Synthesis, characterization and investigation of the role of CXCL10-derived peptides on experimental models of arboviral diseases

• Grant number: 20/02456-5
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date: November 02, 2020
• End date: October 30, 2021
• Field of knowledge: Biological Sciences - Pharmacology
• Principal Investigator: Rafael Elias Marques Pereira Silva
• Grantee: Ana Carolina de Carvalho
• Supervisor: Paul Proost
• Host Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia e Inovação (Brasil). Campinas , SP, Brazil
• Institution abroad: University of Leuven, Leuven (KU Leuven), Belgium
• Associated to the scholarship: 18/02993-0 - Development of the first experimental model of Ilheus Virus (ILHV) infection in mice and design of therapeutic strategies, BP.DD

Abstract

Arboviruses ("arthropod-borne viruses") are a global health issue. Public health agencies and populations in tropical regions have been alarmed by the emergence of arboviruses such as Chikungunya and Zika, which were associated with epidemics and significant human suffering in recent years. Ilhéus virus (ILHV, genus Flavivirus) is a neglected arbovirus first isolated in the state of Bahia, Brazil, in 1944. Since, ILHV circulation has been documented through all Latin America, encompassing a variety of hosts, from mosquitoes of the Aedes and Culex genus to birds, equines, buffaloes, sloths and non-human primates. Although few cases of ILHV-associated disease in humans are described, infection has been associated with the occurrence of severe neurological disease, such as encephalitis, similar to flaviviruses such as Saint Louis Encephalitis virus (SLEV) and Rocio virus (ROCV). However, ILHV biology, epidemiology and disease pathogenesis are poorly understood. There is no treatment or vaccine available against ILHV infection. Previous studies from our group indicate that ILHV may cause severe neurological disease. Such situation is alarming as ILHV may emerge and lead to outbreaks, posing a significant risk to the brazilian population. The cytokine CXCL10 (or interferon-³ induced protein 10, "IP-10") has been described as a potential treatment target in infectious diseases for its pro-inflammatory properties, especially regarding CXCR3-expressing cells. Studies exploring the role of CXCL10 on infection by West Nile Virus - closely related to Ilheus virus - showed that neutralization or congenital deficiency in CXCL10 results in higher viral titers in the brain and increase in morbidity and mortality, with reduced infiltration of TCD8+ CXCR3+ cells, important for elimination of West Nile Virus from infected neurons, into the CNS. Our hypothesis is that CXCL10 may play a similar role in the pathogenesis of flavivirus infections in general and thus can be investigated as a possible innovative therapeutic target for this class of diseases. Thereafter, our objective is to synthesize fractions of CXCL10 ("CXCL10-derived peptides") related to different parts of the cytokine to assess which parts are involved in the chemotactic, pro-inflammatory effect described in the literature. Understanding the upstream and downstream signaling pathways involved in the inflammatory process mediated by CXCL-10 is recognized as a necessary step towards the development of a new class of therapeutic strategies against infectious diseases, mediated by this cytokine. (AU)