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Genetic Screen in Chlamydia muridarum Reveals Role for an Interferon-Induced Host Cell Death Program in Antimicrobial Inclusion Rupture.

dc.contributor.author Coers, Jorn
dc.contributor.author Giebel, Amanda M
dc.contributor.author Hu, Shuai
dc.contributor.author Rajaram, Krithika
dc.contributor.author Finethy, Ryan
dc.contributor.author Toh, Evelyn
dc.contributor.author Brothwell, Julie A
dc.contributor.author Morrison, Sandra G
dc.contributor.author Suchland, Robert J
dc.contributor.author Stein, Barry D
dc.contributor.author Morrison, Richard P
dc.contributor.author Nelson, David E
dc.date.accessioned 2019-05-01T20:35:29Z
dc.date.available 2019-05-01T20:35:29Z
dc.date.issued 2019-04-09
dc.identifier mBio.00385-19
dc.identifier.issn 2150-7511
dc.identifier.issn 2150-7511
dc.identifier.uri https://hdl.handle.net/10161/18525
dc.description.abstract Interferon-regulated immune defenses protect mammals from pathogenically diverse obligate intracellular bacterial pathogens of the genus Chlamydia Interferon gamma (IFN-γ) is especially important in controlling the virulence of Chlamydia species and thus impacts the modeling of human chlamydial infection and disease in mice. How IFN-γ contributes to cell-autonomous defenses against Chlamydia species and how these pathogens evade IFN-γ-mediated immunity in their natural hosts are not well understood. We conducted a genetic screen which identified 31 IFN-γ-sensitive (Igs) mutants of the mouse model pathogen Chlamydia muridarum Genetic suppressor analysis and lateral gene transfer were used to map the phenotype of one of these mutants, Igs4, to a missense mutation in a putative chlamydial inclusion membrane protein, TC0574. We observed the lytic destruction of Igs4-occupied inclusions and accompanying host cell death in response to IFN-γ priming or various proapoptotic stimuli. However, Igs4 was insensitive to IFN-γ-regulated cell-autonomous defenses previously implicated in anti-Chlamydia trachomatis host defense in mice. Igs4 inclusion integrity was restored by caspase inhibitors, indicating that the IFN-γ-mediated destruction of Igs4 inclusions is dependent upon the function of caspases or related prodeath cysteine proteases. We further demonstrated that the Igs4 mutant is immune restricted in an IFN-γ-dependent manner in a mouse infection model, thereby implicating IFN-γ-mediated inclusion destruction and host cell death as potent in vivo host defense mechanisms to which wild-type C. muridarum is resistant. Overall, our results suggest that C. muridarum evolved resistance mechanisms to counter IFN-γ-elicited programmed cell death and the associated destruction of intravacuolar pathogens.IMPORTANCE Multiple obligatory intracellular bacteria in the genus Chlamydia are important pathogens. In humans, strains of C. trachomatis cause trachoma, chlamydia, and lymphogranuloma venereum. These diseases are all associated with extended courses of infection and reinfection that likely reflect the ability of chlamydiae to evade various aspects of host immune responses. Interferon-stimulated genes, driven in part by the cytokine interferon gamma, restrict the host range of various Chlamydia species, but how these pathogens evade interferon-stimulated genes in their definitive host is poorly understood. Various Chlamydia species can inhibit death of their host cells and may have evolved this strategy to evade prodeath signals elicited by host immune responses. We present evidence that chlamydia-induced programmed cell death resistance evolved to counter interferon- and immune-mediated killing of Chlamydia-infected cells.
dc.language eng
dc.publisher American Society for Microbiology
dc.relation.ispartof mBio
dc.relation.isversionof 10.1128/mBio.00385-19
dc.subject Chlamydia
dc.subject host-pathogen interactions
dc.subject interferon-stimulated genes
dc.subject intracellular pathogens
dc.subject molecular genetics
dc.title Genetic Screen in Chlamydia muridarum Reveals Role for an Interferon-Induced Host Cell Death Program in Antimicrobial Inclusion Rupture.
dc.type Journal article
dc.date.updated 2019-05-01T20:35:23Z
pubs.issue 2
pubs.organisational-group School of Medicine
pubs.organisational-group Duke
pubs.organisational-group Immunology
pubs.organisational-group Basic Science Departments
pubs.organisational-group Molecular Genetics and Microbiology
pubs.publication-status Published
pubs.volume 10


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