title: Protein phosphatase, Mg2+/Mn2+-dependent 1A controls the innate antiviral and antibacterial response of macrophages during HIV-1 and Mycobacterium tuberculosis infection.
abstract: Co-infection with HIV-1 and Mycobacterium tuberculosis (Mtb) is a major public health issue. While some research has described how each pathogen accelerates the course of infection of the other pathogen by compromising the immune system, very little is known about the molecular biology of HIV-1/Mtb co-infection at the host cell level. This is somewhat surprising, as both pathogens are known to replicate and persist in macrophages. We here identify Protein Phosphatase, Mg2+/Mn2+-dependent 1A (PPM1A) as a molecular link between Mtb infection and increased HIV-1 susceptibility of macrophages. We demonstrate that both Mtb and HIV-1 infection induce the expression of PPM1A in primary human monocyte/macrophages and THP-1 cells. Genetic manipulation studies revealed that increased PPMA1 expression rendered THP-1 cells highly susceptible to HIV-1 infection, while depletion of PPM1A rendered them relatively resistant to HIV-1 infection. At the same time, increased PPM1A expression abrogated the ability of THP-1 cells to respond to relevant bacterial stimuli with a proper cytokine/chemokine secretion response, blocked their chemotactic response and impaired their ability to phagocytose bacteria. These data suggest that PPM1A, which had previously been shown to play a role in the antiviral response to Herpes Simplex virus infection, also governs the antibacterial response of macrophages to bacteria, or at least to Mtb infection. PPM1A thus seems to play a central role in the innate immune response of macrophages, implying that host directed therapies targeting PPM1A could be highly beneficial, in particular for HIV/Mtb co-infected patients.
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Jim
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Kaitlyn
authors.initials: K
authors.lastname: Schaaf
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Duverger
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Wolschendorf
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.|Department of Medical Microbiology and Infection Control, VU University Medical Center, Amsterdam, Netherlands.
authors.forename: Alexander
authors.initials: A
authors.lastname: Speer
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Frederic
authors.initials: F
authors.lastname: Wagner
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Niederweis
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Olaf
authors.initials: O
authors.lastname: Kutsch
mesh_terms: D060085:Coinfection / Q000276:immunology*; D015658:HIV Infections / Q000150:complications / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology; D009169:Mycobacterium tuberculosis / Q000276:immunology; D000071636:Protein Phosphatase 2C / Q000276:immunology*; D000074084:THP-1 Cells; D014376:Tuberculosis / Q000150:complications / Q000276:immunology*
chemical_list: C000607456:PPM1A protein, human; D000071636:Protein Phosphatase 2C
keywords: HIV-1; Immune response; Immunity; Immunology and Microbiology Section; Mycobacterium tuberculosis; PPM1A; macrophages; persistent infection