The protozoan parasite Plasmodium is the causative agent of malaria, which remains one of the most prominent public health challenges in the world today. Plasmodium-specific antibody responses are important for protecting against subsequent reinfections in humans and mice. However, while mice are protected after a single infection, protective immunity is slow to develop in humans due to the requirement of repeated infections for the generation of protective antibodies. Our long-term goal is to determine how protective antibody responses are generated and maintained in mice after Plasmodium infection, so that we can utilize this information to understand why antibody-mediated immunity is slow to develop in humans. Plasmodium-specific memory B cells are generated after infection in mice and humans; however, surprisingly little information is available regarding their specificity, phenotype, origin and affinity for malarial antigens. Our preliminary studies indicate that there are layers of heterogeneity within the memory B cell pool after Plasmodium infection and we hypothesize that this heterogeneity in the memory B cell pool contributes to functional diversity in a secondary infection. We propose to (Aim 1) characterize heterogeneous populations of memory B cells after P. yoelii 17X infection in mice and determine their origin. We will then (Aim 2) determine the function of distinct subsets of memory B cells after secondary infection. Additionally, our preliminary studies have identified two populations of memory T cells that express markers associated with follicular helper T cells. We propose to (Aim 3) determine if these populations of memory T cells are capable of differentiating into functional follicular helpe T cells that can support Ab production in a secondary infection and whether they are required for protection after challenge. To accomplish these goals we have developed innovative tools to track parasite- specific B cell responses at the cellular level utilizing parasites engineered to express hen egg-white lysozyme (HEL). Using HEL-specific transgenic B cells and a novel magnetic-bead based enrichment technique we can monitor and track the fate of antigen-specific B cells after infection with HEL expressing parasites. These innovative tools and approaches will provide valuable insight into understanding how protective immunity against Plasmodium is generated, is maintained, and functions in a secondary immune response and will identify key components involved in this process.

Public Health Relevance

Malaria is a disease caused by protozoan parasites of the genus Plasmodium, which is transmitted by mosquitos. Despite the availability of effective anti-malarial drugs and ongoing eradication campaigns this disease remains a global burden to human health, resulting in over 200 million of deaths per year, primarily in children under the age of five. Thus, an emphasis has been placed on understanding how the immune response, cell- and antibody-mediated, mediates protection against this infection in order to determine how protective immunity can be enhanced in a vaccine setting to ultimately provide and maintain immunity against this disease.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Pathogenic Eukaryotes Study Section (PTHE)
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Pesce, John T
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University of Arkansas for Medical Sciences
Schools of Medicine
Little Rock
United States
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Wikenheiser, Daniel J; Brown, Susie L; Lee, Juhyung et al. (2018) NK1.1 Expression Defines a Population of CD4+ Effector T Cells Displaying Th1 and Tfh Cell Properties That Support Early Antibody Production During Plasmodium yoelii Infection. Front Immunol 9:2277
Ghosh, Debopam; Brown, Susie L; Stumhofer, Jason S (2017) IL-17 Promotes Differentiation of Splenic LSK- Lymphoid Progenitors into B Cells following Plasmodium yoelii Infection. J Immunol 199:1783-1795
Wikenheiser, Daniel J; Stumhofer, Jason S (2016) ICOS Co-Stimulation: Friend or Foe? Front Immunol 7:304
Ghosh, Debopam; Wikenheiser, Daniel J; Kennedy, Brian et al. (2016) An Atypical Splenic B Cell Progenitor Population Supports Antibody Production during Plasmodium Infection in Mice. J Immunol 197:1788-800
Wikenheiser, Daniel J; Ghosh, Debopam; Kennedy, Brian et al. (2016) The Costimulatory Molecule ICOS Regulates Host Th1 and Follicular Th Cell Differentiation in Response to Plasmodium chabaudi chabaudi AS Infection. J Immunol 196:778-91