Plasmid-Deficient Chlamydia muridarum Fail to Induce Immune Pathology and Protect against Oviduct Disease

Abstract

Chlamydia trachomatis is the most prevalent sexually transmitted bacterial infection in the world. In women, genital infection can cause endometritis and pelvic inflammatory disease with the severe sequelae of ectopic pregnancy or infertility. Chlamydia sp. do not damage tissues directly, but induce an injurious host inflammatory response at the infected site. In the murine model of genital disease with Chlamydia muridarum, TLR2 plays a role in both early production of inflammatory mediators and development of chronic oviduct pathology. We report the results of studies with plasmid-cured C. muridarum mutants that retain the ability to infect the murine genital tract, but fail to cause disease in the oviduct. These mutants do not stimulate TLR2-dependent cytokine production in mice, nor in innate immune cells or epithelial cells in vitro. They induce an effective Th1 immune response, with no evidence for Th1-immune-mediated collateral tissue damage. Furthermore, mice previously infected with the plasmid-deficient strains are protected against oviduct disease upon challenge with virulent C. muridarum. If plasmid-cured derivatives of human C. trachomatis biovars exhibit similar phenotypic characteristics, they have the potential to serve as vaccines to prevent human disease.

Plasmid deficiency in urogenital isolates ofChlamydia trachomatisreduces infectivity and virulence in a mouse model

“…glycogen accumulation) and in controlling the expression of certain genes on the Chlamydia chromosome. Overall, studies of infection with both wild‐type and plasmid‐free C. trachomatis and C. muridarum strains in mouse urogenital infection indicate that the plasmid modulates infectivity and may be essential for pathogenic immune responses (O'Connell et al ., 2007; Carlson et al ., 2008; Olivares‐Zavaleta et al ., 2010; Russell et al ., 2011). It is all but certain that either C. muridarum plasmid gene products or products of plasmid responsive loci on the bacterial chromosome engage Toll‐like receptor‐2 (TLR‐2) causing deleterious responses in mouse urogenital infections with C. muridarum (O'Connell et al ., 2011).…”

“…It is not possible to predict whether any of these SNPs contributed directly to the differences we have observed in the mouse model. However, our observations are quite consistent with the aforementioned in vivo observations of plasmid‐free strains in human disease (Bjartling et al ., 2009; Harris et al ., 2012) and in other animal models (O'Connell et al ., 2007; Carlson et al ., 2008; Olivares‐Zavaleta et al ., 2010; Russell et al ., 2011). Thus, we feel the most logical inference is to attribute the differences seen to presence and function of the plasmid.…”

“…Thus, one should be mindful of these host and pathogen differences when interpreting our data. Nonetheless, it is pleasing that our findings largely support and agree with those of others investigating the chlamydial plasmid in mouse urogenital tract infections with LGV strains either C. muridarum or C. trachomatis (O'Connell et al ., 2007; Carlson et al ., 2008; Olivares‐Zavaleta et al ., 2010; Russell et al ., 2011). In the context of what has already been reported by others regarding the chlamydial plasmid and in vivo fitness, our results add to the growing body of evidence that in many hosts and at specific anatomical sites, the plasmid plays a role in modulating infectivity and virulence, but this role is not universal.…”

“…This has led some to assert that plasmid‐free strains may be effective attenuated vaccines (Olivares‐Zavaleta et al ., 2010; Kari et al ., 2011). Similar results have been reported in the mouse model of urogenital infection with the mouse pathogen, C. muridarum (O'Connell et al ., 2007). It is also important to note that none of the aforementioned studies have utilized urogenital isolates of C. trachomatis, and thus, it could be hypothesized that the plasmid of urogenital isolates possesses different qualities and would behave differently in an animal model when compared to the others thus far examined.…”

CPAF selectively degrades chlamydial T cell antigens for inhibiting antigen presentation

“…Recently, it was hypothesized that both adequate ascension to and induction of the appropriate inflammatory response in the upper genital tract is necessary for hydrosalpinx development [6][7][8][9]. To overcome the host immunity barriers, and establish the successful infection, chlamydia may utilize virulence factors as previously proposed [10].…”