PATHOGENESIS OF LEPTOSPIROSIS

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The candidate, Dr. Albert Ko, is an infectious disease clinician whose long-term commitment has focused on research in international health and microbial pathogenesis. At present, he is receiving field training under the direction of Dr. Lee Riley at University of California, Berkeley and Dr. Warren Johnson at Cornell University Medical College, while establishing active surveillance and community-based studies for emerging pathogens in Salvador, Brazil. The focus of these activities has been leptospirosis, a spirochetal zoonoses, which investigations in Salvador have demonstrated to be an emerging cause of large urban epidemics. The candidate's future goal is to apply an integrated laboratory and population-based approach to infectious diseases. For this purpose, immediate objectives are to: 1) obtain the laboratory skills to characterize strain-specific determinants of pathogenesis and 2) acquire the advanced epidemiological and statistical tools that will enhance future field studies. During the proposed award period, training will be performed through a research project on leptospirosis in Dr. Lee Riley's laboratory and course work at the School of Public Health, University of California at Berkeley. In leptospirosis, multisystem complications can develop which include jaundice, acute renal failure, pulmonary hemorrhage and severe anemia. Factors that contribute to the development of these complications after an infection are not known. Such factors may relate to strain-specific characteristics, host susceptibility, or epidemiologic factors that determine infectious inoculum size. This specific project will focus on the strain-specific factors. Adherence and entry into non-phagocytic host cells in vitro have been correlated with virulence of several bacterial organisms in animal models. However, no studies have addressed this association in human leptospirosis. Little progress has been made in identifying the genes encoding virulence factors. The specific aims of this project, therefore, are to: 1) compare virulence characteristics of leptospiral strains isolated from severe, mild, and asymptomatic human infections using a) a guinea pig infection model, and b) tissue culture assays for bacterial adherence, invasion, and cytotoxicity , and 2) identify specific bacterial factors that mediate mammalian cell association. Completion of the research aims of the proposed award will provide the basis to investigate the structure-function of the gene products and determine whether the identified genes are virulence factors. By the end of this award period, the candidate will have developed the complementary laboratory and epidemiological skills needed to identity host, strain and inoculum-specific factors in transmission and pathogenesis of leptospirosis. Such skills focused on this emerging pathogen should enable him to establish his own research focus as an independent investigator.