Abstract
Mycobacterium avium subsp. hominissuis (MAH) is an environmental bacteria that infects immunocompromised humans. MAH cases are increasing in incidence, making it crucial to gain knowledge of the pathogenic mechanisms associated with the bacterium. MAH infects macrophages and after several days the infection triggers the phagocyte apoptosis. Many of the intracellular MAH escape the cell undergoing apoptosis leading to infection of neighboring macrophages. We screened a transposon bank of MAH mutants in U937 mononuclear phagocytes for the inability to escape macrophages undergoing apoptosis. Mutations in genes; MAV_2235, MAV_2120, MAV_2410, and MAV_4563 resulted in the inability of the bacteria to exit macrophages upon apoptosis. Complementation of the mutations corrected the phenotype either completely or partially. Testing for the ability of the mutants to survive in macrophages compared to the wild-type bacterium revealed that the mutant clones were not attenuated up to 4 days of infection. Testing in vivo, however, demonstrated that all the MAH clones were attenuated compared with the wild-type MAC 104 in tissues of mice. Although the mechanism associated with the bacterial inability to leave apoptotic macrophages is unknown, the identification of macrophage cytoplasm targets for the MAH proteins suggest that they interfere either with protein degradation machinery or post-translation mechanisms. The identification of tatC as a MAH protein involved in the ability of MAH to leave macrophages, suggests that secreted effector(s) are involved in the process. The study reveals a pathway of escape from macrophages, not shared with Mycobacterium tuberculosis.
Highlights
Mycobacterium avium subsp. hominissuis (MAH) is an environmental bacterium that can infect the human host causing both lung pathology and disseminated disease (Falkinham, 1996)
Several studies in the Mycobacterium tuberculosis field have demonstrated that bacterium in many occasions can inhibit macrophage-triggered apoptosis (Danelishvili et al, 2003; Velmurugan et al, 2007), and recent findings have shown, at least in one model, that M. avium subsp. paratuberculosis infection is associated with suppression of apoptosis (Kabara and Coussens, 2012)
Screening for Clones That Were Unable to Exit Apoptotic Macrophages Past work has demonstrated that once macrophages are infected with MAH for 4 or more days, they begin undergoing apoptosis, followed by many bacteria leaving the cell (Early et al, 2011)
Summary
Mycobacterium avium subsp. hominissuis (MAH) is an environmental bacterium that can infect the human host causing both lung pathology and disseminated disease (Falkinham, 1996). The bacterium inhibits the acidification of the mycobacterial vacuole, as well as the fusion of phagasomes with lysosomes (Sturgill-Koszycki et al, 1994) and delivery of toxic elements to the vacuole environment. It appears that as the last resource, to be able to eliminate the pathogen, M. avium-infected macrophages undergo apoptosis (Early et al, 2011). Several studies in the Mycobacterium tuberculosis field have demonstrated that bacterium in many occasions can inhibit macrophage-triggered apoptosis (Danelishvili et al, 2003; Velmurugan et al, 2007), and recent findings have shown, at least in one model, that M. avium subsp. Work by Lee et al (2006) demonstrated that infection of macrophages with M.tuberculosis using a high MOI resulted in cell death by pyroptosis, while infection low MOI inhibited apoptosis
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