title: Mycobacterium tuberculosis keto-mycolic acid and macrophage nuclear receptor TR4 modulate foamy biogenesis in granulomas: a case of a heterologous and noncanonical ligand-receptor pair.
abstract: The cell wall of Mycobacterium tuberculosis is configured of bioactive lipid classes that are essential for virulence and potentially involved in the formation of foamy macrophages (FMs) and granulomas. Our recent work established crosstalk between M. tuberculosis cell wall lipids and the host lipid-sensing nuclear receptor TR4. In this study, we have characterized, identified, and adopted a heterologous ligand keto-mycolic acid from among M. tuberculosis lipid repertoire for the host orphan NR TR4. Crosstalk between cell wall lipids and TR4 was analyzed by transactivation and promoter reporter assays. Mycolic acid (MA) was found to transactivate TR4 significantly compared with other cell wall lipids. Among the MA, the oxygenated form, keto-MA, was responsible for transactivation, and the identity was validated by TR4 binding assays followed by TLC and nuclear magnetic resonance. Isothermal titration calorimetry revealed that keto-MA binding to TR4 is energetically favorable. This keto-MA-TR4 axis seems to be essential to this oxygenated MA induction of FMs and granuloma formation as evaluated by in vitro and in vivo model of granuloma formation. TR4 binding with keto-MA features a unique association of host nuclear receptor with a bacterial lipid and adds to the presently known ligand repertoire beyond dietary lipids. Pharmacologic modulation of this heterologous axis may hold promise as an adjunct therapy to frontline tuberculosis drugs.
authors.affiliation: Council of Scientific and Industrial Research-Institute of Microbial Technology, Chandigarh 160036, India; and.
authors.forename: Hedwin Kitdorlang
authors.initials: HK
authors.lastname: Dkhar
authors.affiliation: Council of Scientific and Industrial Research-Institute of Microbial Technology, Chandigarh 160036, India; and.
authors.forename: Ravikanth
authors.initials: R
authors.lastname: Nanduri
authors.affiliation: Council of Scientific and Industrial Research-Institute of Microbial Technology, Chandigarh 160036, India; and.
authors.forename: Sahil
authors.initials: S
authors.lastname: Mahajan
authors.affiliation: Council of Scientific and Industrial Research-Institute of Microbial Technology, Chandigarh 160036, India; and.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Dave
authors.affiliation: Council of Scientific and Industrial Research-Institute of Microbial Technology, Chandigarh 160036, India; and.
authors.forename: Ankita
authors.initials: A
authors.lastname: Saini
authors.affiliation: Council of Scientific and Industrial Research-Institute of Microbial Technology, Chandigarh 160036, India; and.
authors.forename: Arun Kumar
authors.initials: AK
authors.lastname: Somavarapu
authors.affiliation: Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Ashish
authors.initials: A
authors.lastname: Arora
authors.affiliation: Council of Scientific and Industrial Research-Institute of Microbial Technology, Chandigarh 160036, India; and.
authors.forename: Raman
authors.initials: R
authors.lastname: Parkesh
authors.affiliation: Council of Scientific and Industrial Research-Institute of Microbial Technology, Chandigarh 160036, India; and.
authors.forename: Krishan Gopal
authors.initials: KG
authors.lastname: Thakur
authors.affiliation: Council of Scientific and Industrial Research-Institute of Microbial Technology, Chandigarh 160036, India; and.
authors.forename: Shanmugam
authors.initials: S
authors.lastname: Mayilraj
authors.affiliation: Council of Scientific and Industrial Research-Institute of Microbial Technology, Chandigarh 160036, India; and pawan@imtech.res.in.
authors.forename: Pawan
authors.initials: P
authors.lastname: Gupta
mesh_terms: D005487:Foam Cells / Q000276:immunology* / Q000473:pathology; D006099:Granuloma / Q000276:immunology* / Q000473:pathology; D006801:Humans; D009169:Mycobacterium tuberculosis / Q000737:chemistry / Q000276:immunology*; D009171:Mycolic Acids / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D011987:Receptors, Steroid / Q000276:immunology*; D011988:Receptors, Thyroid Hormone / Q000276:immunology*; D015533:Transcriptional Activation / Q000187:drug effects / Q000276:immunology*; D014376:Tuberculosis / Q000276:immunology* / Q000473:pathology
chemical_list: D009171:Mycolic Acids; C490515:NR2C2 protein, human; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone