performed a structural equation modelling (SEM) analysis to relate TB severity to Mtb genetic features. Results: 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 statistically associated with moderate/severe disease. SEM and model comparisons indicated that TB severity was associated with the detection of Mtb micro-diversity within clinical isolates and to the espR SNP. Conclusions: Taken together, these results provide a new insight to better understand TB pathophysiology and could provide new prognosis tool for pulmonary TB severity.

Mots clés: Genetic heterogeneity; Genome-wide association study; Mycobacterium tuberculosis; Pulmonary tuberculosis; Structural equation modeling; Whole genome sequencing

Domaines: Immunologie; Santé publique et épidémiologie

Charlotte Genestet, Guislaine Refrégier, Elisabeth Hodille, Rima Zein-Eddine, Adrien Le Meur, et al.. Mycobacterium tuberculosis genetic features associated with pulmonary tuberculosis severity. International Journal of Infectious Diseases, 2022, 125, pp.74-83. ⟨10.1016/j.ijid.2022.10.026⟩. ⟨hal-03836738⟩