title: HIV impairs TNF-alpha mediated macrophage apoptotic response to Mycobacterium tuberculosis.
abstract: The factors that contribute to the exceptionally high incidence of Mycobacterium tuberculosis (MTb) disease in HIV(+) persons are poorly understood. Macrophage apoptosis represents a critical innate host cell response to control MTb infection and limit disease. In the current study, virulent live or irradiated MTb (iMTbRv) induced apoptosis of differentiated human U937 macrophages in vitro, in part dependent on TNF-alpha. In contrast, apoptosis of differentiated HIV(+) human U1 macrophages (HIV(+) U937 subclone) was markedly reduced in response to iMTbRv and associated with significantly reduced TNF-alpha release, whereas apoptosis and TNF-alpha release were intact to TLR-independent stimuli. Furthermore, reduced macrophage apoptosis and TNF-alpha release were independent of MTb phagocytosis. Whereas surface expression of macrophage TLR2 and TLR4 was preserved, IL-1 receptor associated kinase-1 phosphorylation and NF-kappaB nuclear translocation were reduced in HIV(+) U1 macrophages in response to iMTbRv. These findings were confirmed using clinically relevant human alveolar macrophages (AM) from healthy persons and asymptomatic HIV(+) persons at clinical risk for MTb infection. Furthermore, in vitro HIV infection of AM from healthy persons reduced both TNF-alpha release and AM apoptosis in response to iMTbRv. These data identify an intrinsic specific defect in a critical macrophage cellular response to MTb that may contribute to disease pathogenesis in HIV(+) persons.
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. npatel@bidmc.harvard.edu
authors.forename: Naimish R
authors.initials: NR
authors.lastname: Patel
authors.forename: Jinping
authors.initials: J
authors.lastname: Zhu
authors.forename: Souvenir D
authors.initials: SD
authors.lastname: Tachado
authors.forename: Jianmin
authors.initials: J
authors.lastname: Zhang
authors.forename: Zhi
authors.initials: Z
authors.lastname: Wan
authors.forename: Jussi
authors.initials: J
authors.lastname: Saukkonen
authors.forename: Henry
authors.initials: H
authors.lastname: Koziel
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000276:immunology; D017209:Apoptosis / Q000276:immunology*; D002467:Cell Nucleus / Q000276:immunology / Q000378:metabolism; D005260:Female; D006678:HIV / Q000276:immunology*; D015658:HIV Infections / Q000150:complications / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000276:immunology*; D008297:Male; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D010587:Phagocytosis / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism; D014376:Tuberculosis / Q000209:etiology / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D020298:U937 Cells
chemical_list: D016328:NF-kappa B; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha