Legionnaires' disease is a highly fatal pneumonia that occurs worldwide in both epidemic and endemic form. An estimated 100,000 cases occur annually in the United States. The causative bacterial agent, Legionella pneumophila, is an intracellular pathogen, and thus belongs to a group of human pathogens that are extremely important causes of morbidity and mortality worldwide. Millions of people are affected by such intracellular parasites as Mycobacterium tuberculosis, Mycobacterium leprae, Trypanosoma cruzi, Leishmania sp., Chlamydia trachomatis, and Toxoplasma gondii. Prevention and therapy for many of these diseases is unsatisfactory in part because more needs to be learned about the interaction of these pathogens with the human immune system. Legionella pneumophila infection of human mononuclear phagocytes is an excellent in vitro model for studies of intracellular parasitism, macrophage activation, and the roles of humoral and cell-mediated immunity. This proposal seeks to exploit this model to systematically explore critical aspects of the interaction between L. pneumophila and components of the human cellular and humoral immune defense system. Such studies should provide rational strategies for prevention and treatment of Legionnaires' disease and, hopefully, other diseases caused by intracellular pathogens.
Specific aims are to: a) Determine the capacity of specific L. pneumophila antigens to stimulate human cell-mediated immunity; b) Determine the influence of antibody to specific L. pneumophila surface components on survival of the bacterium in human serum; c) Determine the influence of antibody to specific L. pneumophila surface antigens on the survival and multiplication of L. pneumophila in activated and nonactivated human monocytes; d) Determine the influence of antibody against specific L. pneumophila surface antigens on intracellular interactions between the L. pneumophila phagosome and cytoplasmic organelles of activated and nonactivated monocytes; e) Determine the influence of gamma interferon - activated monocytes on L. pneumophila in the presence of specific antibodies against L. pneumophial surface antigens and in the presence of antibiotics; f) Determine which of several bacterial components or products induce specific cell-mediated immunity and cutaneous delayed-type hypersensitivity in immunized guinea pigs and which induce antibody responses; g) Determine if immunization of guinea pigs with one of several L. pneumophila components or products induces protection against challenge with virulent L. pnuemophila.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI022421-02
Application #
3133457
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1985-09-01
Project End
1988-08-31
Budget Start
1986-09-01
Budget End
1987-08-31
Support Year
2
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Blander, S J; Horwitz, M A (1993) Major cytoplasmic membrane protein of Legionella pneumophila, a genus common antigen and member of the hsp 60 family of heat shock proteins, induces protective immunity in a guinea pig model of Legionnaires' disease. J Clin Invest 91:717-23
Byrd, T F; Horwitz, M A (1993) Regulation of transferrin receptor expression and ferritin content in human mononuclear phagocytes. Coordinate upregulation by iron transferrin and downregulation by interferon gamma. J Clin Invest 91:969-76
Clemens, D L; Horwitz, M A (1993) Hypoexpression of major histocompatibility complex molecules on Legionella pneumophila phagosomes and phagolysosomes. Infect Immun 61:2803-12
Horwitz, M A (1992) Interactions between macrophages and Legionella pneumophila. Curr Top Microbiol Immunol 181:265-82
Clemens, D L; Horwitz, M A (1992) Membrane sorting during phagocytosis: selective exclusion of major histocompatibility complex molecules but not complement receptor CR3 during conventional and coiling phagocytosis. J Exp Med 175:1317-26
Marra, A; Blander, S J; Horwitz, M A et al. (1992) Identification of a Legionella pneumophila locus required for intracellular multiplication in human macrophages. Proc Natl Acad Sci U S A 89:9607-11
Blander, S J; Horwitz, M A (1991) Vaccination with Legionella pneumophila membranes induces cell-mediated and protective immunity in a guinea pig model of Legionnaires' disease. Protective immunity independent of the major secretory protein of Legionella pneumophila. J Clin Invest 87:1054-9
Blander, S J; Horwitz, M A (1991) Vaccination with the major secretory protein of Legionella induces humoral and cell-mediated immune responses and protective immunity across different serogroups of Legionella pneumophila and different species of Legionella. J Immunol 147:285-91
Byrd, T F; Horwitz, M A (1991) Chloroquine inhibits the intracellular multiplication of Legionella pneumophila by limiting the availability of iron. A potential new mechanism for the therapeutic effect of chloroquine against intracellular pathogens. J Clin Invest 88:351-7
Byrd, T F; Horwitz, M A (1991) Lactoferrin inhibits or promotes Legionella pneumophila intracellular multiplication in nonactivated and interferon gamma-activated human monocytes depending upon its degree of iron saturation. Iron-lactoferrin and nonphysiologic iron chelates reverse mon J Clin Invest 88:1103-12

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