An epistatic effect of apaf-1 and caspase-9 on chlamydial infection.
Chlamydia is an obligate intracellular bacterial pathogen that replicates solely within a membrane-bound vacuole termed an inclusion. Chlamydia seems to perturb multiple cellular processes of the host, such as, rearrangement of the membrane trafficking system for its intracellular multiplication, and inhibition of host cell apoptosis for persistent infection. In an attempt to clarify host factor involvement in apoptosis regulation, we found that inhibition of Caspase-9 restricted, while Apaf-1 promoted, Chlamydia pneumoniae infection in HEp-2, HeLa, and mouse epithelial fibroblast (MEF) cells. These opposition contributions to the chlamydial infection were confirmed using caspase-9 (-/-) and apaf-1 (-/-) MEFs. Similar phenomena also appeared in the case of infection with Chlamydia trachomatis. Interestingly, caspase-9 in apaf-1 (-/-) MEFs was activated by chlamydial infection but during the infection caspase-3 was not activated. That is, caspase-9 was activated without support for multiplication and activation by Apaf-1, and the activated caspase-9 may be physically disconnected from the caspase cascade. This may be partially explained by the observation of caspase-9 accumulation within chlamydial inclusions. The sequestration of caspase-9 by chlamydia seems to result in apoptosis repression, which is crucial for the chlamydial development cycle. Because Apaf-1 shares domains with intracellular innate immune receptor NOD1, it may play a key role in the strategy to regulate chlamydial infection.
Department of Microbiology and Immunology, Yamaguchi University School of Medicine, 1-1-1, Minamikogushi, Ube, Yamaguchi, 755-8505, Japan.
Mohd Akhlakur
MA
Rahman
Mutsunori
M
Shirai
Md Abdul
MA
Aziz
Rie
R
Ushirokita
Sayuri
S
Kubota
Harumi
H
Suzuki
Yoshinao
Y
Azuma
D000818:Animals; D017209:Apoptosis; D053477:Apoptotic Protease-Activating Factor 1 / Q000235:genetics* / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D002689:Chlamydia / Q000378:metabolism*; D002690:Chlamydia Infections / Q000378:metabolism*; D004198:Disease Susceptibility / Q000378:metabolism; D004843:Epistasis, Genetic; D004847:Epithelial Cells / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D055786:Gene Knockout Techniques; D054884:Host-Pathogen Interactions; D006801:Humans; D051379:Mice
C506592:APAF1 protein, human; C506593:Apaf1 protein, mouse; D053477:Apoptotic Protease-Activating Factor 1; D053148:Caspase 3; D053453:Caspase 9