<i>Chlamydia trachomatis</i>Persistence in the Female Mouse Genital Tract: Inducible Nitric Oxide Synthase and Infection Outcome

STAT1 mediates signaling in response to IFN-α, -β, and -γ, cytokines required for protective immunity against several viral, bacterial, and eukaryotic pathogens. The protective role of STAT1 in the control of intranasal infection with the obligate intracellular bacterium Chlamydia pneumoniae was analyzed. IFN-γ−/− or IFN-γ receptor (R)−/− mice were highly susceptible to infection with C. pneumoniae. We found that STAT1−/− mice were even more susceptible to C. pneumoniae than IFN-γ−/− or IFN-γR−/− mice. Phosphorylation of STAT1 was detected in the lungs of C. pneumoniae-infected wild-type, IFN-γR−/−, and IFN-αβR−/− mice, but not in mice lacking both IFN-αβR and IFN-γR. In line with this, IFN-αβR−/−/IFN-γR−/− mice showed increased susceptibility to infection compared with IFN-γR−/− mice. However, C. pneumoniae-infected IFN-αβR−/− or IFN regulatory factor 3−/− mice showed no increased susceptibility and similar IFN-γ expression compared with wild-type mice. CD4+ or CD8+ cells released IFN-γ in vivo and conferred protection against C. pneumoniae in a STAT1-independent manner. In contrast, STAT1 mediated a nonredundant protective role of nonhemopoietic cells but not of hemopoietic cells. Nonhemopoietic cells accounted for the expression of STAT1-mediated indoleamine 2, 3-dioxygenase and the p47 GTPase LRG-47, but not inducible NO synthase mRNA. In summary, we demonstrate that STAT1 mediates a cooperative effect of IFN-αβ and IFN-γ on nonhemopoietic cells, resulting in protection against C. pneumoniae.

Section: Discussionmentioning

confidence: 68%

STAT1 Regulates IFN-αβ- and IFN-γ-Dependent Control of Infection withChlamydia pneumoniaeby Nonhemopoietic Cells

Rothfuchs

Trumstedt

Mattei

et al. 2006

“…IFN-␥ is clearly important in host defense against chlamydiae, with direct and indirect inhibitory effects demonstrated in vitro (63)(64)(65)(66)(67)(68)(69) and in vivo (2-4, 37, 70 -72). IL-6 has been shown to be partly responsible for blocking the suppressor activity of CD4 ϩ CD25 ϩ -regulatory T cells (T R ), allowing for activation of pathogen-specific adaptive immune responses (73).…”

Section: Discussionmentioning

confidence: 99%

Toll-Like Receptor-2, but Not Toll-Like Receptor-4, Is Essential for Development of Oviduct Pathology in Chlamydial Genital Tract Infection

Darville

O'Neill

Andrews

et al. 2003

261

293

The roles of Toll-like receptor (TLR) 2 and TLR4 in the host inflammatory response to infection caused by Chlamydia trachomatis have not been elucidated. We examined production of TNF-α and IL-6 in wild-type TLR2 knockout (KO), and TLR4 KO murine peritoneal macrophages infected with the mouse pneumonitis strain of C. trachomatis. Furthermore, we compared the outcomes of genital tract infection in control, TLR2 KO, and TLR4 KO mice. Macrophages lacking TLR2 produced significantly less TNF-α and IL6 in response to active infection. In contrast, macrophages from TLR4 KO mice consistently produced higher TNF-α and IL-6 responses than those from normal mice on in vitro infection. Infected TLR2-deficient fibroblasts had less mRNA for IL-1, IL-6, and macrophage-inflammatory protein-2, but TLR4-deficient cells had increased mRNA levels for these cytokines compared with controls, suggesting that ligation of TLR4 by whole chlamydiae may down-modulate signaling by other TLRs. In TLR2 KO mice, although the course of genital tract infection was not different from that of controls, significantly lower levels of TNF-α and macrophage-inflammatory protein-2 were detected in genital tract secretions during the first week of infection, and there was a significant reduction in oviduct and mesosalpinx pathology at late time points. TLR4 KO mice responded to in vivo infection similarly to wild-type controls and developed similar pathology. TLR2 is an important mediator in the innate immune response to C. trachomatis infection and appears to play a role in both early production of inflammatory mediators and development of chronic inflammatory pathology.

“…The evidence that Chlamydia persists in vivo (22,25) led us to look at the expression of IL-7R on CrpA 63-71 -specific T cells. We saw a significant decrease in IL-7R ϩ memory cells in Chlamydia-infected mice compared with mice that had been immunized with a recombinant vaccinia virus expressing the Chlamydia CrpA protein (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, there is evidence that Chlamydia may also persist in vivo (21,22) suggesting the possibility that the reduced activation of Chlamydia-specific T EM cells and subsequent failure of immune mice to mount a robust recall response may result from continuous low level T cell stimulation by persistent Chlamydia Ag. To test whether the elimination of organisms that may be persisting below detectable levels would improve the ability of Chlamydia-specific memory cells to respond to antigenic challenge we treated mice with the antibiotic doxycycline before challenge.…”

Section: Chlamydia-primed Cd8 ϩ T Cells Are Limited In Their Capacitymentioning

confidence: 99%

Chlamydia trachomatis Infection Alters the Development of Memory CD8+ T Cells

Loomis

Starnbach

2006

The obligate intracellular bacterium Chlamydia trachomatis is the most common cause of bacterial sexually transmitted disease in the United States and the leading cause of preventable blindness worldwide. Prior exposure to C. trachomatis has been shown to provide incomplete protection against subsequent infection. One possible explanation for the limited immunity afforded by prior C. trachomatis infection is poor activation of Chlamydia-specific memory CD8+ T cells. In this study, we examined the development of CD8+ memory T cell responses specific for the Chlamydia Ag CrpA. The percentage of CrpA63–71-specific T cells expressing an effector memory T cell phenotype (IL-7R+ CD62low) was dramatically diminished in mice immunized with C. trachomatis, compared with mice immunized with vaccinia virus expressing the CrpA protein. These alterations in memory T cell development were correlated with a significant reduction in the capacity of convalescent mice to mount an enhanced recall response to Chlamydia Ags, compared with the primary response. CrpA-specific memory T cells primed during VacCrpA infection also failed to respond to a challenge with Chlamydia. We therefore investigated whether C. trachomatis infection might have a global inhibitory effect on CD8+ T cell activation by coinfecting mice with C. trachomatis and Listeria monocytogenes and we found that the activation of Listeria-specific naive and memory CD8+ T cells was reduced in the presence of C. trachomatis. Together, these results suggest that Chlamydia is able to alter the development of CD8+ T cell responses during both primary and secondary infection, perhaps accounting for the incomplete protection provided by prior Chlamydia infection.