TitleSecreted Mycobacterium tuberculosis Rv3654c and Rv3655c proteins participate in the suppression of macrophage apoptosis.
Publication TypeJournal Article
Year of Publication2010
AuthorsDanelishvili, L, Yamazaki, Y, Selker, J, Bermudez, LE
JournalPLoS One
Date Published2010 May 04
KeywordsAmino Acid Sequence, Animals, Apoptosis, Bacterial Proteins, Cell Line, Cell Survival, DNA Transposable Elements, Genetic Complementation Test, Genetic Testing, Humans, Macrophages, Mice, Molecular Sequence Data, Mutation, Mycobacterium tuberculosis, Necrosis, Phenotype, RNA, Small Interfering, Signal Transduction, Transfection, Tuberculosis, Tumor Necrosis Factor-alpha

BACKGROUND: Inhibition of macrophage apoptosis by Mycobacterium tuberculosis has been proposed as one of the virulence mechanisms whereby the pathogen avoids the host defense. The mechanisms by which M. tuberculosis H37Rv strain suppress apoptosis and escapes human macrophage killing was investigated.

METHODOLOGY/PRINCIPAL FINDINGS: The screening of a transposon mutant bank identified several mutants, which, in contrast to the wild-type bacterium, had impaired ability to inhibit apoptosis of macrophages. Among the identified genes, Rv3659c (31G12 mutant) belongs to an operon reminiscent of type IV pili. The Rv3654c and Rv3655c putative proteins in a seven-gene operon are secreted into the macrophage cytoplasm and suppress apoptosis by blocking the extrinsic pathway. The operon is highly expressed when the bacterium is within macrophages, compared to the expression level in the extracellular environment. Rv3654c recognizes the polypyrimidine tract binding Protein-associated Splicing Factor (PSF) and cleaves it, diminishing the availability of caspase-8. While M. tuberculosis inhibits apoptosis by the extrinsic pathway, the pathogen does not appear to affect the intrinsic pathway. Inactivation of the intrinsic pathway by pharmacologic agents afftects M. tuberculosis and induces cell necrosis. Likewise, inactivation of PSF by siRNA significantly decreased the level of caspase-8 in macrophages.

CONCLUSION: While M. tuberculosis inhibits the extrinsic pathway of apoptosis, it appears to activate the intrinsic pathway leading to macrophage necrosis as a potential exit strategy.

Alternate JournalPLoS One
PubMed ID20454556
PubMed Central IDPMC2864267
Grant ListP30 ES000210 / ES / NIEHS NIH HHS / United States
R21 AI064018 / AI / NIAID NIH HHS / United States
P30 ES00210 / ES / NIEHS NIH HHS / United States
R21-AI064018 / AI / NIAID NIH HHS / United States