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Gan, Huixian

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Gan

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Huixian

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Gan, Huixian

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2008 - 200912010 - 20171

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Author's Publications: search.filters.isAuthorOfPublication.fb696edb-04c9-4069-8d36-2639c14b9f90

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    Mycobacterium tuberculosis blocks annexin-1 crosslinking and thus apoptotic envelope completion on infected cells to maintain virulence
    (2017) Gan, Huixian; Lee, Jinhee; Ren, Fucheng; Chen, Minjian; Kornfeld, Hardy; Remold, Heinz
    Macrophages infected with attenuated Mycobacterium tuberculosis strain H37Ra become apoptotic, limiting bacterial replication and facilitating antigen presentation. Here, we demonstrate that cells infected with H37Ra became apoptotic after formation of an apoptotic envelope on their surface was complete. This process required exposure of phosphatidylserine on the cell surface followed by deposition of the phospholipid-binding protein annexin-1 and then transglutaminase-mediated crosslinking of annexin-1 via its N-terminal domain. In macrophages infected with virulent strain H37Rv, in contrast, the N-terminal domain of annexin-1 was removed by proteolysis thus preventing completion of the apoptotic envelope, which results in macrophage death by necrosis. Host defense of virulent Mycobacterium tuberculosis thus occurs by failure to form the apoptotic envelope, which leads to macrophage necrosis and dissemination of infection in the lung.
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    Lipid Mediators in Innate Immunity Against Tuberculosis: Opposing Roles of PGE2 and LXA4 in the Induction of Macrophage Death
    (Rockefeller University Press, 2008) Chen, Minjian; Divangahi, Maziar; Gan, Huixian; Shin, Daniel S.J.; Hong, Song; Lee, David Marvin; Serhan, Charles; Behar, Samuel M.; Remold, Heinz
    Virulent Mycobacterium tuberculosis (Mtb) induces a maladaptive cytolytic death modality, necrosis, which is advantageous for the pathogen. We report that necrosis of macrophages infected with the virulent Mtb strains H37Rv and Erdmann depends on predominant LXA4 production that is part of the antiinflammatory and inflammation-resolving action induced by Mtb. Infection of macrophages with the avirulent H37Ra triggers production of high levels of the prostanoid PGE2, which promotes protection against mitochondrial inner membrane perturbation and necrosis. In contrast to H37Ra infection, PGE2 production is significantly reduced in H37Rv-infected macrophages. PGE2 acts by engaging the PGE2 receptor EP2, which induces cyclic AMP production and protein kinase A activation. To verify a role for PGE2 in control of bacterial growth, we show that infection of prostaglandin E synthase (PGES)−/− macrophages in vitro with H37Rv resulted in significantly higher bacterial burden compared with wild-type macrophages. More importantly, PGES−/− mice harbor significantly higher Mtb lung burden 5 wk after low-dose aerosol infection with virulent Mtb. These in vitro and in vivo data indicate that PGE2 plays a critical role in inhibition of Mtb replication.