Mycobacterium tuberculosis blocks crosslinking of annexin-1 and apoptotic envelope formation on infected macrophages to maintain virulence

Heinz G Remold, et al. Nature Immunology. 9:1189-97, 2008

Student: Yun-Ju Song (宋昀儒)                                               Time: 14:00~15:00, Dec. 31, 2008

Commentator: Dr. Chi-Chang Shieh (謝奇璋 老師)              Place: Room 601

Abstract:

    Mycobacterium tuberculosis (Mtb), the causative agent of pulmonary tuberculosis, is a highly adapted human pathogen that has evolved to employ multiple strategies in its attempt to avoid an efficient host immune response. Infection with attenuated Mtb strain H37Ra induced predominantly apoptosis¹, including apoptotic envelope formation that did not seem in virulent Mtb strain H37Rv infected macrophage replacing by necrosis². The process involves the exposure of phosphatidylserine (PS) from inner to outer cell membrane, phospholipid-binding protein annexin-1 recruited from the cytosol to cell surface and then colocalized with PS in Ca²⁺ dependent way³ followed by tissue transglutaminase (tTG)-mediated crosslinking. The phenomenon also existed in mouse macrophage RAW264.7 with etoposide-induced apoptosis. In contrast, infection of macrophage with H37Rv resulted in the decreased synthesis of plasminogen activator inhibitor type 2 (PAI2), which decreased the protease activity of tTG and then more proteolytic cleavage in amino-terminal domain of annexin-1. The truncation of crosslinking annexin-1 blocked apoptotic envelope formation and resulted in macrophage death by necrosis that release viable bacilli to spread infection and promote tissue damage characteristic of advanced tuberculosis disease. Those results were confirmed by in vivo experiments. In mice challenged by tracheal instillation of virulent H37Rv, which interfered in apoptotic envelope formation and led to more necrotic cells producing that could provid a proinflammatory necrotic milieu for altering pulmonary leukocyte population and production of inflammatory chemokines.

References:

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2.            Park, J.S. et al. Virulent clinical isolates of Mycobacterium tuberculosis grow rapidly and induce cellular necrosis but minimal apoptosis in murine macrophages. J. Leukoc. Biol. 79, 80–86 (2006).

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