Rickettsial CspA proteins and host microRNAs in exosome formation and pathogenesis

Rickettsioses are devastating human infections that present major public health concerns and challenges. Microvascular endothelial cells (ECs) are the primary targets of Rickettsia infection; vascular dysfunction in the brain and/or lungs can lead to fatal outcomes. Despite the global distribution and climate change-related emergence of Rickettsia spp., there are sizable knowledge gaps in our understanding of the pathogenic mechanisms of rickettsioses. Using diverse sources of EC-derived exosomes (Exos) collected during R. parkeri infection, we have previously shown that: i) the endothelia can efficiently uptake Exos in vivo; ii) the functions of Exos seem to be linked to their RNA cargos; iii) microvasculopathy-related microRNA (miR23a, miR30b) are selectively sorted into Exos (using infected human umbilical vein EC); iv) only miR23a-27a-24 cluster and miR30b, but not other tested ones, are selectively enriched in Exos (using infected human dermal microvascular EC); and v) exosomal targeting of miR23a during infection ameliorates microvascular dysfunction. While common sequence motifs seem to be shared exclusively among the miR23a cluster and miR30b, the selective enrichment mechanisms remain unclear. We have recently detected rickettsial cold shock protein A (CspA) in Exos, in association with miR27a. Our findings led to the central hypothesis that rickettsial CspA functions as exosome-specific RNA-binding protein (exoRBP) for miR23a/27a/24/30b, regulating selective enrichment of these detrimental exosomal miRs in R. parkeri infection.