The Gram-negative a-proteobacteria of the genus Rickettsia are small (0.3-0.5 x 0.8-1.0 m), obligate intracellular organisms. They are categorized into two major groups, the Spotted Fever Group (SFG) and Typhus Group (TG), which can be distinguished by antigenicity and intracellular actin-based motility. Members of this genus are responsible for severe human diseases and several species including R. conorii, R. rickettsii, R. prowazekii, and R. typhi, have been classified as Category B and C Priority Pathogens by the National Institute of Allergy and Infectious Diseases (NIAID) for their potential use as tools for biological terrorism. The pathogenesis SFG rickettsia, upon transmission into the host, depends on the pathogen's ability to bind to and invade target host cells. Although endothelial cells are the primary target cells in the host, many non-endothelial cell lines can als be efficiently invaded by rickettsial strains, suggesting that either multiple receptors govern hos cell interactions or that a putative receptor is ubiquitously expressed in many cell types. Analysi of several completed rickettsial genomes has revealed the presence of at least 17 open reading frames (orfs) termed sca (surface cell antigens) whose putative products exhibit high homology to auto- transporter protein families in Gram-negative bacteria. At least four members of this family, Sca0, Sca1, Sca2, and Sca5 are highly conserved among most pathogenic SFG rickettsia. Interestingly, these proteins have been shown to be involved in rickettsial adherence and invasion into normally non-phagocytic mammalian cells using cell culture models of infection; however, very little is known about the function of other conserved Sca proteins in pathogenesis in vivo. This application will focus on the following two avenues of research: a) Elucidation of the roles of conserved outermembrane proteins from R. conorii and R. rickettsii in the pathogenesis of rickettsial disease. b) The generation of protective humoral immune responses against SFG rickettsiae using purified recombinant Sca proteins in an established murine model of infection.
Rickettiae are transmitted by tick bite inoculation into the skin of the human host and can ultimately damage target endothelial cells especially in the lungs and brain leading to 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 and other spotted fever infections 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.
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