Malaria is a major public health concerns worldwide. It is estimated that up to 216 million new cases occurred during 2010. Severe malaria is a leading cause of death among infants and pregnant women in endemic areas. Overall, malaria was reported to cause approximately 655,000 deaths in 2010, 86% of them among children under 5 years of age. Infection with the P. berghei ANKA strain in mice is the most used experimental model for fatal human cerebral malaria. During the liver-stage of malaria, induction of pro-inflammatory cytokines (IL-12, TNF, IFN-,) and subsequent induction of cell-mediated immunity against the parasite protects the host. However, during blood-stage malaria, continued production of once protective mediators, such as IFN- and TNF, can become deleterious and cause organ damage, especially during cerebral malaria. The mechanisms that drive lethal cerebral disease are not completely understood. It is clear, however, that brain microvascular endothelial cell-mediated parasite sequestration as well as exuberant pro-inflammatory responses are central components, indicating insufficient counter-regulation of the immune response. We previously reported that the 5-lipoxygenase (LO)-derived anti-inflammatory lipid mediator, lipoxin (LX)A4 restrains the immune response to Plasmodium berghei ANKA strain, Mycobacterium tuberculosis and Toxoplasma gondii. Notably, 5-LO-deficient mice exhibit increased pro-inflammatory responses, all of which is reversed by LXA4 treatment. Notably, our novel preliminary data indicate that: (a) genetic deficiency of 5-LO is associated with earlier mortality during murine cerebral malaria, concomitant with failure to upregulate LXA4 production; and (b) lipoxin therapy protects mice (both 5-LO knockouts and wild type mice) from fatal cerebral malaria, suggesting a novel therapeutic approach to this important disease. Our data also indicate that the up- regulation of endothelial cell ICAM-1, CD36 and Endothelial C reactive protein receptor (EPCR) (adhesion molecules associated with brain parasite sequestration) is modulated by lipoxins in vitro. Taken together, these data suggest the inter-related hypotheses underlying this proposal, that: (a) LXs protect the host by restraining up-regulation of adhesion molecules (ICAM1, CD36 and EPCR) in endothelial cells; and (b) stable LX analogues have therapeutic potential in established cerebral malaria. To test these hypotheses, we aim to: 1. Define the mechanisms by which immune counter-regulation by LXA4 interrupts the pathogenesis of cerebral malaria. (A) We will address whether in vitro IFN-- or TNF-induced up-regulation of CD36, ICAM1 and EPCR as well as cyto-adhesion of P. falciparum-iRBC's in human cells or Plasmodium berghei ANKA strain in mouse cells can be modulated by LXA4 in vitro. (B) We will address whether FPR2 and/or AhR mediate endogenously produced LXA4 protective effects in vivo in delaying CM onset by using Cre-Lox system with endothelial cell- or macrophage-conditional knock-out mouse lineages. 2. Determine the therapeutic potential of LXs in cerebral malaria. Our preliminary data show that in vivo treatment with 15-epi-LXA4 - a stable analog of LXA4 - prevent cerebral malaria in Plasmodium berghei ANKA-infected mice.
We aim here to expand these studies and investigate whether there is potential therapeutic adjunctive effect of 15-epi-LXA4 treatment along with currently used anti-malarials in preventing mortality after infection in mice. This proposal aims t establish the mechanisms of protection provided by the 5LO/LXA4 pathway in cerebral malaria. Furthermore the completion of the aims of this proposal will provide critical pre-clinical data for human trials of LXA4 analogs in treatment of severe malaria.
Malaria, endemic in sub-Saharan Africa, South Asia and parts of South America, killed approximately 655,000 people in 2010, of which 91% were of children under 5 years of age. Cerebral malaria is the leading cause of malarial death among children. In spite of preventive measures, available treatments and promising new vaccine candidates, cerebral malaria remains a grave public health concern and economic burden. A thorough understanding of its pathogenesis is urgently needed to improve prophylaxis and therapy. Here we aim to understand how the anti-inflammatory mediator Lipoxin can induce protection against cerebral malaria and propose pre-clinical studies for the use of lipoxin stable analogs as an adjunctive therapy for treatment of cerebral malaria.
| Bastos, Marcele F; Kayano, Ana Carolina A V; Silva-Filho, João Luiz et al. (2018) Inhibition of hypoxia-associated response and kynurenine production in response to hyperbaric oxygen as mechanisms involved in protection against experimental cerebral malaria. FASEB J 32:4470-4481 |
| Kayano, Ana Carolina A V; Dos-Santos, João Conrado K; Bastos, Marcele F et al. (2016) Pathophysiological Mechanisms in Gaseous Therapies for Severe Malaria. Infect Immun 84:874-882 |
