Uninfected Mosquito Bites Confer Protection against Infection with Malaria Parasites

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Abstract
Despite decades of research and multiple initiatives, malaria continues to be one of the world's most debilitating infectious diseases. New insights for malaria control and vaccine development will be essential to thwart the staggering worldwide impact of this disease (A. Bjorkman and A. Bhattarai, Acta Trop. 94:163-169, 2005); ultimately successful vaccine strategies will undoubtedly be multifactorial, incorporating multiple antigens and targeting diverse aspects of the malaria parasites' biology (M. F. Good et al., Immunol. Rev. 201:254-267, 2004). Using a murine model of malaria infection, we show here that exposure to bites from uninfected mosquitoes prior to Plasmodium yoelii infection influences the local and systemic immune responses and limits parasite development within the host. In hosts preexposed to bites from uninfected mosquitoes, reduced parasite burdens in the livers were detected early, and during the blood-stage of the life cycle, these burdens remained lower than those in hosts that received mosquito bites only at the time of infection. Repeated exposure to bites from uninfected mosquitoes skewed the immune response towards a T-helper 1 (Th1) phenotype as indicated by increased levels of interleukin-12, gamma interferon, and inducible nitric oxide synthase. These data suggest that the addition of mosquito salivary components to antimalaria vaccines may be a viable strategy for creating a Th1-biased environment known to be effective against malaria infection. Furthermore, this strategy may be important for the development of vaccines to combat other mosquito-transmitted pathogens.