title: Mycobacterium tuberculosisEsxL inhibits MHC-II expression by promoting hypermethylation in class-II transactivator loci in macrophages.
abstract: Mycobacterium tuberculosisis known to modulate the host immune responses to facilitate its persistence inside the host cells. One of the key mechanisms includes repression of class-II transactivator (CIITA) and MHC-II expression in infected macrophages. However, the precise mechanism of CIITA and MHC-II down-regulation is not well studied.M. tuberculosis6-kDa early secretory antigenic target (ESAT-6) is a known potent virulence and antigenic determinant. TheM. tuberculosisgenome encodes 23 such ESAT-6 family proteins. We herein report thatM. tuberculosisandM. bovisbacillus Calmette-Guérin infection down-regulated the expression of CIITA/MHC-II by inducing hypermethylation in histone H3 lysine 9 (H3K9me2/3). Further, we showed thatM. tuberculosisESAT-6 family protein EsxL, encoded byRv1198, is responsible for the down-regulation of CIITA/MHC-II by inducing H3K9me2/3. We further report thatM. tuberculosis esxLinduced the expression of nitric-oxide synthase, NO production, and p38 MAPK pathway, which in turn was responsible for the increased H3K9me2/3 in CIITA via up-regulation of euchromatic histone-lysineN-methyltransferase 2 (G9a). In contrast, inhibition of nitric-oxide synthase, p38 MAPK, and G9a abrogated H3K9me2/3, resulting in increased CIITA expression. A chromatin immunoprecipitation assay confirmed that hypermethylation at the promoter IV region of CIITA is mainly responsible for CIITA down-regulation and subsequent antigen presentation. We found that co-culture of macrophages infected withesxL-expressingM. smegmatisand mouse splenocytes led to down-regulation of IL-2, a key cytokine involved in T-cell proliferation. In summary, we demonstrate thatM. tuberculosisEsxL inhibits antigen presentation by enhancing H3K9me2/3 at the CIITA promoter, thereby repressing its expression through NO and p38 MAPK activation.
authors.affiliation: From the School of Biotechnology, KIIT University, Bhubaneswar, Orissa 751024, India.
authors.forename: Srabasti
authors.initials: S
authors.lastname: Sengupta
authors.affiliation: the National Institute of Immunology, New Delhi, Delhi 110067, India, and.
authors.forename: Saba
authors.initials: S
authors.lastname: Naz
authors.affiliation: From the School of Biotechnology, KIIT University, Bhubaneswar, Orissa 751024, India.
authors.forename: Ishani
authors.initials: I
authors.lastname: Das
authors.affiliation: the Institute of Life Science, Nalco Square, Bhubaneswar, Orissa 751023, India.
authors.forename: Abdul
authors.initials: A
authors.lastname: Ahad
authors.affiliation: From the School of Biotechnology, KIIT University, Bhubaneswar, Orissa 751024, India.
authors.forename: Avinash
authors.initials: A
authors.lastname: Padhi
authors.affiliation: From the School of Biotechnology, KIIT University, Bhubaneswar, Orissa 751024, India.
authors.forename: Sumanta Kumar
authors.initials: SK
authors.lastname: Naik
authors.affiliation: From the School of Biotechnology, KIIT University, Bhubaneswar, Orissa 751024, India.
authors.forename: Geetanjali
authors.initials: G
authors.lastname: Ganguli
authors.affiliation: From the School of Biotechnology, KIIT University, Bhubaneswar, Orissa 751024, India.
authors.forename: Kali Prasad
authors.initials: KP
authors.lastname: Pattanaik
authors.affiliation: the Institute of Life Science, Nalco Square, Bhubaneswar, Orissa 751023, India.
authors.forename: Sunil Kumar
authors.initials: SK
authors.lastname: Raghav
authors.affiliation: the National Institute of Immunology, New Delhi, Delhi 110067, India, and.
authors.forename: Vinay Kumar
authors.initials: VK
authors.lastname: Nandicoori
authors.affiliation: From the School of Biotechnology, KIIT University, Bhubaneswar, Orissa 751024, India, asonawane@kiitbiotech.ac.in.
authors.forename: Avinash
authors.initials: A
authors.lastname: Sonawane
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000942:Antigens, Bacterial / Q000378:metabolism; D001426:Bacterial Proteins / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019175:DNA Methylation; D016680:Genome, Bacterial; D006657:Histones / Q000378:metabolism; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D009163:Mycobacterium bovis / Q000378:metabolism*; D009169:Mycobacterium tuberculosis / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics*; D000067996:RAW 264.7 Cells; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000166:cytology; D015534:Trans-Activators / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D006657:Histones; D007376:Interleukin-2; D015850:Interleukin-6; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D048051:p38 Mitogen-Activated Protein Kinases
keywords: EsxL; Mycobacterium smegmatis; Mycobacterium tuberculosis; histone methylation; macrophage; major histocompatibility complex (MHC); nitric oxide; nitric oxide synthase; p38 MAPK