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Determination of the Toll like receptor-activated cell producing gamma-interferon during experimental Trypanosoma Cruzi infection

Grant number: 10/13467-6
Support type:Scholarships in Brazil - Master
Effective date (Start): March 01, 2011
Effective date (End): June 30, 2012
Field of knowledge:Biological Sciences - Immunology
Principal Investigator:Maria Regina D'Império Lima
Grantee:Letícia Sarturi Pereira Severi
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Malaria is a disease responsible for the deaths of over a million people every year worldwide, making it a serious public health problem. Humans infected by Plasmodium parasites develop syndromes such as cerebral malaria, respiratory syndrome and severe anemia, which seem to be related to heightened immune response to infection. Thus, although the immune system acts to be protective against parasites, it also seems to contribute to the worsening of the disease. On the other hand, the development of the acquired immune response is associated with the establishment of clinical immunity, while sterile immunity against human malaria is probably never achieved. It has been observed an intense type 1 response from CD4+ and CD8+ T cells in mice infected with P. chabaudi during the acute phase of the disease. This immune response contributes to the protection of mice and the control of parasitemia acute, but is also responsible for clinical manifestations malaria. The acute immune response has short duration, and regulatory mechanisms seem to be essential for its control, providing the development of acquired immune response. Inhibitory molecules such as PD-1 and its ligand PDL-1 are expressed at high levels in CD4+ and CD8+ cells from mice in the acute phase of infection with P. chabaudi. It is known that these molecules inhibit the phosphorylation of T cell receptor (TCR), braking the activation and killing these cells. Thus, the interaction between PD-1 and PDL-1 would act as a regulatory mechanism to ensure homeostasis, reducing the damage for host caused by immune response. Therefore, this project aims to verify the role of PD-1 and PDL-1 molecules in activation and death of CD4+, CD4+ Foxp3+ and CD8+ T cells from spleen of mice during acute infection with P. chabaudi. It is intended to assess: 1) The kinetics of expression of PD-1 and PDL-1 molecules in vivo and in vitro during the first ten days post infection, 2) The in vitro effect of treatment with monoclonal anti-PDL-1 and RNA interference for PDL-1 on activation and death of CD4+, CD4+ Foxp3+ and CD8+ T cells stimulated with infected red blood cells and 3) The ability of T cells from infected mice which express high levels of PDL-1 to regulate the activation of T cells from uninfected mice. This study aims to amplify the understanding of inhibitory mechanisms involved in regulating the immune response against malaria.

Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
SEVERI, Letícia Sarturi Pereira. Papel das moléculas PD-1 e PD-L1 na regulação da resposta aguda dos linfócitos T CD4+ e CD8+ à infecção pelo Plasmodium chabaudi.. 2012. Master's Dissertation - Universidade de São Paulo (USP). Instituto de Ciências Biomédicas São Paulo.

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