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.
Highlights
As gatekeepers of the innate immunity, macrophages contribute significantly to Human Immunodeficiency Virus-1 (HIV-1) pathogenesis throughout the course of viral infection
Standard experimental protocols that use differentiated macrophages do not reproduce the formation of Mycobacterium tuberculosis (Mtb)/macrophage aggregates, it is these aggregate structures or granulomas that have been reported to host persistent Mtb infection and that serve as the interface for Mtb and HIV-1 co-infection [28,29,30]
We reasoned that direct Mtb infection of primary monocytes with a high MOI would increase the likelihood of Mtb/macrophage aggregate formation
Summary
As gatekeepers of the innate immunity, macrophages contribute significantly to Human Immunodeficiency Virus-1 (HIV-1) pathogenesis throughout the course of viral infection. Compared to our vast understanding of HIV1 pathogenesis in T cells, relatively little is known about HIV-1 infection in macrophages. This is true in the setting of HIV-1 and Mycobacterium tuberculosis (Mtb) co-infection. We demonstrate how Mtb infection boosted the expression of Protein Phosphatase, Mg2+/Mn2+ Dependent 1A (PPM1A) in macrophages, a phenotype that undermined the intrinsic antiviral cellular response to promote HIV-1 infection. In the context of HIV-1/Mtb co-infection, our results suggest that infection by either pathogen will enforce phenotypic biomolecular changes that render macrophages into highly vulnerable targets for HIV-1 or Mtb infection, a process that is linked at the molecular level by the pathogen-induced up-regulation of PPM1A expression
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