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Evidence for genes associated with the ability of Mycobacterium avium subsp. hominissuis to escape apoptotic macrophages.

Bermudez LE, Danelishvili L, Babrack L, Pham T - Front Cell Infect Microbiol (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Sciences, College of Veterinary Medicine, Oregon State University Corvallis, OR, USA ; Department of Microbiology, College of Science, Oregon State University Corvallis, OR, USA ; Program of Molecular and Cell Biology, Oregon State University Corvallis, OR, USA.

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.

No MeSH data available.


Related in: MedlinePlus

C57/BL6 black mice were infected with MAH (WT and mutants) and the course of bacterial infection was monitored for 3 weeks. *p < 0.05 compared with the number of bacteria in mice infected with the WT MAC104.
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Figure 2: C57/BL6 black mice were infected with MAH (WT and mutants) and the course of bacterial infection was monitored for 3 weeks. *p < 0.05 compared with the number of bacteria in mice infected with the WT MAC104.

Mentions: To determine whether the identified mutants were attenuated in mice, C57BL/six black mice were infected intravenously and 10 mice were harvested after 3 weeks. The spleens were obtained and the viable bacterial number determined after plating. As seen in Figure 2, while the number of bacteria in MAC 104 infected mice increased over time, none of the mutants showed ability to grow in the mouse tissue in a manner comparable to the WT bacteria.


Evidence for genes associated with the ability of Mycobacterium avium subsp. hominissuis to escape apoptotic macrophages.

Bermudez LE, Danelishvili L, Babrack L, Pham T - Front Cell Infect Microbiol (2015)

C57/BL6 black mice were infected with MAH (WT and mutants) and the course of bacterial infection was monitored for 3 weeks. *p < 0.05 compared with the number of bacteria in mice infected with the WT MAC104.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4548235&req=5

Figure 2: C57/BL6 black mice were infected with MAH (WT and mutants) and the course of bacterial infection was monitored for 3 weeks. *p < 0.05 compared with the number of bacteria in mice infected with the WT MAC104.
Mentions: To determine whether the identified mutants were attenuated in mice, C57BL/six black mice were infected intravenously and 10 mice were harvested after 3 weeks. The spleens were obtained and the viable bacterial number determined after plating. As seen in Figure 2, while the number of bacteria in MAC 104 infected mice increased over time, none of the mutants showed ability to grow in the mouse tissue in a manner comparable to the WT bacteria.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Sciences, College of Veterinary Medicine, Oregon State University Corvallis, OR, USA ; Department of Microbiology, College of Science, Oregon State University Corvallis, OR, USA ; Program of Molecular and Cell Biology, Oregon State University Corvallis, OR, USA.

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.

No MeSH data available.


Related in: MedlinePlus