Hijack the host or get killed: delineating Rickettsia survival strategies for development of targeted therapeutic strategies

Overview

Project Summary

Given the re-emerging and global character of tick-borne rickettsiosis they are expected to result in an increasing burden factor in public health, strengthening the importance of identifying new factors that may work as potential targets for the development of more efficacious therapies. Understanding how pathogens exploit their toolbox of survival strategies to establish a successful intracellular niche is critical to develop new therapeutic interventions, either host- or pathogen-directed. For rickettsiae, the underlying mechanisms governing differences in pathogenicity by different species, as well as their full spectra of evasion strategies to avoid killing by host cells and the bactericidal activity of serum proteins are still to be understood. Herein, we propose to explore 2 different aspects of rickettsial survival/evasion strategies in 2 different WPs: WPA.To define the global landscape of macrophage responses to pathogenic and non-pathogenic spotted fever group rickettsiae. The goal of this Aim is to test the hypothesis that bacterial interactions with distinct macrophage factors contribute for species-specific patterns of rickettsial cellular tropism and pathogenicity. Rationale: We recently showed that 2 pathogenic (R.conorii (RC) and R. parkeri (RP)) and a non-pathogenic (R. montanensis (RM)) rickettsiae have opposite intracellular fates (proliferation vs. death, respectively) in human THP-1 macrophages. RM were rapidly destroyed whereas RC and RP were observed as intact bacteria and free in the cytoplasm. WPB.To elucidate how the retropepsin APRc contributes to rickettsial survival strategies. Herein we will test the hypothesis that APRc is a moonlighting protein, acting as a novel Ig-binding protein in addition to its catalytic function. Rationale: We previously showed that APRc is an active protease and provided evidence for its potential role in processing of other OM rickettsial proteins (rOmpB and rOmpA). Recently, we demonstrated that recombinant and native APRc (and homologues from different species) bind IgG. Given the unique features of APRc, we propose to further explore its binding and proteolytic roles in host-pathogen interaction.

Main Goals

The goal of this study is to identify novel mechanisms underlying rickettsiae-macrophage tropic vs. non-tropic interactions and to map key proteases modulating host-rickettsiae interaction that may be explored as new therapeutic targets

Project Details