Malarial disease, caused by Plasmodium species, remains an unresolved global health burden that impacts >40% of the world's population. Although the availability of insecticide treated bed nets and antimalarial drugs has reduced the incidence and severity of malaria in some regions, ~200,000,000 cases still occur annually with ~850,000 fatalities in 2013. Thus, vaccines to prevent malaria remain an as yet unrealized but critical goal to combat this global threat. As shown in our preliminary data, only some of Plasmodium antigens that elicit CD8 T cell responses were targets of CD8 T cell mediated sterilizing immunity.
Aim 1 will address the mechanisms that determine whether a specific Plasmodium antigen is the target of effective protection by memory CD8 T cells. Information generated from this aim will provide a practical basis to select new candidate antigens, from the expressed pool of ~5,000 ORF, for evaluation as subunit vaccines to protect against human malaria. Importantly, despite repeated exposures, sterilizing immunity (defined as prevention of blood-stage parasitemia after sporozoite infection) does not develop in individuals living in malaria endemic areas. Indeed our preliminary data reveal both numerical and functional impairment of memory CD8 T cells generated during malaria infection.
In aim 2, we will use our newly developed tool-chest, including TCR-retrogenic mice specific for recently identified Plasmodium antigens, to determine how memory CD8 T cells generated after malaria infection are numerically and functionally impaired. Our long-term goal is to understand the mechanisms underlying protective CD8 T cell immunity to liver- stage Plasmodium infection in order to aid in the rational development of effective vaccines. SA 1. Determine why some, but not all Plasmodium antigens are targets of protective CD8 T cells. SA2. Determine the mechanism(s) by which Plasmodium infection results in compromised memory CD8 T cell populations.

Public Health Relevance

Much emphasis in the field of subunit vaccines for malaria has been placed on improving the vector systems for antigen-delivery and these empirical approaches are likely to improve the existing delivery platforms and potentially reveal new platforms. However, despite the more than 40 years of research in malaria vaccines, we still know very little about 1) the identity of the target antigens that would be included in optimal subunit vaccines and 2) why individuals living in malaria endemic areas do not develop sterilzing immunity. Addressing these knowledge gaps would aid in the rational design of malaria vaccines and is the goal of this proposal.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI085515-10
Application #
9850193
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Pesce, John T
Project Start
2009-12-01
Project End
2021-01-31
Budget Start
2020-02-01
Budget End
2021-01-31
Support Year
10
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Iowa
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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Doll, Katherine L; Pewe, Lecia L; Kurup, Samarchith P et al. (2016) Discriminating Protective from Nonprotective Plasmodium-Specific CD8+ T Cell Responses. J Immunol 196:4253-62
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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
Starbeck-Miller, Gabriel R; Badovinac, Vladimir P; Barber, Daniel L et al. (2014) Cutting edge: Expression of Fc?RIIB tempers memory CD8 T cell function in vivo. J Immunol 192:35-9
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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