title: Perforin is detrimental to controlling [corrected] C. muridarum replication in vitro, but not in vivo.
abstract: CD4 T cells are critical for clearing experimental Chlamydia muridarum genital tract infections. Two independent in vitro CD4 T cell mechanisms have been identified for terminating Chlamydia replication in epithelial cells. One mechanism, requiring IFN-γ and T cell-epithelial cell contact, terminates infection by triggering epithelial production of nitric oxide to chlamydiacidal levels; the second is dependent on T cell degranulation. We recently demonstrated that there are two independent in vivo clearance mechanisms singly sufficient for clearing genital tract infections within six weeks; one dependent on iNOS, the other on Plac8. Redundant genital tract clearance mechanisms bring into question negative results in single-gene knockout mice. Two groups have shown that perforin-knockout mice were not compromised in their ability to clear C. muridarum genital tract infections. Because cell lysis would be detrimental to epithelial nitric oxide production we hypothesized that perforin was not critical for iNOS-dependent clearance, but posited that perforin could play a role in Plac8-dependent clearance. We tested whether the Plac8-dependent clearance was perforin-dependent by pharmacologically inhibiting iNOS in perforin-knockout mice. In vitro we found that perforin was detrimental to iNOS-dependent CD4 T cell termination of Chlamydia replication in epithelial cells. In vivo, unexpectedly, clearance in perforin knockout mice was delayed to the end of week 7 regardless of iNOS status. The discordant in vitro/in vivo results suggest that the perforin's contribution to bacterial clearance in vivo is not though enhancing CD4 T cell termination of Chlamydia replication in epithelial cells, but likely via a mechanism independent of T cell-epithelial cell interactions.
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA. raymjohn@iupui.edu
authors.forename: Raymond M
authors.initials: RM
authors.lastname: Johnson
authors.forename: Micah S
authors.initials: MS
authors.lastname: Kerr
authors.forename: James E
authors.initials: JE
authors.lastname: Slaven
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D023502:Chlamydia muridarum / Q000502:physiology*; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D005260:Female; D055786:Gene Knockout Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D054353:Perforin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D060737:Reproductive Tract Infections / Q000276:immunology / Q000378:metabolism / Q000382:microbiology
chemical_list: D054353:Perforin; D052247:Nitric Oxide Synthase Type II