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Chlamydia trachomatis-infected host cells resist dsRNA-induced apoptosis.
Cell Microbiol. 2010 Sep 1; 12(9):1340-51
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13 Oct 2010
Interesting Hypothesis, New Finding
DOI: 10.3410/f.5397956.5431066
Böhme et al. describe a novel anti-apoptotic mechanism in Chlamydia-infected cells. These cells are resistant to dsRNA-induced apoptosis, which is dependent on the caspase-8 modulator cFlip.
Apoptosis is a form of programmed cell death that is an essential component of the innate immune system so as...Continue reading
Apoptosis is a form of programmed cell death that is an essential component of the innate immune system so as...Continue reading
Böhme et al. describe a novel anti-apoptotic mechanism in Chlamydia-infected cells. These cells are resistant to dsRNA-induced apoptosis, which is dependent on the caspase-8 modulator cFlip.
Apoptosis is a form of programmed cell death that is an essential component of the innate immune system so as to prevent the spread of infection. Several pathogens have evolved mechanisms to manipulate this host cell defense in order to survive and replicate. Obligate intracellular pathogens such as Chlamydia spp. have developed anti-apoptotic strategies to be able to colonize host cells, leading to chronic infection. Several studies have shown that Chlamydia-infected cells are resistant to several forms of apoptosis upstream of the mitochondria. In this paper, the authors describe a novel anti-apoptotic mechanism in which Chlamydia trachomatis-infected cells are resistant to dsRNA. Utilizing synthetic dsRNA (polyl:C) that mimics viral infections, Böhme et al. clearly show that Chlamydia-infected cells have decreased caspase-8, caspase-9 and caspase-3 cleavage products, as well as decreased caspase activity. Surprisingly, treatment of Chlamydia-infected cells with tumor necrosis factor (TNF)-alpha led to caspase-8 activation. This result suggested that C. trachomatis blocks apoptosis, with distinct mechanisms depending on the stimuli. Previous studies indicated that polyl:C induces apoptosis through the dsRNA-dependent protein kinase (PKR) leading to caspase-8 activation. The initial hypothesis by Böhme et al. was that Chlamydia directly inhibited PKR, leading to apoptotic resistance. However, both PKR and eIF2-alpha were still activated in Chlamydia-infected cells. Upon further investigation, this group found that cFlip, a modulator of caspase-8, is necessary for the prevention of dsRNA-dependent apoptosis. The exact mechanism by which Chlamydia interferes with cFlip remains unknown; however, the authors suggest that an unidentified Chlamydia effector protein affects local cFlip activity, which prevents dsRNA-dependent apoptosis.
Apoptosis is a form of programmed cell death that is an essential component of the innate immune system so as to prevent the spread of infection. Several pathogens have evolved mechanisms to manipulate this host cell defense in order to survive and replicate. Obligate intracellular pathogens such as Chlamydia spp. have developed anti-apoptotic strategies to be able to colonize host cells, leading to chronic infection. Several studies have shown that Chlamydia-infected cells are resistant to several forms of apoptosis upstream of the mitochondria. In this paper, the authors describe a novel anti-apoptotic mechanism in which Chlamydia trachomatis-infected cells are resistant to dsRNA. Utilizing synthetic dsRNA (polyl:C) that mimics viral infections, Böhme et al. clearly show that Chlamydia-infected cells have decreased caspase-8, caspase-9 and caspase-3 cleavage products, as well as decreased caspase activity. Surprisingly, treatment of Chlamydia-infected cells with tumor necrosis factor (TNF)-alpha led to caspase-8 activation. This result suggested that C. trachomatis blocks apoptosis, with distinct mechanisms depending on the stimuli. Previous studies indicated that polyl:C induces apoptosis through the dsRNA-dependent protein kinase (PKR) leading to caspase-8 activation. The initial hypothesis by Böhme et al. was that Chlamydia directly inhibited PKR, leading to apoptotic resistance. However, both PKR and eIF2-alpha were still activated in Chlamydia-infected cells. Upon further investigation, this group found that cFlip, a modulator of caspase-8, is necessary for the prevention of dsRNA-dependent apoptosis. The exact mechanism by which Chlamydia interferes with cFlip remains unknown; however, the authors suggest that an unidentified Chlamydia effector protein affects local cFlip activity, which prevents dsRNA-dependent apoptosis.
Disclosures
None declared
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Brumell J and Brabant D: F1000Prime Recommendation of [Böhme L et al., Cell Microbiol 2010, 12(9):1340-51]. In F1000Prime, 13 Oct 2010; DOI: 10.3410/f.5397956.5431066. F1000Prime.com/5397956#eval5431066
F1000Prime Recommendations, Dissents and Comments for [Böhme L et al., Cell Microbiol 2010, 12(9):1340-51]. In F1000Prime, 25 May 2013; F1000Prime.com/5397956
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Human pathogenic Chlamydia trachomatis have evolved sophisticated mechanisms to manipulate host cell signalling pathways in order to prevent apoptosis. We show here that host cells infected with C. trachomatis resist apoptosis induced by polyI:C, a synthetic double-stranded RNA that mimics viral infections. Infected cells displayed significantly reduced levels of PARP cleavage, caspase-3 activation and a decrease in the TUNEL positive population in the presence of polyI:C. Interestingly, the chlamydial block of apoptosis was upstream of the initiator caspase-8. Processing of caspase-8 was reduced in infected cells and coincided with a decrease in Bid truncation and downstream caspase-9 cleavage. Moreover, the enzymatic activity of caspase-8, measured by a luminescent substrate, was significantly reduced in infected cells. Caspase-8 inhibition by Chlamydia was dependent on cFlip as knock-down of cFlip decreased the chlamydial block of caspase-8 activation and consequently reduced apoptosis inhibition. Our data implicate that chlamydial infection interferes with the host cell's response to viral infections and thereby influences the fate of the cell.
DOI: 10.1111/j.1462-5822.2010.01473.x
PMID: 20482554
