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. It is an important cause of fatal nosocomial pneumonia, and it plagues major transplant centers. The causative agent, Legionella pneumophila, is an intracellular bacterial pathogen. Previous studies from this laboratory have extensively explored the interaction of L. pneumophila with human mononuclear phagocytes and defined immune responses to this pathogen. These studies have indicated that cell-mediated immunity plays a dominant role in host defense against this organism. Investigations conducted during the first 2 years of this project have identified 3 L. pneumophila vaccines effective against L. pneumophila infection in an animal mode. These investigations have laid the foundation for further studies aimed at identifying molecules and epitopes of these molecules important to cell-mediated and protective immunity against L. pneumophila. Such studies hold great promise for the development of an effective vaccine against Legionnaires' disease.
Specific aims of this proposal are to: A. Determine optimal conditions for induction of protective immunity by L. pneumophila vaccines; B. Determine if immunization with L. pneumophila vaccines induces long- lasting immunity in guinea pigs; C. Determine if immunization with vaccines derived from L. pneumophila serogroup I induces protective immunity to other serogroups of L. pneumophila and other species in the Family Legionellaceae; D. Identify key epitopes of antigens that induce protective immunity; E. Identify additional L. pneumophila components and products to which immune guinea pigs have developed a cell-mediated and humoral immune response; F. Determine the capacity of additional L. pneumophila components or products to induce specific cell-mediated and humoral immune responses in guinea pigs; G. Determine if immunization with additional L. pneumophila components and products that induce cell- mediated immunity establishes protective immunity against L. pneumophila in guinea pigs; H. Determine the capacity of specific L. pneumophila components or products to stimulate human cell-mediated immunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI022421-06
Application #
3133460
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Project Start
1985-09-01
Project End
1994-06-30
Budget Start
1991-07-01
Budget End
1992-06-30
Support Year
6
Fiscal Year
1991
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
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
Horwitz, M A (1992) Interactions between macrophages and Legionella pneumophila. Curr Top Microbiol Immunol 181:265-82
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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