Infection with Leishmania amazonensis (La) can cause diverse forms of leishmaniasis in humans in the New World, and results in non-healing cutaneous lesions in most inbred mouse strains. Host factors responsible for this generalized susceptibility are poorly understood;however, it is clear that control of this infection relies on the induction of a strong Th1-type immune response. Evidence generated during the previous funding period has highlighted unique aspects of host-parasite interaction, and supports a novel hypothesis that this parasite not only suppresses activation of innate and Th1 responses via an IL-4-independent mechanism, but also takes advantage of the adaptive immune system for its propagation and persistence. This application is to seek continued support in three specific areas of research that are cohesively linked. First, we will examine whether susceptibility to La infection is due to defects at the level of dendritic cells (DC) via alteration of their antigen-presenting functions. Comparative studies will be conducted using a mouse strain that gives rise to different disease outcomes following infection with La and L. major. Secondly, we will focus on the La infection model and examine the impact of DC-stimulating agents on parasite-specific immunity and disease outcome. Studies employing cytokines, chemokines, and ligands for Toll-like receptors (TLR) will provide a mechanistic explanation of defects in La-infected DCs. Finally, we will examine the mechanisms and potential of modulating regulatory T cells for the control of La infection in naive and immunized mice. Approaches will include cell depletion prior to treatment/immunization and adoptive transfer of traceable cells to wild-type or gene-targeted knockout mice. Completion of this proposed study will aid in designing new control strategies for Leishmania and other chronic infections for which therapeutic/preventive interventions are not available.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI043003-11
Application #
7778212
Study Section
Special Emphasis Panel (ZRG1-IDM-M (03))
Program Officer
Wali, Tonu M
Project Start
1998-12-01
Project End
2012-02-28
Budget Start
2010-03-01
Budget End
2012-02-28
Support Year
11
Fiscal Year
2010
Total Cost
$243,338
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Wanderley, J L M; Thorpe, P E; Barcinski, M A et al. (2013) Phosphatidylserine exposure on the surface of Leishmania amazonensis amastigotes modulates in vivo infection and dendritic cell function. Parasite Immunol 35:109-119
Soong, Lynn; Henard, Calvin A; Melby, Peter C (2012) Immunopathogenesis of non-healing American cutaneous leishmaniasis and progressive visceral leishmaniasis. Semin Immunopathol 34:735-51
Franca-Costa, Jaqueline; Wanderley, Joao Luiz Mendes; Deolindo, Poliana et al. (2012) Exposure of phosphatidylserine on Leishmania amazonensis isolates is associated with diffuse cutaneous leishmaniasis and parasite infectivity. PLoS One 7:e36595
Desai, Mayura M; Gong, Bin; Chan, Tehsheng et al. (2011) Differential, type I interferon-mediated autophagic trafficking of hepatitis C virus proteins in mouse liver. Gastroenterology 141:674-85, 685.e1-6
Sun, Jiaren; Desai, Mayura M; Soong, Lynn et al. (2011) IFN-?/? and autophagy: tug-of-war between HCV and the host. Autophagy 7:1394-6
Xin, L; Wanderley, J L; Wang, Y et al. (2011) The magnitude of CD4(+) T-cell activation rather than TCR diversity determines the outcome of Leishmania infection in mice. Parasite Immunol 33:170-80
Xu, Wei; Xin, Lijun; Soong, Lynn et al. (2011) Sphingolipid degradation by Leishmania major is required for its resistance to acidic pH in the mammalian host. Infect Immun 79:3377-87
Wang, Yingwei; Chen, Yang; Xin, Lijun et al. (2011) Differential microbicidal effects of human histone proteins H2A and H2B on Leishmania promastigotes and amastigotes. Infect Immun 79:1124-33
Vargas-Inchaustegui, Diego A; Hogg, Alison E; Tulliano, Gianfranco et al. (2010) CXCL10 production by human monocytes in response to Leishmania braziliensis infection. Infect Immun 78:301-8
Xin, Lijun; Vargas-Inchaustegui, Diego A; Raimer, Sharon S et al. (2010) Type I IFN receptor regulates neutrophil functions and innate immunity to Leishmania parasites. J Immunol 184:7047-56

Showing the most recent 10 out of 25 publications