Lymphatic filariasis is a major cause of morbidity in the tropics, and is caused by mosquito-borne filarial nematodes in the general Wuchereria and Brugia. The life cycle of these nematodes is complex, and relies on transmission of larval stages from mosquito to human, and vice versa. Our long-term objectives are to characterize parasite molecules that are crucial for the infectivity of the L1 stage parasites (microfilariae) for the mosquito host, in the hopes that they can be targeted to curtail man-to-vector transmission. Within the lymphatics of the human host, adult worms copulate and the females shed live immature microfilariae. The larvae are carried into the peripheral circulation and are ingested by the mosquito vector during a blood meal. Newborn microfilariae, however, are not immediately effective for the mosquito host, but must undergo a maturation process in the bloodstream prior to uptake. Maturation is accompanied by changes in microfilarial protein expression, and our hypothesis is that the difference in infectivity between immature and mature microfilariae can be explained by differences in gene expression. We will test this hypothesis by comparing gene expression patterns of immature and mature microfilariae using microarray technology.
The specific aims of this project are to: (1) demonstrate the difference in infectivity status of immature and mature Brugia malayi microfilariae using mosquito infectivity assays, (2) use microarray hybridization technology to identify microfilarial genes that are differentially expressed during maturation, and (3) develop candidates for further study by grouping differentially expressed gene products by proposed function and verifying transcriptional patterns using real time PCR. This approach will allow us to identify molecules that promote maturation of newborn B. malayi larvae that allow transmission from man to the disseminating mosquito vector. It's conceivable that parasite molecules that play integral roles in the maturation process can be targeted by drugs or vaccines designed to inhibit reproduction or curtail transmission to the mosquito. These strategies have the potential for breaking the transmission cycle of lymphatic filariasis and reducing the burden of illness and disability in tropical nations. ? ? ?
