CD8+ T cells play a major protective role in immunity to malaria infection by inhibiting the development of liver stages. Vaccination studies using malaria sporozoites, and recombinant viral vectors as well as synthetic constructs such as DNA, have provided important new information regarding the protective role of these T cells. Our recent studies on CD8+ T cell responses against the CS protein of P. yoelii established that when sporozoites are delivered by mosquito bites, the T cell response is induced by dendritic cells (DCs) in skin draining lymph nodes (LN). Primed cells migrate to peripheral organs including the liver, where they develop memory CD8+ populations. Upon challenge these liver resident CD8+ T cells are able to eliminate malaria infection. To protect, T cells have to see antigen in the context of liver parenchymal cells - presumably infected hepatocytes - and need not be re-stimulated by bone-marrow derived DCs. Thus the processes of priming the CD8+ T cell response and eliciting effector function from those cells involve different cellular and molecular interactions. We propose to undertake studies aimed at characterizing some basic aspects of the in vivo CD8+ T cell responses against the liver stages of P. yoelii. These studies aim to define basic features of the key initial interactions that occur between sporozoites, DCs and pattern recognition receptors which lead to the acquisition and presentation of parasite antigen to CD8+ T cells in LN. We also propose studies on liver-resident memory CD8 cells which aim at characterizing the mechanisms that mediate their homing to the liver, at defining their functional properties and evaluating conditions that may modulate the permanence and anti-parasite activity of these memory cells. These studies will be facilitated by the availability of TCR transgenic mice and transgenic parasites expressing model CD8 epitopes developed in my laboratory. These enable us to track CD8 T cells throughout their differentiation in both normal and gene-knockout animals. Finally, we will develop research aimed at studying the functional properties and evolution of memory responses against the P. yoelii CS protein. We will evaluate the fate of these memory cells under continued antigen stimulation which normally occurs due to repeated parasite exposure and antigen persistence. We will study the renewal mechanisms of memory populations and the relationship between different memory cell subsets i.e., those residing in the liver (effector memory and those from lymph nodes (central memory).

Public Health Relevance

The proposal aims at investigating basic features of CD8+ T cell responses against Malaria liver stages. We propose to characterize the role of dendritic cell subsets in induction of this response, the role of adhesion molecule in homing and functional properties of liver-resident anti-Malaria memory T cells and study the mechanisms controlling the evolution and maintenance of protective memory CD8+ T cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI044375-15
Application #
8520154
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Wali, Tonu M
Project Start
1999-02-15
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
15
Fiscal Year
2013
Total Cost
$518,470
Indirect Cost
$202,330
Name
Johns Hopkins University
Department
Microbiology/Immun/Virology
Type
Schools of Public Health
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Espinosa, Diego A; Radtke, Andrea J; Zavala, Fidel (2016) Development and Assessment of Transgenic Rodent Parasites for the Preclinical Evaluation of Malaria Vaccines. Methods Mol Biol 1403:583-601
Karen, Kasey A; Deal, Cailin; Adams, Robert J et al. (2015) A replicating adenovirus capsid display recombinant elicits antibodies against Plasmodium falciparum sporozoites in Aotus nancymaae monkeys. Infect Immun 83:268-75
Radtke, Andrea J; Tse, Sze-Wah; Zavala, Fidel (2015) From the draining lymph node to the liver: the induction and effector mechanisms of malaria-specific CD8+ T cells. Semin Immunopathol 37:211-20
Whitacre, David C; Espinosa, Diego A; Peters, Cory J et al. (2015) P. falciparum and P. vivax Epitope-Focused VLPs Elicit Sterile Immunity to Blood Stage Infections. PLoS One 10:e0124856
Espinosa, Diego A; Gutierrez, Gabriel M; Rojas-López, Maricarmen et al. (2015) Proteolytic Cleavage of the Plasmodium falciparum Circumsporozoite Protein Is a Target of Protective Antibodies. J Infect Dis 212:1111-9
Radtke, Andrea J; Kastenmuller, Wolfgang; Espinosa, Diego A et al. (2015) Lymph-node resident CD8*+ dendritic cells capture antigens from migratory malaria sporozoites and induce CD8+ T cell responses. PLoS Pathog 11:e1004637
Deal, Cailin; Balazs, Alejandro B; Espinosa, Diego A et al. (2014) Vectored antibody gene delivery protects against Plasmodium falciparum sporozoite challenge in mice. Proc Natl Acad Sci U S A 111:12528-32
Sack, Brandon K; Miller, Jessica L; Vaughan, Ashley M et al. (2014) Model for in vivo assessment of humoral protection against malaria sporozoite challenge by passive transfer of monoclonal antibodies and immune serum. Infect Immun 82:808-17
Tse, Sze-Wah; Radtke, Andrea J; Espinosa, Diego A et al. (2014) The chemokine receptor CXCR6 is required for the maintenance of liver memory CD8⁺ T cells specific for infectious pathogens. J Infect Dis 210:1508-16
Luo, Kun; Zhang, Hong; Zavala, Fidel et al. (2014) Fusion of antigen to a dendritic cell targeting chemokine combined with adjuvant yields a malaria DNA vaccine with enhanced protective capabilities. PLoS One 9:e90413

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