Throughout his clinical work in veterinary medicine and his Ph.D. training in molecular biology the candidate's interests have focused on host- pathogen relationships and host factors involved in the resistance to disease. During these studies he has developed an appreciation for innate host defense mechanisms. This proposal represents an excellent opportunity for the candidate to work closely with the sponsor in a well regarded research environment which will contribute immensely to the candidate's working knowledge of immunology. This proposal is based on the remarkable finding that C57B/1O and C3H mice are resistant to infection with the parasite Leishmania major but are susceptible to infection with the related parasite Leishmania amazonensis. This susceptibility is manifested by a persistent non-healing cutaneous lesion accompanied by a poor cellular immune response. The disparity of the C3H immune response to these parasites provides an excellent opportunity to study factors critical to host resistance and susceptibility while minimizing known and unknown variables. Resistance to Leishmania is mediated by the development of a CD4+ Th1 response which is initiated by the cytokine IL-12. Our hypothesis is that lowered IL-12 production, IL-12 receptor expression, or differences in the levels of cytokines that positively or negatively influence IL-12 function are responsible for the inability of C3H mice to develop a Th1 response to L. amazonensis and heal. This proposal aims to characterize the role of IL- 12 in the immune response of the C3H mouse using competitive quantitative PCR to analyze cytokine gene expression during the course of L. amazonensis and L. major infection. The experiments in this proposal will also study the macrophage, the cell at the interface of the host-parasite interaction. These cells play a central role in the development of the adaptive immune response. This proposal aims to compare the macrophage response in these two infections and to identify the cytokine expression pattern of the L.amazonensis parasitized macrophage that presumably leads to susceptibility. The candidate's and sponsor's interests are in understanding the basis of the immune response which leads to resistance or susceptibility. The efforts of this proposal will have direct application to the development of more effective vaccines and treatments for infectious diseases.
| Jones, D E; Buxbaum, L U; Scott, P (2000) IL-4-independent inhibition of IL-12 responsiveness during Leishmania amazonensis infection. J Immunol 165:364-72 |
| Jones, D E; Elloso, M M; Scott, P (1998) Host susceptibility factors to cutaneous leishmaniasis. Front Biosci 3:D1171-80 |
| Jones, D; Elloso, M M; Showe, L et al. (1998) Differential regulation of the interleukin-12 receptor during the innate immune response to Leishmania major. Infect Immun 66:3818-24 |
