Contributors: Individualité microbienne et infection - Microbial Individuality and Infection; Institut Pasteur Paris (IP)-Université Paris Cité (UPCité); Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB; Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN); Université de Caen Normandie (UNICAEN); Normandie Université (NU)-Normandie Université (NU); Hub d'analyse d'images - Image Analysis Hub (Platform) (IAH); Spectrométrie de Masse pour la Biologie – Mass Spectrometry for Biology (UTechS MSBio); Institut Pasteur Paris (IP)-Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité); AP-HP - Hôpital Bichat - Claude Bernard Paris; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP); Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)); Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord; Service des maladies infectieuses et tropicales; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP); Agence Nationale de la Recherche, https://ror.org/00rbzpz17, ANR-10-LABX-62-IBEID, ANR-17-CE11-0007-01, ANR-21-CE15-0045, ANR-24-INBS-0005 FBI BIOGENInstitut Carnot Pasteur Microbes & Health, INNOV-68-20Institut Pasteur, https://ror.org/0495fxg12European Commission, IMI 2 Joint Undertaking Grant 853989; ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010); ANR-17-CE11-0007,PersisTB,Lutter contre l'épidémie mondiale de tuberculose: Exploiter la variation cellule à cellule afin d'entraver la persistance adaptative(2017); ANR-21-CE15-0045,TREATABLE,Cibler la variation phénotypique pour améliorer le traitement de la tuberculose(2021); ANR-24-INBS-0005,FBI (BIOGEN) (JVCE),France-BioImaging (Biological Imaging Next-Generation Instrument)(2024)
نبذة مختصرة : Tuberculosis is characterized by broad clinical heterogeneity that hinders infection control, with differences in lesion development, progression, and treatment outcomes. This complexity is likely associated with Mycobacterium tuberculosis inherent phenotypic variation and its capacity to diversify under host microenvironmental and antimicrobial stressors. Here, we analyze M. tuberculosis at the single-cell and subpopulation level using fluorescent reporters, imaging, transcriptomic, and functional assays. We identify RNA signatures specific to stress-responsive bacilli with translational potential. Focusing on the clinically validated chaperone GroEL2, we find that it correlates with M. tuberculosis growth rate and stress tolerance in vitro and intracellularly. Furthermore, GroEL2 phenotypic diversity influences innate responses in macrophages, which experience different polarization, in turn affecting GroEL2 expression. We also show that targeting GroEL2 impairs pathogen survival and dampens inflammation. This study provides a link between pathogen phenotypic variation and macrophage fates, with implications for early infection outcomes, local disease progression, and subpopulation-targeted interventions.
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