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.
Highlights
Chlamydia trachomatis genital tract infections have been, and continue to be, the most common bacterial sexually transmitted infections in Western societies [1]
Investigations into Chlamydia genital tract protective immunity in the C. muridarum model have shown that CD4 T cells are critical to bacterial clearance [6], while CD8 T cells have been associated with immunopathology [7,8]
We tested the role of perforin in Plac8-dependent clearance by treating perforin knockout mice with the inducible nitric oxide synthetase (iNOS) inhibitor MLA and infecting them vaginally with C. muridarum
Summary
Chlamydia trachomatis genital tract infections have been, and continue to be, the most common bacterial sexually transmitted infections in Western societies [1]. Antibiotic-based public health measures have not decreased the incidence of infection and may be partially counterproductive, reducing Chlamydia immunopathology and herd immunity [2,3,4] Based on this epidemiologic reality many public health officials and sexually transmitted disease healthcare providers believe that a Chlamydia vaccine is the only intervention likely to reduce the incidence of infections and their associated monetary and personal costs. Critical to a vaccine effort is defining the relevant host defense mechanism for protective immunity; i.e. the immunologic goal of vaccination This is especially important for Chlamydia vaccines as early attempts with crude whole Chlamydia vaccines were associated with poor protection and excess immunopathology in humans and experimental primate models [5]. Investigations into Chlamydia genital tract protective immunity in the C. muridarum model have shown that CD4 T cells are critical to bacterial clearance [6], while CD8 T cells have been associated with immunopathology [7,8]
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