title: Induction of serine protease inhibitor 9 by Mycobacterium tuberculosis inhibits apoptosis and promotes survival of infected macrophages.
abstract: Our recent microarray analysis of infected human alveolar macrophages (AMs) found serine protease inhibitor 9 (PI-9) to be the most prominently expressed of a cluster of apoptosis-associated genes induced by virulent Mycobacterium tuberculosis. In the current study, we show that induction of PI-9 occurs within hours of infection with M. tuberculosis H37Rv and is maintained through 7 days of infection in both AMs and blood monocytes. Inhibition of PI-9 by small inhibitory RNA decreased M. tuberculosis-induced expression of the antiapoptotic molecule Bcl-2 and resulted in a corresponding increase in production of caspase 3, a terminal effector molecule of apoptosis. Further, PI-9 small inhibitory RNA mediated a significant reduction in the subsequent survival of M. tuberculosis within AMs. Thus PI-9 induction within human mononuclear phagocytes by virulent M. tuberculosis serves to protect these primary targets of infection from elimination by apoptosis and thereby promotes intracellular survival of the organism.
authors.affiliation: Divisions of Infectious Diseases, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Toossi
authors.forename: Mianda
authors.initials: M
authors.lastname: Wu
authors.forename: Roxana
authors.initials: R
authors.lastname: Rojas
authors.forename: Barbara
authors.initials: B
authors.lastname: Kalsdorf
authors.forename: Htin
authors.initials: H
authors.lastname: Aung
authors.forename: Christina S
authors.initials: CS
authors.lastname: Hirsch
authors.forename: Jessica
authors.initials: J
authors.lastname: Walrath
authors.forename: Angela
authors.initials: A
authors.lastname: Wolbink
authors.forename: Marieke
authors.initials: M
authors.lastname: van Ham
authors.forename: Richard F
authors.initials: RF
authors.lastname: Silver
mesh_terms: D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D016676:Macrophages, Alveolar / Q000378:metabolism* / Q000382:microbiology; D009000:Monocytes / Q000378:metabolism / Q000382:microbiology; D009169:Mycobacterium tuberculosis / Q000472:pathogenicity*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015843:Serpins / Q000378:metabolism*
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; C102316:SERPINB9 protein, human; D015843:Serpins; D053148:Caspase 3
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