Recent research milestones in the pathogenesis of human rickettsioses and opportunities ahead.

Infections caused by pathogenic Rickettsia species continue to scourge human health across the globe. From the point of entry at the site of transmission by arthropod vectors, hematogenous dissemination of rickettsiae occurs to diverse host tissues leading to 'rickettsial vasculitis' as the salient feature of pathogenesis. This perspective article accentuates recent breakthrough developments in the context of host-pathogen-vector interactions during rickettsial infections. The subtopics include potential exploitation of circulating macrophages for spread, identification of new entry mechanisms and regulators of actin-based motility, appreciation of metabolites acquired from and effectors delivered into the host, importance of the toxin-antitoxin module in host-cell interactions, effects of the vector microbiome on rickettsial transmission, and niche-specific riboregulation and adaptation. Further research on these aspects will advance our understanding of the biology of rickettsiae as intracellular pathogens and should enable design and development of new approaches to counter rickettsioses in humans and other hosts.