Malarial remains a global health burden that impacts >40% of humans. Although bed nets and antimalarial drugs have reduced the incidence and severity of malaria, ~200,000,000 cases still occur annually with high mortality in children from sub-Saharan Africa. Additionally, front line drug therapies are now threatened by spread of resistant parasites. Thus, new approaches to effective vaccines and therapeutics are in need. A critical limitation is our incomplete understanding of how the parasite manipulates host immune responses to permit chronic and recurring blood-stage infections. We used rodent malaria models to evaluate the cellular dynamics of the CD4 T cell and B cell responses generated during chronic blood-stage infection and then compared these findings to humans living in endemic areas. These studies reveal that Tregs, which expand in both humans and rodents during blood-stage malaria, interfere with conventional T helper (Th) responses and the Follicular T helper (Tfh) cell:B cell partnership in germinal centers. Importantly, the negative impact of Tregs occurs in a previously unrecognized but critical temporal window after infection to impede protective immunity, through CTLA-4. Precisely timed targeting of Tregs or CTLA-4 enhanced immune responses, accelerated clearance, and generated species-transcending immunity to blood-stage malaria. Thus, our preliminary data uncover a critical mechanism of immune-suppression associated with blood-stage malaria. A full understanding of the cellular and molecular basis for compromised immunity in blood-stage malaria is the long-term goal of this competitive renewal application. We will address these issues with the following specific aims: SA 1: Determine how precisely timed Treg-depletion and CTLA-4 blockade impacts malaria-specific T cell and B cell responses to facilitate clearance of PRIMARY blood-stage infections. SA 2: Determine how precisely timed Treg-depletion and/or CTLA-4 blockade impacts malaria-specific memory T cell and B cell responses to facilitate species transcending control of SECONDARY blood-stage infections. SA 3: Dissect how and when inhibitory pathways and cells limit clearance of PRIMARY infection and prevent development of species transcending control of SECONDARY infections.
Malaria parasites persist in the blood of infected humans for extended periods and immunity, capable of preventing new malaria infections, does not develop. These immune failures strongly suggest that the parasite is capable of diverting or dampening protective immune responses. Understanding how this occurs is the goal of the current proposal and has the potential to aid in therapeutic and vaccine approaches to protect against malaria.
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|Van Braeckel-Budimir, Natalija; Gras, Stephanie; Ladell, Kristin et al. (2017) A T Cell Receptor Locus Harbors a Malaria-Specific Immune Response Gene. Immunity 47:835-847.e4|
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|Doll, Katherine L; Harty, John T (2014) Correlates of protective immunity following whole sporozoite vaccination against malaria. Immunol Res 59:166-76|
|Doll, Katherine L; Butler, Noah S; Harty, John T (2014) CD8 T cell independent immunity after single dose infection-treatment-vaccination (ITV) against Plasmodium yoelii. Vaccine 32:483-91|
|Nolz, Jeffrey C; Harty, John T (2014) IL-15 regulates memory CD8+ T cell O-glycan synthesis and affects trafficking. J Clin Invest 124:1013-26|
|Gorman, Jacob V; Starbeck-Miller, Gabriel; Pham, Nhat-Long L et al. (2014) Tim-3 directly enhances CD8 T cell responses to acute Listeria monocytogenes infection. J Immunol 192:3133-42|
|Starbeck-Miller, Gabriel R; Xue, Hai-Hui; Harty, John T (2014) IL-12 and type I interferon prolong the division of activated CD8 T cells by maintaining high-affinity IL-2 signaling in vivo. J Exp Med 211:105-20|
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