Regulatory mechanisms of inflammatory responses in the severity of visceral leishmaniasis

Abstract

Visceral Leishmaniasis (VL) is a serious problem of public health, causing high morbidity and mortality in several countries, including Brazil. Among those infected, 85% remain asymptomatic, while the remaining 15% present clinical manifestations, ranging from oligosymptomatic forms (mild) to more severe symptomatic forms that may evolve to death. In the absence of efficient and effective vaccine strategies, therapy with amphotericin B and Pentavalent antimonial drugs are routinely used in the clinic for the treatment of VL. However, these drugs present adverse reactions and acquired resistance with its use over time. Patients with severe form of the disease usually present with jaundice, edema, elevated liver enzymes, and pancytopenia, severe neutropenia and generally they are refractory to treatment, and may progress to death. It is remarkable also in these patients, the systemic levels of proinflammatory cytokines and certain immunological markers are associated with lethality. An important question that arises is whether the refractoriness of critically ill patients may be the result of combined and redundant actions of proinflammatory mediators released systemically. Another aspect that deserves attention is that the period of therapeutic inefficacy harms the patient due to delayed start of alternative therapies, worsening the symptoms. Despite the scientific and technological advances in the last decade, there is a limited understanding of the factors and mechanisms underlying the development and persistence of chronic inflammatory response in refractory patients. Moreover, the absence of methods for diagnosis early interferes with the choice of an effective treatment. Thus, the understanding of the inflammatory process as a whole, including the identification and characterization of genes whose functions are altered in patients with greater severity, has a high impact prospects for discovery of prognostic biomarkers of therapeutic efficacy, because it may improve the process of choice the most effective therapies. The relevance of altered genes found in refractory patients can be investigated using experimental models, such as transgenic animals and gene deletions. The identification of targets, validated in an experimental model of the disease will increase the chances of therapeutic success and efficiency of patients with VL. Another aspect is that the neutropenia in refractory patients may lead to tissue complications by retaining these cells in organs. Neutrophils are sources of microbicides substances that may promote tissue damage, contributing to the worsening of the clinical condition of the patient. Due to a large number of molecules, cytokines and mediators involved in the activation and regulation of neutrophil effector function, it is possible that the presence of polymorphnuclear cells also reflects in the development of innate and adaptive immune responses that contribute to disease chronicity. Thus, the project presents three clear objectives: 1) identifying the genes alteration resulting from inflammatory responses that may be involved in neutropenia in patients with LV and validate them in an experimental model, 2) characterizing the role of cells, mediators and molecular mechanism involved in the neutrophils recruitment and activation and 3) determining effector and regulatory mechanisms of neutrophils in VL. (AU)