IFNγ insufficiency during mouse intravaginal Chlamydia trachomatis infection exacerbates alternative activation in macrophages with compromised CD40 functions

Abstract Chlamydia trachomatis (C . tr) , an obligate intracellular pathogen, causes asymptomatic genital infections in women and is also a leading cause of preventable blindness. Limited mouse model of chronic C . tr infection are available to study the host immune response. We have developed in vivo mice models of acute and chronic infections for C. trachomatis to explore the significance of macrophage-directed response in mediating immune activation/suppression. During chronic and repeated infections, IFNγ secretion from T cells is abated while TGFβ and IL-10 secretion is enhanced. An increase in exhaustion ( PD1, CTLA4 ) and anergic ( Klrg3, Tim3 ) T cell markers is also observed during chronic infection. It was observed that alternatively-activated macrophages with low CD40 expression promote Th2 and Treg differentiation and lead to sustained C. trachomatis genital infection. Macrophages infected with C. trachomatis or treated with supernatant of infected epithelial cells drive them to alternately-activated phenotype. C. trachomatis infection prevents increase in CD40 expression. Low IFNγ, as observed in chronic infection leads to incomplete clearance of bacteria and poor immune activation. C. trachomatis decapacitates IFNγ responsiveness in macrophages via hampering IFNγRI and IFNγRII expression which can be correlated with poor expression of MHC-II, CD40, iNOS and NO release even following IFNγ supplementation. Alternatively-activated macrophages during C. trachomatis infection express low CD40 rendering immunosuppressive, Th2 and Treg differentiation which could not be reverted even after IFNγ supplementation. The alternative macrophages also harbour high bacterial load and are poor responders to IFNγ, thus promoting immunosupression. Thus, C. trachomatis modulate the innate immune cells attenuating the anti-chlamydial functions of T cells in a manner that involves decreased CD40 expression on macrophages.