Genomes and Genes
Characterization of CCR5-like Molecules in Leishmania
Principal Investigator: Lynn Soong
Abstract: DESCRIPTION (provided by applicant): Leishmania infection can cause a broad spectrum of leishmaniases in humans. Although it is well known that host- and parasite-derived factors contribute to disease outcome, our knowledge about their molecular interactions is still relatively limited. The long-term goal of this application is to define the mechanism(s) underlying the host susceptibility to L. amazonensis (La) infection. A hallmark of cutaneous leishmaniasis associated with La infection is the profound deficiency in cellular immunity to the parasite. An insufficient production of Th1 cytokines and inflammatory CC-chemokines is correlated with disease progression in murine La infection. Our antibody- and ligand-based studies have revealed that lesional and cultured La and L. mexicana parasites can express CCR5-like molecules. These findings have led to the hypothesis that Leishmania parasites express one or more molecules that mimic and interfere with the host CCR5 system, thus promoting homing of parasites to their target cells and/or modulating chemokine responses in situ. This hypothesis will be tested concurrently in two Specific Aims. Aim 1 is to confirm the expression of CCR5-like molecules in different species/strains of Leishmania and to examine the biological relevance of their expression in host-parasite interaction. Our efforts will mostly be placed on conducting functional studies (Ca++ influx, chemotaxis and ligand binding/internalization assays) using murine and human CCR5 ligands, as well as ligands that do not bind to CCR5. Aim 2 is to characterize the gene encoding parasite-derived CCR5 and define the nature of these proteins. The gene encoding CCR5-like molecules will be used for sequence comparison with their mammalian or viral counterparts. Stable cell lines expressing LaCCR5 and antibodies specific to leishmanial CCR5-like proteins will be generated for re-evaluation in functional assays. This proposed study is novel and highly significant because, while solid evidence exists for molecular mimicry of host cytokines/chemokines and their receptors by many pathogens, including DNA viruses, Toxoplasma gondii, and Schistosoma mansoni, such mimicry has not been identified for trypanosomatids. The fact that reagents are in place, linked with the PI's experience in immunology and molecular biology, ensures the feasibility of this exploratory grant. If proven correct, this study would, for the first time, demonstrate the presence of a functional CCR5 homologue(s) in Leishmania parasites. This application would greatly extend our current understanding of Leishmania biology and lay the foundation for additional in-depth investigations of host-parasite interactions.
Funding Period: ----------------2008 - ---------------2011-
more information: NIH RePORT
- Immunopathogenesis of non-healing American cutaneous leishmaniasis and progressive visceral leishmaniasisLynn Soong
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555 1070, USA
Semin Immunopathol 34:735-51. 2012..A better understanding of the quality and regulation of innate immunity and T cell responses triggered by Leishmania will aid in the rational control of pathology and the infection...
- Phosphatidylserine exposure on the surface of Leishmania amazonensis amastigotes modulates in vivo infection and dendritic cell functionJ L M Wanderley
Morphological Sciences Program, Biomedical Sciences Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
Parasite Immunol 35:109-19. 2013..This study provides new information regarding the mechanism of immune suppression in Leishmania infection...
- Differential microbicidal effects of human histone proteins H2A and H2B on Leishmania promastigotes and amastigotesYingwei Wang
College of Veterinary Medicine, China Agricultural University, Beijing, China 100193
Infect Immun 79:1124-33. 2011..We discuss the influence of promastigote major surface molecules in the leishmaniacidal effect of histone proteins. This study provides new information on host innate immunity to different developmental stages of Leishmania parasites...