Innate immune responses to Rickettsia: emerging themes and contrasts between species

Over 10 species of Rickettsia cause serious human disease across the globe, including deadly spotted fever and typhus. These arthropod-borne microbes and their close relatives are the only bacteria that obligately reside in the eukaryotic cytosol, making them distinctive tools to study innate immunity. Yet, the molecular details on how Rickettsia species interact with innate immunity have remained largely enigmatic. Recent advances are revealing that Rickettsia species are not only distinct from other bacterial pathogens that reside in the cytosol, but in some cases, they are highly distinct from one another in how they manipulate mammalian immune pathways. Here, we review an emerging paradigm that detection of Rickettsia species by inflammasomes appears largely conserved, whereby the pathogenic species largely evade inflammasomes, yet subpopulations can be detected after infrequent bacteriolysis. In contrast, different Rickettsia species have highly unique interactions with antibacterial autophagy (xenophagy), whereby some species evolved sophisticated mechanisms to avoid ubiquitylation, whereas others co-opt xenophagy to their benefit. Lastly, we review emerging literature regarding the role of immune cells in infection, which are increasingly appreciated as major targets in vivo. These insights set the stage for an exciting era of leveraging Rickettsia as powerful microbial tools to unravel how cytosolic pathogens subvert mammalian innate immune systems.