Epidemic typhus is an acute human disease caused by the obligate intracellular bacterium, Rickettsia prowazekii. R. prowazekki has a predilection for growth within the endothelial cells and an ability to multiply within the macrophages of the host. The host has mechanisms for defending itself against infection because epidemic typhus in the absence of antibiotics is not uniformly fatal. However, these mechanisms have not been delineated. We first described a species-specific lymphokine that prevented the growth of rickettsiae in fibroblasts and macrophage-like cells and would cause cytotoxicity in infected macrophage-like cells. From our recent work we now know that the lymphokine responsible for these effects is interferon-gamma (IFN-Y). Our goals involve the in vitro characterization of the mechanisms by which growth inhibition and cytotoxicity occur and a definition of a non-IFN-Y factor which inhibits initial infection by: I. Characterization of the kinetics of IFN-Y and delineation of the antirickettsial role of type I interferons. II. Determination of the mechanism of inhibition of rickettsial growth by examining the structure and function of rickettsiae in IFN-Y-treated cells; testing of lysates of IFN-Y treated cells on the metabolism of isolated rickettsiae; analysis of the metabolite pools of IFN-Y-treated cells for constituents for which the rickettsiae are likely to be auxotrophic; and analysis of protein profiles in human cells that become antirickettsial by cocultivation with murine IFN-Y and murine fibroblasts. III. Identification of the non-IFN-Y factor responsible for the inhibition of the initial infection of lymphokine-treated cells by rickettsiae through the use of monoclonal anti-IFN-Y antibody and reconstitution experiments. IV. Exploitation of various existing cell lines and isolation of new mutant cells in order to analyze the mechanisms involved in the induction of the antirickettsial state. V. Characterization and differentiation of the mechanisms by which cytotoxicity occurs in macrophages, macrophage-like cells and fibroblasts. Attention will be given to macromolecular synthesis, phagocytosis, phospholipase A activity, induction of the oxidative burst, and interference by rickettsiae with the systems which protect cells from endogenous reactive oxygen intermediates.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Method to Extend Research in Time (MERIT) Award (R37)
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Tropical Medicine and Parasitology Study Section (TMP)
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University of South Alabama
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Turco, J; Liu, H; Gottlieb, S F et al. (1998) Nitric oxide-mediated inhibition of the ability of Rickettsia prowazekii to infect mouse fibroblasts and mouse macrophagelike cells. Infect Immun 66:558-66
Turco, J; Winkler, H H (1994) Relationship of tumor necrosis factor alpha, the nitric oxide synthase pathway, and lipopolysaccharide to the killing of gamma interferon-treated macrophage-like RAW264.7 cells by Rickettsia prowazekii. Infect Immun 62:2568-74
Turco, J; Winkler, H H (1994) Cytokine sensitivity and methylation of lysine in Rickettsia prowazekii EVir and interferon-resistant R. prowazekii strains. Infect Immun 62:3172-7
Winkler, H H; Day, L; Daugherty, R et al. (1993) Effect of gamma interferon on phospholipid hydrolysis and fatty acid incorporation in L929 cells infected with Rickettsia prowazekii. Infect Immun 61:3412-5
Gao, Q; Turco, J; Winkler, H H (1993) Synthesis of DNA, rRNA, and protein by Rickettsia prowazekii growing in untreated or gamma interferon-treated mouse L929 cells. Infect Immun 61:2383-9
Turco, J; Winkler, H H (1993) Role of the nitric oxide synthase pathway in inhibition of growth of interferon-sensitive and interferon-resistant Rickettsia prowazekii strains in L929 cells treated with tumor necrosis factor alpha and gamma interferon. Infect Immun 61:4317-25
Turco, J; Winkler, H H (1991) Comparison of properties of virulent, avirulent, and interferon-resistant Rickettsia prowazekii strains. Infect Immun 59:1647-55
Turco, J; Winkler, H H (1990) Selection of alpha/beta interferon- and gamma interferon-resistant rickettsiae by passage of Rickettsia prowazekii in L929 cells. Infect Immun 58:3279-85
Turco, J; Winkler, H H (1990) Interferon-alpha/beta and Rickettsia prowazekii: induction and sensitivity. Ann N Y Acad Sci 590:168-86
Keysary, A; McCaul, T F; Winkler, H H (1989) Roles of the Fc receptor and respiratory burst in killing of Rickettsia prowazekii by macrophagelike cell lines. Infect Immun 57:2390-6

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