Effect of immunomodulatory drugs on cellular activation pathways that determine inflammatory and anti-inflammatory responses in susceptible mice (cba and c57bl / 6) or not (balb / c) to cerebral malaria

Malaria continues to cause an estimated 241 million clinical cases and nearly half a million deaths each year. The hyperactivation of the immune system plays a central role in the disease’s pathogenesis, and various approaches have been explored to modulate this immune hyperactivity, including the use of pleiotropic immunomodulatory drugs. Parasite antigens trigger intracellular signaling cascades that lead to inflammatory cytokine production, involving distinct choices between TNF receptors 1 and 2, adapter proteins, and downstream pathways. These signaling routes may result in divergent outcomes such as cell activation, inflammatory mediator release, or cell death via apoptosis. The intracellular flexibility in these signaling events appears critical to determining specific immune responses. Among the key signaling axes, the NF-kappa B pathway intersects with the eicosanoid and PPAR-gamma pathways, all of which contribute to the production of oxygen and nitrogen radicals and share regulatory molecules. Despite their importance, these intracellular pathways remain poorly defined in the context of malaria and could be directly related to the clinical progression and severity of the disease. There remains a need to clarify whether immunomodulatory drugs that show potential for use in malaria, specifically pentoxifylline and thalidomide modulate these intracellular pathways. To address this, the study proposes using both susceptible and resistant murine models of cerebral malaria to assess two complementary investigative approaches. The first involves tracking key molecules involved in NF-kappa B, PPAR-gamma, and eicosanoid pathway activation through techniques such as confocal microscopy, flow cytometry, and immunohistochemistry. This includes evaluating the expression of TNF receptors 1 and 2 in immune and brain cells, associated adapter proteins, signaling preferences within the NF-kappa B pathway, production of inflammatory cytokines, and enzymes involved in nitric oxide and hydrogen peroxide synthesis. The second approach focuses on analyzing the eicosanoid signaling pathway and conducting histopathological evaluations of affected organs. Insights gained from this work are expected to contribute to a deeper understanding of the cellular and molecular mechanisms that drive different forms and severities of malaria. Ultimately, this may inform the development of adjunct immunomodulatory strategies to complement antimalarial drug therapy.

Basic Science

Jun 2017 — May 2020

Brazil