Abstract
BackgroundAlthough Tim-3 & PD-L1 signaling pathways play important roles in negatively regulating immune responses, their roles in chlamydial infection have not been evaluated.MethodsNeutralization antibodies targeting Tim-3 and PD-L1 were used to treat mice. Following an intravaginal infection with C. muridarum organisms, mice with or without the dual antibody treatment were compared for live chlamydial organism shedding from the lower genital tract and inflammatory pathology in the upper genital tract.ResultsMice treated with anti-Tim-3 and anti-PD-L1 antibodies displayed a time course of live organism shedding similar to that of mice treated with equivalent amounts of isotype-matched IgG molecules. The combined antibody blocking failed to alter either the lower genital tract cytokine or systemic humoral and cellular adaptive responses to C. muridarum infection. However, the antibody blocking significantly enhanced C. muridarum-induced pathologies in the upper genital tract, including more significant hydrosalpinx and inflammatory infiltration in uterine horn and oviduct tissues.ConclusionsThe Tim-3 and PD-L1-mediated signaling can significantly reduce pathologies in the upper genital tract without suppressing immunity against chlamydial infection, suggesting that Tim-3 and PD-L1-mediated negative regulation may be manipulated to attenuate tubal pathologies in women persistently infected with C. trachomatis organisms.
Highlights
Tim-3 & PD-L1 signaling pathways play important roles in negatively regulating immune responses, their roles in chlamydial infection have not been evaluated
All mice shed more than 100 thousand live organisms during the first 2 weeks after C. muridarum infection
By day 28, most mice cleared infection. These observations suggest that inhibition of Tim-3 and PD-L1 signaling during the first 2 weeks post infection did not significantly affect host immunity against C. muridarum intravaginal infection
Summary
Tim-3 & PD-L1 signaling pathways play important roles in negatively regulating immune responses, their roles in chlamydial infection have not been evaluated. Chlamydia trachomatis causes the most frequent sexually transmitted bacterial infections [1,2,3], which, if untreated, can lead to complications characterized with tubal inflammatory damages, including pelvic inflammatory diseases, ectopic pregnancy and infertility [1,4,5] Both intracellular replication of C. trachomatis organisms and host responses to C. trachomatis antigens may significantly contribute to inflammatory pathologies [6,7,8,9], the precise pathogenic mechanisms of C. trachomatis-induced. It is hypothesized that excessive and/or prolonged cellular ( CD + 8 T cell) responses may contribute to tubal pathologies during chlamydial infection [13,14] How these protective and pathogenic cellular responses are regulated remains unknown. We evaluated the role of these two negative regulatory signaling pathways in chlamydial urogenital infection in the current study
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