The role of macrophage signal transduction pathways in the reactivation process from the fungus Cryptococcus neoformans dormant state

• Grant number: 23/18258-6
• Support Opportunities: Regular Research Grants
• Start date: October 01, 2024
• End date: September 30, 2026
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Anamelia Lorenzetti Bocca
• Grantee: Anamelia Lorenzetti Bocca
• Host Institution: Plataforma de Pesquisa e Medicina Translacional. Fundação Oswaldo Cruz (Fiocruz). Ministério da Saúde (Brasil). Ribeirão Preto , SP, Brazil
• Associated researchers: João Santana da Silva ; Luciana Benevides ; Luiz Gustavo Araujo Gardinassi

Abstract

Fungal infections have increased in recent decades, representing an essential threat to human health. Since the 1950s, it has been proposed that the pathology of cryptococcosis is like that described for tuberculosis, where inhaled infectious propagules initiate a pulmonary infection, with a granulomatous immune response containing the yeasts in nodules and draining lymph nodes. In immunocompetent individuals, yeast would develop a state of latency, generating dormant cells. With changes in the host's immune response, these dormant yeasts could reactivate, proliferate, and disseminate to any organ, preferably the central nervous system (CNS), causing cryptococcal meningitis. The reactivation of dormant cells depends on specific stimuli, whether endogenous or exogenous. Still, the reactivation of fungal cells needs to be studied more when compared to the dormancy observed in bacteria. Recently, the dormancy mechanism of Cryptococcus neoformans was described, and data from our group demonstrated the gene expression pattern of macrophages infected with dormant cells in stationary and logarithmic growth. We observed a distinct pattern of genes modulated by dormant cells, negatively regulating the expression of genes related to phagocytosis, apoptosis, inflammation, antigen presentation, and histone deacetylation, which may favor the longer permanence of these cells within macrophages.Furthermore, our data showed that the interaction between macrophages and dormant cells induces the production of nitric oxide (NO) depending on the activation of macrophages and that this mediator can eliminate dormant cells. The secretion of vesicles by murine or human macrophages could reactivate cell dormancy like pantothenic acid. We hypothesize that dormant cells negatively modulate macrophage activation, allowing them to remain inside as a safe niche. Changes in the tissue microenvironment can contribute to the non-lytic extrusion of cells. In this process, macrophages secrete vesicles that contribute to the reactivation of fungi, leading to the re-establishment of the infectious process when they occur without NO. Although the data obtained to date support this hypothesis, many points need to be elucidated, such as the role of some signaling pathways in macrophages, such as those mediated by the TLR9/MyD88/CD200 axis, which reduce the activation of iNOS/NO, contributing to the maintenance of the M2 profile of macrophages, as well as interferon regulatory factor 4 (Irf4). Another critical point is the phosphatidyl-inositol three kinase (PI3Kg) pathway involved in cell growth, proliferation, differentiation, mobility, and survival of macrophages. This project aims to evaluate the main macrophage signaling ways involved in maintaining latent infections, making hosts more susceptible, and how these pathways impact the production of vesicles capable of promoting the reactivation of dormant fungal cells. (AU)