Book of Abstracts: Albany 2003
June 17-21 2003
Modeling of a Leishmania Antigen eIF-4A : A Potential Epitope Implicated in the Adjuvant Effect is Identified
In leishmaniasis, the development of an effective vaccine depends on its capacity to elicit Th1 immune responses. Despite many approaches, recent vaccines do not induce sufficient levels of protection and long-term memory. To overcome this problem, vaccines are used with adjuvants that drive immunity towards Th1 and enhance endogenous production of IL-12, a Th1-promoting cytokine. Although exogenous IL-12 may act as an effective adjuvant, it has an elevated cost and toxic effects. Therefore, it is important to develop cheap and safer adjuvants that trigger endogenous IL-12. Of particular interest is LmeIF a unique Leishmania protein that provides significant adjuvant effects by stimulating high IL-12 production.
This investigation was designed to identify the structural factors responsible for the adjuvant effects of LmeIF by establishing the 3D models of LmeIF and MueIF (mouse) by homology modeling based on the X-ray structure of their homologs in yeast and comparing their stereo-electronic properties. The molecular electrostatic potential was computed around each model and used to localize the active site and the most different amino acids between LmeIF and MueIF. Sequence alignment of LmeIF with eIF-4 from other species showed three residues (Q186, A189, E214) in the active site which were peculiar to the Leishmania protein. Long MD simulation was carried out on LmeIF fragment 129-261 to compare its folding with the native protein. Despite a high degree of sequence similarity with different species, we have identified in LmeIF a set of residues unique to the protozoan parasite Leishmania which may be potentially responsible for its adjuvant property. Using LmeIF model, a plausible surface region for binding with its receptor was also identified.
1Unité de Modélisation Moléculaire,