CGRP and PKM2 immunomodulation during cutaneous leishmaniasis infection

• Grant number: 23/10450-5
• Support Opportunities: Scholarships in Brazil - Support Program for Fixating Young Doctors
• Start date: August 01, 2023
• End date: June 30, 2025
• Field of knowledge: Biological Sciences - Immunology - Applied Immunology
• Agreement: CNPq
• Principal Investigator: João Santana da Silva
• Grantee: Maria Tays Mendes
• Host Institution: Plataforma de Pesquisa e Medicina Translacional. Fundação Oswaldo Cruz (Fiocruz). Ministério da Saúde (Brasil). Ribeirão Preto , SP, Brazil
• Associated research grant: 23/01533-4 - CGRP and PKM2 immunomodulation during cutaneous leishmaniasis infection, AP.R

Abstract

Leishmaniasis is one of the most neglected infectious diseases worldwide. Its transmission occurs through the bite of infected sandflies. In this environment, the interaction between vector saliva, parasites and host cells occurs. Neutrophils are the first cells to migrate and their interaction with antigen-presenting cells is crucial in setting up the immune response. IL-17, the main cytokine produced in the Th17 response, participates in the recruitment of neutrophils. The production of IL-17 as a result of the interaction between ³´ and Langerhans T cells can be stimulated by Calcitonin Gene-Related Peptide (CGRP). In Leishmaniasis, CGRP expression is lower in a disease-susceptible model, supposedly modulating Th17 differentiation. Although IL-17 does not induce cellular recruitment directly, it binds to keratinocytes, and through the participation of the enzyme pyruvate kinase M2 (PKM2), it activates the transcription factor NF-kB resulting in the production of cytokines and chemokines, which once released act on the neutrophil recruitment. To date, neither the role of CGRP nor PKM2 has been evaluated in leishmaniasis. The profile of the initial response is decisive and critical for subsequent immunity, therefore, assessing the role of CGRP and PKM2 is necessary. Preliminary results suggest that PKM2 plays a role in the protective response to the disease, because in the absence of it, the injury generated is greater. In this sense, the objective of this project is to evaluate the immunomodulatory role of CGRP and PKM2 during cutaneous leishmania infection through immunological assays, animal models, cellular assays, and skin analysis of patients. Understanding the factors involved in the assembly of the immune response is essential for developing new therapeutic strategies.