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Advisory Committee Chair

Oralee H Branch

Advisory Committee Members

Peter D Burrows

Louis B Justement

Robert A Oster

Julian C Rayner

Document Type

Dissertation

Date of Award

2010

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Each year 300-500 million cases of Plasmodium falciparum malaria occur, leading to more than 1 million deaths. In high malaria transmission regions, development of immunity from severe infection requires 2-10 years of persistent parasitemia. This delay has been attributed to difficulties in the development of protective humoral responses. Indeed, anti-malarial antibody responses tend to be short-lived, and immunologic memory seems to be dysfunctional in high-transmission regions. In contrast, in the low-transmission Peruvian Amazon >60% of infections are asymptomatic, suggesting that clinical immunity occurs despite low parasite exposure. To analyze more precisely the naturally-acquired humoral responses to malarial antigens and their clinical implications in this low-transmission region, three specific aims were developed. In Aim I, the immunogenicity of various P. falciparum antigens and the duration of their antibody responses were evaluated. Associations among longevity of antibody responses and age as well as amount of prior parasite exposure were also examined. In Aim II, antibody data were compared to clinical information to determine the role of anti-malarial antibody responses in generating clinical protection. In addition, clinical infection type was correlated to Ig isotype prevalence to gauge the functionality of the anti-malarial response. In Aim III, B cell dynamics were evaluated in post-infection samples by using flow cytometry and malaria antigen-specific ELISPOT assays to determine whether Peruvians are able to generate malaria-specific immunologic memory. We found that, independent of age, many individuals living in this region are capable of maintaining long-lived responses to blood-stage antigens such as Merozoite Surface Protein-1 19kD (MSP-119) and AMA-1, lasting for more than a year post-infection. In addition, asymptomatic individuals are more likely than symptomatic individuals to have strong anti-MSP IgG and IgG subclass responses. We also found an expansion of the plasmablast (CD19+, CD27+, CD38high) population in most individuals shortly after infection, and evidence of MSP-1-specific memory B cells was demonstrated by ELISPOT analysis. Collectively, this data suggest that normal and relatively rapid development of immunity to P. falciparum is possible under the right conditions, such as those found in the low-transmission Peruvian Amazon.

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