Innate Immune Responses to the Intracellular Pathogens Chlamydia trachomatis and Shigella flexneri

Abstract

Certain bacterial pathogens are able to invade and replicate within host cells, making them susceptible to detection by intracellular pattern recognition receptors (PRRs) of the innate immune system. For many pathogens, the PRRs that are activated and the effects of downstream signaling on bacterial clearance and development of adaptive immunity are not fully understood. Chlamydia trachomatis is an obligate intracellular pathogen that replicates within an inclusion and modulates the host cell environment to survive. Given this close interaction, we asked which intracellular PRR pathways are activated during C. trachomatis infection and what are the effects on primary and secondary infection in vivo. We found that the PRR adaptor molecules MAVS and STING are activated during infection in vitro, but PRRs NOD2 and TLR3 are not. Following mouse transcervical infection, MAVS exacerbates primary infection, but contributes to protection against secondary infection. Next, we explored the roles of type I and type III interferons (IFNs), which can be expressed downstream of MAVS activation. In contrast to MAVS, type I IFN signaling helped control primary C. trachomatis infection in vivo and type III IFN signaling had no effect. These data suggest MAVS functions independently of type I and III IFN signaling to exacerbate primary infection. However, both type I and III IFN signaling contribute to protection against secondary infection. Our results demonstrate an important connection between complex innate signals and adaptive immunity. Bacterial pathogens can also evade innate immune detection. Previous studies showed that the intracellular pathogen Shigella flexneri inhibits STING activation in MEFs. Since S. flexneri invades multiple cell types, we asked whether STING is activated in macrophages. We found that STING is not activated and does not affect bacterial survival during S. flexneri infection in macrophages. We also found that STING does not affect S. flexneri infection in vivo or type I IFN secretion in the lungs during infection. These data support previous findings that STING signaling does not affect S. flexneri infection. Together, these data shed light on the interplay between the host and intracellular pathogens and the importance of the innate immune response in the outcome of infection.