Unraveling the regulatory mechanisms of host-parasite interaction of Leishmania: focus on post-transcriptional and post-translational changes

Abstract

The life cycle of species of the genus Leishmania is complex and involves flagellated promastigote forms present in the sandfly vector and amastigote forms present inside the macrophages of the mammalian host. During the transition from one host to another, the parasite encounters different environmental conditions that lead to changes in its gene expression, protein synthesis, metabolism and morphology for its survival and multiplication. The mechanisms that allow Leishmania to adapt to this transition are still poorly understood. One hypothesis is that the parasite uses RNA post-transcriptional and protein post-translational modifications to regulate gene expression/protein synthesis and the function of key proteins involved in its differentiation. Another important factor during the Leishmania life cycle is how the parasite manages to escape the macrophages' defense mechanisms during infection. Some aspects of this life-cycle step have already been investigated and point to changes in the levels of chromatin acetylation and the expression of specific macrophage genes. Thus, in this project we will have two focus of investigation: one on the parasite and how the acetylation of RNA (ac4C) and proteins can affect the processes that are important for Leishmania stage differentiation; and another focused on the host cell and how Leishmania infection can lead to RNA and protein modifications in the macrophage, affecting the immune response against the parasite. For this, we will investigate the role: 1) of ac4C RNA modification in the Leishmania stages differentiation; 2) of protein acetylation in the parasite stages differentiation, using the lysine deacetylases (KDACs) as a study model; 3) of protein acetylation in macrophages during Leishmania infection, focusing on the host cell KDACs and their role in the immune response; 4) of m6A RNA modification in the host cell during Leishmania infection, and how this process impacts the parasite proliferation. The investigation of these mechanisms will lead to a deeper understanding of the biology of Leishmania during its life cycle and will map new processes that may constitute potential targets for new drugs in the control of leishmaniasis. (AU)