Infections with Plasmodium parasites, the causative agents of malaria, constitute one of the world's largest disease burdens with up to 300 million infections and 1.2 million deaths each year. The parasite maintains an incredibly complex life cycle between mosquito vector and mammalian host. After transmission, it will pass through the skin and bloodstream as sporozoites, which infect liver hepatocytes, then develops as liver stages and emerges back into the blood as red blood cell-infective merozoites. The pre-erythrocytic (sporozoites and liver stages) phase is an ideal target for vaccine development as it is asymptomatic and has limited parasite numbers. However, as only one parasite can cause a fulminant blood stage infection, preventing blood stage disease with pre-erythrocytic immunity faces a challenge. Immunization with attenuated parasites which invade and infect the liver but fail to progress to blood stage have been highly effective in preclinical and clinical studies. The conventional understanding is that this protection relies predominantly by CD8+ T cells. However, I have shown that both monoclonal antibodies (mAb) against the sporozoite protein CSP and polyclonal antibodies (pAb) elicited by immunization with whole parasites are capable of providing robust protection against an infectious mosquito bite. The Abs elicited by whole parasite immunization (WPI) can also control a direct blood stage infection independent of T cell help. Little is known about the antibody effector mechanisms mediating this protection at either stage, but the cross-stage protection afforded by WPI provides an ideal platform on which to investigate these mechanisms. I propose to use this model to investigate the contributions of neutralization, complement-mediated lysis and opsonization underlying Ab-mediated protection in a rodent model of malaria.
Aim 1 will focus on protection against sporozoite infection by passive transfer of mutant mAb which lack specific FC-mediated effector functions. These mutant mAb will be compared to WT mAb for their ability to reduce liver stage burden following infection by mosquito bite. Furthermore, passive transfer of WPI serum followed by mosquito bite challenge in mice deficient in complement, FC receptor binding or both will elucidate the role of each mechanism in the context of WPI.
Aim 2 will expand this model to examine antibody-mediated protection in the blood stage of disease. Again, passive transfer of WPI serum to mice deficient in complement, FC receptor binding or both will be followed by direct blood stage challenge. By monitoring subsequent parasitemia, we will be able to determine the respective contributions (if any) of each effector mechanism to control of blood stage malaria. The studies proposed here represent the first comprehensive and exhaustive analysis of the mechanisms conferring antibody-mediated protection against both the sporozoite and blood stages of Plasmodium. Knowledge of the specific type of antibody response required for effective protection at these stages will guide the rational design of the next generation of malaria vaccines aimed at preventing infection.
Malaria continues to be one of the largest health burdens in the world and is caused by infection with an incredibly complex parasite. Understanding the precise details of how the immune system can control infection is key to designing an effective vaccine. This proposal seeks to uncover the details of how antibodies control the parasite at multiple stages of the life in order to apply these to future vaccine design.
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