Malaria, a disease caused by parasitic protozoans in the genus Plasmodium, is transmitted by mosquitoes to humans. Each year, hundreds of millions of people are infected with this organism and millions of fatalities result, mostly in young children. The problem is how worsening because of the increasing resistance of parasites to drugs. Mosquito control is also threatened because of insecticide resistance, increasing costs, and loss of trained personnel. Thus, new methods for malaria control are needed. An important target for research is the interaction between the mosquito and the parasite. The long-term goal of our research is to understand the molecular determinants of vector competence. We study the ways mosquitoes can kill parasites and how parasites avoid these responses as well as the mosquito factors that malaria parasites require for successful development. With this knowledge, we can attempt to enhance mechanisms that cause mosquito/parasite incompatibilitity through genetic or chemical manipulation of vector mosquitoes or to block the transmission of parasites by targeting mosquito molecules essential for parasite development. The proposed research will focus on how c-type lysozymes affect Plasmodium development in Anopheles gambiae. Silencing of the lysozyme c-1 gene results in a dramatic reduction in the number of mosquitoes that become infected with Plasmodium. Unexpectedly, Lys c-1 binds to oocysts, so this protein directly interacts with parasites.
Specific Aim 1 will focus on 1) describing how Lys c-1 interacts with midgut and salivary stages of malaria parasites, using immunohistqchemical techniques; 2) determining whether anti Lys c-1 antibodies can be used to block parasite development; and 3) characterizing the contribution of Lys c-1 to antibacterial immunity, through gene silencing and subsequent infection with bacteria. Two other lysozymes, Lys c-2 and Lys c-7, are upregulated in the mosquito midgut when parasite infection occurs.
Specific Aim 2 will examine 1) the effect of gene knockdown of Lys c-2 or c-7 on parasite development; and, 2) describing the changes in proteins and transcripts that occur during parasite infections, through western blotting, immunohistochemistry, and quantitative PCR. ? ? ?
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