This work involves study of host defenses to leishmania. We have begun by concentrating on the roles of the macrophage and of complement - the main defenses in the initial infection of the non-immune host. We have already shown (i) that promastigotes activate the alternative complement pathway, and (ii) that this activation can lead either to parasite lysis or to binding to the macrophage complement receptor. We wish to pursue this aspect of our work by assessing complement resistance as a parasite virulence factor as follows: (a) by studying infection in decomplemented animals (using Cobra Venom) and in genetically complement-deficient strains (B10-D2/oSnN), (b) by examining the virulence of complement-resistant organisms prepared by selecting and cloning such organisms in vitro, and (c) by comparing the interaction with complement of virulent or avirulent strains of L. tropica. In addition to the complement-mediated interaction, leishmania can also bind directly to macrophages. Using our quantitative parasite binding assay, we propose to prepare both monoclonal and rabbit serum antibodies to the membrane component responsible for this binding, and then use these reagents in a quantitative receptor assay to determine (a) how tissue distribution of the receptor(s) for given species may relate to the capacity of that species to cause visceral or local disease, and (b) how receptor expression may be regulated by macrophage activation, by host age, by infection, or by genetic background (e.g., the Lshr gene for resistance to L. donovani). In addition, these antibodies could be used in vivo to learn how receptor blockade may affect infection. Lastly, we propose to compare the physiology of these two receptor types, in terms of the production of peroxide or other toxic oxygen species, the promotion of parasite uptake, and the ultimate intracellular fate of oganisms taken up by each of the two mechanisms, in order to understand better the relative significance of these two receptor mechanisms for the establishment of clincal disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI019888-02
Application #
3129349
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Project Start
1984-07-01
Project End
1987-06-30
Budget Start
1985-07-01
Budget End
1986-06-30
Support Year
2
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Type
Schools of Medicine
DUNS #
201373169
City
New York
State
NY
Country
United States
Zip Code
10065