: This proposal seeks to test the hypothesis that the intracellular protozoan, Leishmania spp., is able to manipulate both the innate and the adaptive immune response of the host to their advantage. We propose that promastigotes are infectious because they evade the innate immune response. We also propose that amastigotes are infectious because they exploit the adaptive immune response.
The first aim of the proposal will examine innate immune activation by Leishmania promastigotes.
This aim i s built on the observation that Leishmania promastigotes infect leukocytes by a process that fails to induce the production of cytokines and co-stimulatory molecules. This led us to hypothesize that Leishmania promastigotes fail to interact with TLRs, and as a consequence fail to translocate NF-kappaB in macrophages and dendritic cells. The main question that we will ask in Aim 1 is whether this quiescent mechanism of entry is a critical component of parasite virulence. To address this question, we have developed transgenic Leishmania parasites that express TLR activators on their surface. We will measure the infectivity of these transgenic organisms in mice and in cell cultures.
The second aim of this proposal is based on our observation that mice lacking the heavy chain of IgG (JH mice) are resistant to L. major infections despite being on a BALB/c background. We have also observed that the addition of anti-Leishmania IgG to these mice reverts them back to being susceptible to L. major infections. In the second aim of this proposal, we plan to determine how IgG can work to the detriment of the host infected with an intracellular pathogen. We will determine the role of IL-10 in this process, and specifically the role of APC-derived IL-10 as an IgG-induced permissive factor. These studies pertain directly to the pathogenesis of Leishmania infection. They may also provide important basic information about the role of antibody during infections with intracellulars, and about the ability of APCs to influence the nature of an adaptive immune response.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI055576-03
Application #
7224915
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Program Officer
Wali, Tonu M
Project Start
2005-06-01
Project End
2010-02-28
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
3
Fiscal Year
2007
Total Cost
$316,811
Indirect Cost
Name
University of Maryland College Park
Department
Anatomy/Cell Biology
Type
Schools of Earth Sciences/Natur
DUNS #
790934285
City
College Park
State
MD
Country
United States
Zip Code
20742
Yang, Ziyan; Zhang, Xia; Darrah, Patricia A et al. (2010) The regulation of Th1 responses by the p38 MAPK. J Immunol 185:6205-13
Yang, Ziyan; Mosser, David M; Zhang, Xia (2007) Activation of the MAPK, ERK, following Leishmania amazonensis infection of macrophages. J Immunol 178:1077-85
Miles, Suzanne A; Conrad, Sean M; Alves, Renata G et al. (2005) A role for IgG immune complexes during infection with the intracellular pathogen Leishmania. J Exp Med 201:747-54