Lymphatic filariasis remains a major health problem in sub-Saharan Africa, the Indian subcontinent and Southeast Asia. The characterization of cellular immune mechanisms responsible for the induction and regulation of lymphatic lesions remains a central question in filariasis and is the focus of this project. The Brugia -jird model will continue to be used and is uniquely suited for this purpose.
Three specific aims have been formulated.
Specific Aim 1 is to characterize the pattern of cytokine gene expression during the induction, maintenance and down regulation of the granulomatous inflammatory response to parasite antigen. It is hypothesized that parasites induce a shift in cytokine gene expression from a Th0 type to a Th2 type corresponding to increases and decreases in the level of lymphatic inflammation seen. Further, it is hypothesized that immunizations which induce a protective resistance, and /or prolonged inflammatory responses do not induce a shift to a Th2 dominated response. These changes will be assessed by measuring cytokine mRNA and protein levels in various lymphoid compartments following infection.
Specific Aim 2 is to measure the induction of filariae associated inflammation and cytokine expression in jirds primed to posses a dominant Th1 cytokine profile and conversely the effect of a Th1 inducing agent on these inflammatory and cytokine responses during a chronic modulated filarial infection. It is hypothesized that existing cytokine profiles will determine the outcome of filariae induced inflammatory responses and that an increase in lesion severity will correspond to the Type 1 profile and vice versa. Heat killed Brucella abortus a strong inducer of Type 1 cytokine expression, will be used for this purpose.
Specific Aim 3 is to measure the effect of exogenous cytokines on the induction and regulation of granulomatous inflammatory responses and cytokine expression during a primary filarial infection. The hypothesis that Type 1 cytokines promote the induction and maintenance of lymphatic inflammation and that Type 2 cytokines down regulate this response will be tested in vivo by the administration of recombinant jird IFN-gamma, IL-2 and IL-4 to animals at various stages of the infection.
| Zipperer, Ginger R; Arumugam, Sridhar; Chirgwin, Sharon R et al. (2013) Brugia pahangi: immunization with early L3 ES alters parasite migration, and reduces microfilaremia and lymphatic lesion formation in gerbils (Meriones unguiculatus). Exp Parasitol 135:446-55 |
