Macrophages Infected by a Pathogen and a Non-pathogen Spotted Fever Group Rickettsia Reveal Differential Reprogramming Signatures Early in Infection

Abstract

Despite their high degree of genomic similarity, different spotted fever group (SFG) <i>Rickettsia</i> are often associated with very different clinical presentations. For example, <i>Rickettsia conorii</i> causes Mediterranean spotted fever, a life-threatening disease for humans, whereas <i>Rickettsia montanensis</i> is associated with limited or no pathogenicity to humans. However, the molecular basis responsible for the different pathogenicity attributes are still not understood. Although killing microbes is a critical function of macrophages, the ability to survive and/or proliferate within phagocytic cells seems to be a phenotypic feature of several intracellular pathogens. We have previously shown that <i>R. conorii</i> and <i>R. montanensis</i> exhibit different intracellular fates within macrophage-like cells. By evaluating early macrophage responses upon insult with each of these rickettsial species, herein we demonstrate that infection with <i>R. conorii</i> results in a profound reprogramming of host gene expression profiles. Transcriptional programs generated upon infection with this pathogenic bacteria point toward a sophisticated ability to evade innate immune signals, by modulating the expression of several anti-inflammatory molecules. Moreover, <i>R. conorii</i> induce the expression of several pro-survival genes, which may result in the ability to prolong host cell survival, thus protecting its replicative niche. Remarkably, <i>R. conorii</i>-infection promoted a robust modulation of different transcription factors, suggesting that an early manipulation of the host gene expression machinery may be key to <i>R. conorii</i> proliferation in THP-1 macrophages. This work provides new insights into the early molecular processes hijacked by a pathogenic SFG <i>Rickettsia</i> to establish a replicative niche in macrophages, opening several avenues of research in host-rickettsiae interactions.