Project description:The ability of Mycobacterium tuberculosis (Mtb) to tolerate antibiotics is a major impediment in the treatment of tuberculosis. This antibiotic tolerance is influenced by the host cells in which the bacteria reside, as Mtb senses host cues, and the bacterial response can provide an enhanced ability to withstand anti-TB drugs. Previouslyt, we have shown that Mtb exhibits redox heterogeneity in terms of its mycothiol redox potential (EMSH) giving rise to three broad subpopulations EMSH-reduced, EMSH-basal, and EMSH-oxidized Mtb specifically inside the macrophages. Among these, the EMSH-reduced Mtb exhibit enahnced tolerance to several anti-TB drugs while the EMSH-basal and EMSH-oxidized subpopulations are more susceptible. In this study, we explored the transcriptomic level differences between macrophages that harbor the antibiotic tolerant Mtb and those harboring antibiotic susceptible Mtb to get a mechanistic understanding of host factors that influence drug tolerance in intracellular Mtb.
Project description:The ability of Mycobacterium tuberculosis (Mtb) to tolerate antibiotics is a major impediment in the treatment of tuberculosis. This antibiotic tolerance is influenced by the host cells in which the bacteria reside, as Mtb senses host cues, and the bacterial response can provide an enhanced ability to withstand anti-TB drugs. Previouslyt, we have shown that Mtb exhibits redox heterogeneity in terms of its mycothiol redox potential (EMSH) giving rise to three broad subpopulations EMSH-reduced, EMSH-basal, and EMSH-oxidized Mtb specifically inside the macrophages. Among these, the EMSH-reduced Mtb exhibit enahnced tolerance to several anti-TB drugs while the EMSH-basal and EMSH-oxidized subpopulations are more susceptible. In this study, we have discovered a novel host-directed therapy molecule- meclizine, which enhances the drug susceptible population and diminishes the tolerant population.
Project description:THP-1 Macrophages were infected with Mycobacterium tuberculosis clinical isolates from Xinjiang, China, and H37Rv for 24 hours, respectively, and their transcriptomes were sequenced to investigate the specific biological processes that occur after infection of macrophages with Mycobacterium tuberculosis clinical isolates from Xinjiang, China.
Project description:Pulse chase SILAC was used to identify protein turnover within human macrophages infected with mycobacterium tuberculosis CDC1551, a ppe38-71 mutant strain, a complemented strain and an uninfected control.
Project description:Transcriptional profiling of Mycobacterium tuberculosis mRNA enriched from host-pathogen samples from in vivo alveolar macrophages (Mus musculus).
Project description:Innate immune cells such as monocytes and macrophages provide the earliest defense against infection by intracellular pathogens by initiating signaling pathways and restricting pathogen replication. However, the full complement of proteins that mediate cell-autonomous immunity remains incompletely defined. Here, we applied cysteine-directed activity-based protein profiling (ABPP) to map proteome-wide cysteine reactivity changes in THP-1 monocytes and primary human monocyte-derived macrophages during Mycobacterium tuberculosis (Mtb) infection. Across both cell types, we quantified 148 cysteine residues with altered reactivity. Genetic perturbation of a subset of proteins harboring these changes significantly impacted Mtb replication, revealing functional links between site-specific cysteine reactivity and antimicrobial defense. These data define previously unrecognized host protein changes during Mtb infection and provide a resource for investigating post-translational events that regulate innate immune responses to intracellular bacteria.