Dissemination of Chlamydia trachomatis chronic genital tract infection in gamma interferon gene knockout mice

Abstract

Mice (C57BL/6), treated with progesterone and infected intravaginally with the mouse pneumonitis strain of Chlamydia trachomatis (MoPn), acquired genital tract disease that ascended from the endocervix to the uterine horns, oviducts, and ovaries in a temporal fashion before the occurrence of spontaneous microbiological resolution by about 28 days after infection. Surprisingly, dissemination of MoPn in small numbers to draining lymph nodes, the peritoneal cavity, spleen, liver, kidneys, and lungs occurred in normal mice during the early stages of disease (7 to 14 days) in a portion of infected animals but resolved from these tissues, by microbiological criteria, prior to resolution of genital tract involvement. In contrast, gamma interferon knockout (IFN-␥ KO) mice exhibited dissemination of infection to a greater extent and for longer periods in a variety of tissues, and a portion of infected IFN-␥ KO mice failed to microbiologically resolve their genital tract disease. By comparison, C57BL/6 SCID mice uniformly failed to resolve their genital tract disease and exhibited high levels of dissemination to all tissues tested for extended (50-day) periods of times. Interestingly, although IFN-␥ KO mice failed to completely clear organisms from their genital tracts, they exhibited an attenuated infection indistinguishable from that of heterozygous littermates when challenged 112 days after primary infection. These data support a role for IFN-␥ in containing dissemination of MoPn from the genital tract to extragenital sites and in the microbiological resolution of infection. Data also indicate that IFN-␥ is not required for modulating reinfections, which normally follow a shorter and less dramatic course.

Infection of epithelial and dendritic cells byChlamydia trachomatisresults in IL-18 and IL-12 production, leading to interferon-γ production by human natural killer cells

“…C. trachomatis-infected women have higher levels of IFN-c in endocervical secretions than uninfected women [15] and this has also been demonstrated in vivo in murine infection by Chlamydia muridarum [7,16]. Studies using antibody depletion of IFN-c, IFN-c gene knockout mice, or IFN-c receptor gene knockout mice have all shown that IFN-c has a significant role to play in immune defence against various species of chlamydiae [5,6,[17][18][19][20][21]. In various experimental systems, the removal of IFN-c led to higher bacterial loads, reduction in IgG 2a levels, dissemination of infection, failure to resolve disease, and failure to develop protective immunity.…”

A recombinant multivalent combination vaccine protects againstChlamydiaand genital herpes

“…The VCG delivery vector together with the mouse genital infection model provided a convenient ap-proach for evaluating the immunogenicity and protective efficacy of the bivalent combination vaccine formulation comprising rVCG expressing chlamydial MOMP and HSV-2 glycoprotein D. The results obtained are encouraging, because mice immunized with the combination vaccine were prophylactically protected from genital challenge with high doses of live Chlamydia and HSV-2. An effective combination vaccine against Chlamydia and HSV-2 will most probably need to elicit effective Th1 cellmediated immune responses as well as accessory or neutralizing antibodies (Rank, 1994;Cotter, 1997;Perry et al, 1997;Su, 1997). Significant levels of Th1 responses were induced following immunization, as indicated by the production of high levels of IFN-g compared with IL-4 levels that remained unchanged up to 8 weeks postimmunization.…”

“…This is indicated by a decrease in the amount of IFN-g secreted by T cells from mice immunized with the combination vaccine; this formulation contains 50% of the antigen dose present in the single subunit vaccines. High IFN-g and low IL-4 levels are indicative of a Th1 response (Maggi, 1992;Bradley et al, 1995;Igietseme et al, 2003), which has previously been correlated with a degree of protection against both Chlamydia and HSV infections (Rank, 1994;Cotter, 1997;Perry et al, 1997;Su, 1997) (Koelle, 1998;Sin, 1999).…”

Tissue-Resident T Cells as the Central Paradigm of Chlamydia Immunity

“…These results fit naturally into a Th1/Th2 paradigm, with protective immunity ascribed to CD4 T cells making IFN-␥. This narrative was reinforced by the findings that adoptive transfer of Chlamydia-specific Th2 cells (24) and Chlamydia in-fections experimentally skewed toward Th2 responses were accompanied by prolonged and disseminated infection (25)(26)(27)(28). As the cytokine polarization paradigm evolved, these results were extended to include detrimental effects of Th17-skewed responses (29).…”