title: Mycobacterium tuberculosis modulates macrophage lipid-sensing nuclear receptors PPARγ and TR4 for survival.
abstract: Mycobacterium tuberculosis-macrophage interactions are key to pathogenesis and clearance of these bacteria. Although interactions between M. tuberculosis-associated lipids and TLRs, non-TLRs, and opsonic receptors have been investigated, interactions of these lipids and infected macrophage lipid repertoire with lipid-sensing nuclear receptors expressed in macrophages have not been addressed. In this study, we report that M. tuberculosis-macrophage lipids can interact with host peroxisome proliferator-activated receptor γ and testicular receptor 4 to ensure survival of the pathogen by modulating macrophage function. These two lipid-sensing nuclear receptors create a foamy niche within macrophage by modulating oxidized low-density lipoprotein receptor CD36, phagolysosomal maturation block by induction of IL-10, and a blunted innate response by alternative polarization of the macrophages, which leads to survival of M. tuberculosis. These results also suggest possible heterologous ligands for peroxisome proliferator-activated receptor γ and testicular receptor 4 and are suggestive of adaptive or coevolution of the host and pathogen. Relative mRNA expression levels of these receptors in PBMCs derived from clinical samples convincingly implicate them in tuberculosis susceptibility. These observations expose a novel paradigm in the pathogenesis of M. tuberculosis amenable for pharmacological modulation.
authors.affiliation: Institute of Microbial Technology, Chandigarh 160036, India.
authors.forename: Sahil
authors.initials: S
authors.lastname: Mahajan
authors.forename: H Kitdorlang
authors.initials: HK
authors.lastname: Dkhar
authors.forename: Vemika
authors.initials: V
authors.lastname: Chandra
authors.forename: Sandeep
authors.initials: S
authors.lastname: Dave
authors.forename: Ravikanth
authors.initials: R
authors.lastname: Nanduri
authors.forename: Ashok Kumar
authors.initials: AK
authors.lastname: Janmeja
authors.forename: Javed N
authors.initials: JN
authors.lastname: Agrewala
authors.forename: Pawan
authors.initials: P
authors.lastname: Gupta
mesh_terms: D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D005487:Foam Cells / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D006801:Humans; D008024:Ligands; D050356:Lipid Metabolism / Q000276:immunology*; D009169:Mycobacterium tuberculosis / Q000254:growth & development* / Q000276:immunology*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*
chemical_list: D008024:Ligands; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D047495:PPAR gamma