bacterial pathogenesis: cheating death

1
NATURE REVIEWS | MICROBIOLOGY VOLUME 2 | DECEMBER 2004 | 1 Obligate intracellular pathogens, such as Chlamydia, reside and replicate in the relative safety of cytoplasmic vesi- cles. But infected cells often burst this cytoplasmic bubble by committing altruistic suicide through the induc- tion of apoptosis. Now, a recent study in the Journal of Experimental Medicine shows that Chlamydia can inhibit this programmed cell death by eliminating pro-apoptotic proteins. To investigate the molecular mechanisms used by Chlamydia to modulate apoptosis, Georg Häcker and colleagues exposed both Chlamydia-infected and uninfected human cells to UV irradiation. UV irradiation activates pro-apoptotic proteins such as BIM, which in turn activates BAX and BAK. The pathway culminates with the release of cytochrome c from the mitochondria and the induction of the deadly cas- pase cascade. As expected, cells that had been infected with Chlamydia were pro- tected against UV-induced apoptosis. Importantly, cytochrome c was retained in the mitochondria in these cells, in contrast to control cells, which showed cytosolic staining with anti-cytochrome-c antibodies. Infected cells had normal amounts of BAX/BAK protein — the mediators of cytochrome-c release — but the level of activated protein was reduced. So, Fischer et al. turned their attention to the BH3-only protein BIM, and made the startling discov- ery that, despite normal expression of BIM mRNA, the protein had “almost completely disappeared from Chlamydia-infected cells”. The same was true for two other BH3-only pro- teins, PUMA and BAD, and experi- ments using a proteolytic inhibitor implicated the proteosome as the agent of destruction. In normal cells, BIM is protected from activation by sequestration to the cytoskeleton, and disruption of cellular architecture by intracellular infection might release the protein and induce apoptosis. By destroying BIM, Chlamydia prevents host-cell death, thereby ensuring its own sur- vival. Shannon Amoils References and links ORIGINAL RESEARCH PAPER Fischer, S. F. et al. Chlamydia inhibit host cell apoptosis by degradation of proapoptotic BH3-only proteins. J. Exp. Med. 200, 905–916 (2004) FURTHER READING Byrne, G. I. & Ojcius D. M. Chlamydia and apoptosis: life and death decisions of an intracellular pathogen. Nature Rev. Microbiol. 2, 802–808 (2004) Cheating death BACTERIAL PATHOGENESIS RESEARCH HIGHLIGHTS URLS for online links Swiss-Prot http://us.expasy.org/sprot/ BAD http://us.expasy.org/cgi- bin/niceprot.pl?Q92934 BAK http://us.expasy.org/cgi- bin/niceprot.pl?Q16611 BIM http://us.expasy.org/cgi- bin/niceprot.pl?O43521 Entrez: http://www.ncbi.nlm.nih.gov/entrez/ query.fcgi?db=gene BAX http://www.ncbi.nlm.nih.gov/entrez/ query.fcgi?db=gene&cmd=Retrieve &dopt=Graphics&list_uids=581

Upload: shannon

Post on 29-Jul-2016

213 views

Category:

Documents


1 download

TRANSCRIPT

NATURE REVIEWS | MICROBIOLOGY VOLUME 2 | DECEMBER 2004 | 1

Obligate intracellular pathogens, suchas Chlamydia, reside and replicate inthe relative safety of cytoplasmic vesi-cles. But infected cells often burst thiscytoplasmic bubble by committingaltruistic suicide through the induc-tion of apoptosis. Now, a recent studyin the Journal of ExperimentalMedicine shows that Chlamydia caninhibit this programmed cell death byeliminating pro-apoptotic proteins.

To investigate the molecularmechanisms used by Chlamydia tomodulate apoptosis, Georg Häckerand colleagues exposed bothChlamydia-infected and uninfectedhuman cells to UV irradiation. UVirradiation activates pro-apoptoticproteins such as BIM, which in turnactivates BAX and BAK. The pathwayculminates with the release ofcytochrome c from the mitochondriaand the induction of the deadly cas-pase cascade.

As expected, cells that had beeninfected with Chlamydia were pro-tected against UV-induced apoptosis.Importantly, cytochrome c wasretained in the mitochondria in thesecells, in contrast to control cells,which showed cytosolic staining withanti-cytochrome-c antibodies.Infected cells had normal amounts ofBAX/BAK protein — the mediatorsof cytochrome-c release — but thelevel of activated protein wasreduced.

So, Fischer et al. turned theirattention to the BH3-only proteinBIM, and made the startling discov-ery that, despite normal expression of

BIM mRNA, the protein had “almostcompletely disappeared fromChlamydia-infected cells”. The samewas true for two other BH3-only pro-teins, PUMA and BAD, and experi-ments using a proteolytic inhibitorimplicated the proteosome as theagent of destruction.

In normal cells, BIM is protectedfrom activation by sequestration tothe cytoskeleton, and disruption ofcellular architecture by intracellularinfection might release the proteinand induce apoptosis. By destroyingBIM, Chlamydia prevents host-celldeath, thereby ensuring its own sur-vival.

Shannon AmoilsReferences and links

ORIGINAL RESEARCH PAPER Fischer, S. F. etal. Chlamydia inhibit host cell apoptosis bydegradation of proapoptotic BH3-only proteins. J.Exp. Med. 200, 905–916 (2004) FURTHER READING Byrne, G. I. & Ojcius D. M.Chlamydia and apoptosis: life and death decisionsof an intracellular pathogen. Nature Rev. Microbiol.2, 802–808 (2004)

Cheating death

B A C T E R I A L PAT H O G E N E S I S

RESEARCH

HIGHLIGHTS

URLS for online linksSwiss-Prot http://us.expasy.org/sprot/BADhttp://us.expasy.org/cgi-bin/niceprot.pl?Q92934BAKhttp://us.expasy.org/cgi-bin/niceprot.pl?Q16611BIMhttp://us.expasy.org/cgi-bin/niceprot.pl?O43521

Entrez:http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene BAXhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=581