Recent vaccination attempts using different immunogens such as viral vectors, DNA or synthetic constructs expressing pre-erythrocytic malaria antigens or their T cell epitopes, have provided important new information regarding the protective role of these T cells. It was shown that mice immunized with different immunogens, including selected viral vectors, expressing the same plasmodial sequence, induce malaria-specific CD8+ T cells which strongly inhibit liver stage development, conferring sterile immunity to a significant proportion of the immunized mic. These studies and others have raised a number of important questions related to the induction of effector and memory CD8+ T cell responses which need to be answered in order to further advance the design and development of an effective malaria vaccine. 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. We propose to identify the parameters which closely reflect the in vivo anti-parasite activity of effector and memory CD8+ T cells and characterize the optimal conditions to establish efficient effector and memory CD8+ T cell responses. We also propose to study the immuno-regulatory mechanisms controlling the in vivo induction and maintenance of effector and memory CD8+ T cell responses. Using transgenic mice expressing a T cell receptor specific for a CD8+ T cell epitope of the P. yoelii CS protein , recently generated in my laboratory, we will study the molecular and functional properties characterizing the differentiation of CD8+ T cells from naive to effector and memory cells. Other transgenic mice expressing a pertinent class I MHC only in hepatocytes, also recently generated in my laboratory, will be used to evaluate the role of hepatocytes in the induction/activation of effector and memory CD8+ T cells directed against P. yoelii liver stages. Finally we propose studies aimed at enhancing the magnitude and efficacy of effector and memory CD8+ T cell responses by immunization with double recombinant vaccinia viruses expressing the P. yoelii CS protein and cytokines known to exert important immunomodulatory effects on T cell responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI044375-04
Application #
6497122
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Program Officer
Hall, B Fenton
Project Start
1999-09-01
Project End
2003-01-31
Budget Start
2002-02-01
Budget End
2003-01-31
Support Year
4
Fiscal Year
2002
Total Cost
$399,356
Indirect Cost
Name
New York University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10016
Espinosa, Diego A; Christensen, Dennis; Muñoz, Christian et al. (2017) Robust antibody and CD8+ T-cell responses induced by P. falciparum CSP adsorbed to cationic liposomal adjuvant CAF09 confer sterilizing immunity against experimental rodent malaria infection. NPJ Vaccines 2:
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; Kastenmüller, 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
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
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
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
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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