Rickettsia conorii, a member of the spotted fever group (SFG) rickettsia is an obligate intracellular tick borne pathogen and is the causative agent of Mediterranean spotted fever. Aerosol transmission of rickettsia can occur and therefore, represents a bioterrorist threat for the United States. The pathogenesis of R. conorii upon transmission into the host depends on the pathogen's ability to bind to and invade target host cells. Annotation of several sequenced rickettsial genomes has identified a large family of genes termed surface cell antigens (sca) that resemble autotransporter proteins and virulence factors in Gram-negative bacteria. While many genes in this family are degenerate or split, at least 4 genes, sca0 (rompA), sca1, sca2, and sca5 (rompB) are present as complete open reading frames in R. conorii and many other SFG rickettsia. Previous results have demonstrated that Sca0 (rOmpA) and Sca5 (rOmpB) are important for the adhesion to and subsequent invasion of non-phagocytic mammalian cells and in the generation of protective humoral immune responses. However, very little is known about the function of other outermembrane proteins in SFG rickettsia pathogenesis. We have identified the first rickettsial protein-host cell receptor pair (rOmpB-Ku70) that plays an important role in the establishment of a successful infection within target human cells. Interestingly, our results have also suggested that while rOmpB-Ku70 interactions are important during the invasion process, other conserved SFG rickettsia proteins, namely rOmpA, Sca1 and Sca2, likely play important roles during pathogenesis. The experiments outlined in this proposal will address the following research interests: i. The contributions of rOmpB and Ku70 to colonization will be analyzed by using recombinant E. coli, purified proteins and protein coupled latex beads. The induction of host signaling pathways involved in the uptake process will also be analyzed using a cell culture model. ii. We will determine the contribution of rOmpB and Ku70 to the initiation and progression of SFG rickettsial disease in a murine model of infection using wild-type and Ku70 knockout mice. iii. We will also determine the roles of conserved surface antigens, namely rOmpA, Sca1 and Sca2 in mediating invasion of non-phagocytic mammalian cells. The roles of these proteins in generating protective humoral immune responses will be examined in a murine model of infection. In addition, we will identify novel ligands that interact with these conserved surface proteins in the hopes of identifying new receptors that play roles in the pathogenesis of SFG rickettsia.

Public Health Relevance

Rickettsia conorii, the causative agent of Mediterranean spotted fever, is transmitted by tick bite inoculation into the skin of the human host. Damage to target endothelial cells especially in the lungs and brain can result in the most severe manifestations of disease including pulmonary edema and interstitial pneumonia. Although infections are controlled by broad-spectrum antibiotic therapies, untreated or misdiagnosed Mediterranean spotted fever can results in severe morbidity and mortality. With the threat of the potential use of Rickettsiae and other bacteria as agents for biological terrorism, understanding the complex interplay between the pathogen and host cells is vital for the future development of novel anti-microbials and therapies.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Host Interactions with Bacterial Pathogens Study Section (HIBP)
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Mukhopadhyay, Suman
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University of Chicago
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Cruz, Rui; Huesgen, Pitter; Riley, Sean P et al. (2014) RC1339/APRc from Rickettsia conorii is a novel aspartic protease with properties of retropepsin-like enzymes. PLoS Pathog 10:e1004324
Hillman Jr, Robert D; Baktash, Yasmine M; Martinez, Juan J (2013) OmpA-mediated rickettsial adherence to and invasion of human endothelial cells is dependent upon interaction with *2*1 integrin. Cell Microbiol 15:727-41
Chan, Yvonne Gar-Yun; Riley, Sean Phillip; Chen, Emily et al. (2011) Molecular basis of immunity to rickettsial infection conferred through outer membrane protein B. Infect Immun 79:2303-13
Riley, Sean P; Goh, Kenneth C; Hermanas, Timothy M et al. (2010) The Rickettsia conorii autotransporter protein Sca1 promotes adherence to nonphagocytic mammalian cells. Infect Immun 78:1895-904
Chan, Yvonne G Y; Cardwell, Marissa M; Hermanas, Timothy M et al. (2009) Rickettsial outer-membrane protein B (rOmpB) mediates bacterial invasion through Ku70 in an actin, c-Cbl, clathrin and caveolin 2-dependent manner. Cell Microbiol 11:629-44
Cardwell, Marissa M; Martinez, Juan J (2009) The Sca2 autotransporter protein from Rickettsia conorii is sufficient to mediate adherence to and invasion of cultured mammalian cells. Infect Immun 77:5272-80