Dynamic brain imaging during experimental visceral leishmaniasis: investigation of microglial response and Leishmania donovani brain tropism

Abstract

Visceral leishmaniasis (VL) is an anthropozoonotic disease caused by the Leishmania donovani complex, represented by L. donovani and L. infantum. VL can manifest with multisystemic symptoms, including neurological disorders, and although there are some reports of brain inflammatory alterations in naturally infected dogs, divergences in the literature predominate about the origin of this inflammation and about the possibility of migration of the parasite to the central nervous system (CNS). The neurological alterations seen during VL might be attributable to glial cells, especially microglia, that plays a role in every brain alteration and is found in an active state during canine VL. Several investigators have worked with laboratory models to study the pathogenesis of VL; however, their focus was mainly the organs bearing the bulk of parasites burden (e.g. spleen, liver, bone marrow). The analysis of processes within the brain in living animals will provide an innovative and original approach that will contribute to understanding the full extent of VL pathogenesis. Using state-of-the-art fluorescent and functional immunoimaging techniques, we aim to evaluate the extent of Leishmania tropism to the brain, the evolution of associated inflammatory changes and the impact of systemic VL-associated inflammation on the dynamic behavior of the microglia. Further, we will analyze microglial activation using global gene expression profiling (microarray or RNASeq) and validate differentially expressed genes using qPCR and immunochemistry. Together, these results will provide a first comprehensive study of microglial response associated with experimental murine VL. (AU)