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Protective effect of lipoxins against the development of severe forms of malaria

Grant number: 14/02143-6
Support type:Research Grants - Visiting Researcher Grant - International
Duration: May 07, 2014 - June 06, 2014
Field of knowledge:Biological Sciences - Parasitology
Principal Investigator:Fabio Trindade Maranhão Costa
Grantee:Fabio Trindade Maranhão Costa
Visiting researcher: Julio Cesar Soares Aliberti
Visiting researcher institution: Cincinnati Children's Hospital Medical Center, United States
Home Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Associated research grant:12/16525-2 - Plasmodium vivax: pathogenesis and infectivity, AP.TEM

Abstract

Lipoxins are small lipid mediators derived from lipoxygenase-mediated degradation of the arachidonic acid. LXA4, as well as aspirin-triggered LXA4, have been shown by us and others to mediate a growing list of anti-inflammatory actions alongside with the successful development of stable analogs raised the possibility of using lipoxins as a novel therapeutic alternative to control damaging inflammatory conditions. Malaria is a major public health concern worldwide. Severe malaria is a leading cause of death among infants and pregnant women in endemic areas. One of the key pathogenic mechanisms for the development of severe malaria is endothelial cell activation with subsequent up-regulation of adhesion molecules and infected red cell sequestration. Recently, we showed that treatment with exogenous lipoxins prevented the development of experimental cerebral malaria. In light of these results we hypothesize here that lipoxins mediate protection against the development of severe malaria via inhibition of infected red blood cell adhesion. Our long-term objective is to develop LX-based therapies as well as specific biomarkers to predict and therapeutically decrease the pathogenic potential of severe forms malaria. Thus, we aim to evaluate the anti-inflammatory/modulatory actions of lipoxins in the activation of brain endothelial cells, induction of adhesion molecule expression as well as adherence of infected red blood cell and in vivo sequestration. Our collaborator, Dr. Fabio T. M. Costa, has the expertise with in situ analysis of endothelial cell activation, parasite adherence and in vivo parasite sequestration. Our objective is to establish the effect of lipoxins in brain endothelial cell activation/parasite sequestration in vitro and in vivo. To do so, we will test whether lipoxin-treatment modulates TNF- or IFN-³-mediated endothelial cell activation and subsequent adhesion of infected red blood cells. The success of the research delineated in this proposal will allow for further characterization of a novel therapeutic venue for treatment/diagnosis of severe forms of malaria. (AU)