All ETDs from UAB

Advisory Committee Chair

Oralee H Branch

Advisory Committee Members

Julian C Rayner

Scott R Barnum

Elliot J Lefkowitz

Robert A Oster

Document Type

Dissertation

Date of Award

2009

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

GENETIC COMPLEXITY AND POPULATION DIVERSITY OF PLASMODIUM FALCIPARUM IN THE PERUVIAN AMAZON PATRICK LEE SUTTON MICROBIOLOGY GRADUATE PROGRAM ABSTRACT Characterizing the genetic complexity of immunologically relevant proteins, expressed during the life cycle of P. falciparum, is essential for identifying and advancing potential vaccine candidates. The current malaria immunity paradigm is rooted in high transmission studies which have investigated the impact of high genetic diversity on the development of humoral responses. Given the dynamic nature of malaria parasites, especially their ability to acclimate to change, it is likely that regions of low transmission do not share the same malaria immunity paradigm given the decreased environmental pressure. An underexplored, yet relevant, component of characterizing P. falciparum genetic diversity is the consideration of complex infections. Though it is known that complex infections have increased opportunities to out-cross, the consequence of long-term propagation has never been investigated. This study was conducted in the low transmission Peruvian Amazon and was guided by three objectives that were developed into the Specific Aims of this dissertation. In Specific Aim I (Chapter 2), the population-level diversity (PLD) in the antigen encoding vaccine candidate PfMSP119kD was examined and correlated to anti-PfMSP119kD human immune responses. In Specific Aim II (Chapter 3), the polymorphic PfMSP1-B2 was used to characterize the PLD and complexity of infection, permitting a unique opportunity to indentify how complex infections in this region are derived and maintained. In Specific Aim III (Chapter 4), 19 microsatellite loci were used to examine the longitudinal maintenance of genetic diversity within the constituents of complex infections compared to single-clone infections. We report low P. falciparum PLD, with few complex infections as defined by PfMSP1. It was also observed that the majority of the antibody responses to PfMSP119kD appear to be to conserved/shared antigenic sites, with some allele-specific response to the Q-. Further, it was shown that the current complex infections in this population are not expected to be caused by super-infection, but rather by multiple inoculation events. Upon microsatellite analysis, it was found that the constituents of complex infections clustered separately to single-clones infections, suggesting significant differences between clone-types on a genomic level. These observations support the evolutionary selection of complex infections in this cohort study.

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