Epigenetic programming during chronic infectious diseases: tiring out and training the innate immune system

• Grant number: 18/15066-0
• Support Opportunities: Research Grants - Young Investigators Grants - Phase 2
• Start date: August 01, 2019
• End date: October 31, 2025
• Field of knowledge: Biological Sciences - Immunology - Applied Immunology
• Principal Investigator: Fabiani Gai Frantz
• Grantee: Fabiani Gai Frantz
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 11/12199-0 - Elucidation of innate immune response dysfunction of HIV patients: the underlying mechanisms amongst immunological and epigenetic modifications, AP.JP
• Associated scholarship(s): 24/10737-5 - Technical Training for Advanced Techniques in Flow Cytometry, Molecular Biology, and Epigenetics., BP.TT; 23/04338-8 - Identification of potential therapeutic or prognosis targets associated with monocyte exhaustion of chronically infected HIV patients, BP.DD; 23/07506-9 - Role of extracellular vesicles in modulating autophagy in Mycobacterium tuberculosis infection, BP.IC; + associated scholarships 21/12035-0 - Technical training for blood collection, isolation, and cultivation of peripheral blood mononuclear cells, BP.TT; 21/08823-2 - Purification of extracellular vesicles from the plasma of HIV + patients and preparation for omics assays, BP.IC; 20/08436-6 - Proteomic and transcriptomic characterization of plasma extracellular vesicles from HIV+ patients: an epigentic view, BP.PD; 19/11422-0 - Study of immunological and epigenetic markers of extracellular vesicles and their ability to induce early immunosenescence related to HIV infection, BP.DR; 20/02354-8 - Effect of treatment with epidrugs: impact on the training of cells in the innate immune system of HIV+ patients, BP.DD; 19/25348-6 - Standardization of purification and identification of microvesicles of HIV+ pacients plasma, BP.IC - associated scholarships

Abstract

Epigenetic mechanisms are associated with training/programming and polarization of immune cells, which can be induced by the presence of cytokines and molecules present in the microenvironment, like PAMPs (Pathogen-associated molecular pattern) or other mediators of inflammation. Our hypothesis is that during chronic infections such as HIV and TB, PAMPs, cytokines or extracellular vesicles containing epigenetic modifiers, act on non-stimulated cells, causing them to undergo deleterious epigenetic changes that will define the prognosis of diseases. During pulmonary M. tuberculosis infection, cytokines and PAMPs may fall into the circulation and act on circulating or progenitor cells, inducing the training of the innate immune response. On the other hand, in HIV patients, there is a cytokine storm due to disruption of the intestinal barrier and virus immune response. The exacerbated inflammation is associated with the induction of the senescence of innate immune system during infection and uncontrolled inflammatory response. We have shown that monocytes from HIV-infected individuals undergo epigenetic changes that are related to the lack of control in the production of inflammatory cytokines by these cells and in their effector function. In this project, we will test the possibility that extracellular vesicles produced by leukocytes during HIV infection could act in the expansion of the immune senescence phenotype and determine the content of extracellular vesicles present in the plasma of HIV-infected patients. In Tuberculosis, we will evaluate how different conditioning environments can train neutrophils, also determining the epigenetic signature of these profiles and associating the functions and phenotypes of each cell subtype. In addition, we will also evaluate the effects of epidrugs in modulating the function and phenotype of immune cells. (AU)

Scientific publications

(6)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

SOARES, LUANA SILVA; ESPINDOLA, MILENA SOBRAL; ZAMBUZI, FABIANA ALBANI; GALVAO-LIMA, LEONARDO JUDSON; CACEMIRO, MAIRA COSTA; SOARES, MURILO RACY; SANTANA, BARBARA A.; CALADO, RODRIGO T.; BOLLELA, VALDES ROBERTO; FRANTZ, FABIANI GAI. Immunosenescence in chronic HIV infected patients impairs essential functions of their natural killer cells. International Immunopharmacology, v. 84, JUL 2020. (11/24026-3, 18/15066-0, 11/12199-0)

LOUREIRO, LUMA DA COSTA; LOUREIRO, LUANA DA COSTA; GABRIEL-JUNIOR, EDSON ALVES; ZAMBUZI, FABIANA ALBANI; FONTANARI, CAROLINE; SALES-CAMPOS, HELIOSWILTON; FRANTZ, FABIANI GAI; FACCIOLI, LUCIA HELENA; SORGI, CARLOS ARTERIO. Pulmonary surfactant phosphatidylcholines induce immunological adaptation of alveolar macrophages. Molecular Immunology, v. 122, p. 163-172, JUN 2020. (18/15066-0, 14/07125-6, 15/00658-1)

GALVAO-LIMA, LEONARDO J.; ZAMBUZI, FABIANA A.; SOARES, LUANA S.; FONTANARI, CAROLINE; MEIRELE, ALINE F. GALVA; BRAUER, VERONICA S.; FACCIOLI, LUCIA H.; GAMA, LUCIO; FIGUEIREDO, LUIZ T. M.; BOU-HABIB, DUMITH CHEQUER; et al. HIV-1 Gag and Vpr impair the inflammasome activation and contribute to the establishment of chronic infection in human primary macrophages. Molecular Immunology, v. 148, p. 13-pg., 2022-08-01. (18/15066-0, 11/12199-0)

ZAMBUZI, FABIANA ALBANI; CARDOSO-SILVA, PRISCILLA MARIANE; CASTRO, RICARDO CARDOSO; FONTANARI, CAROLINE; EMERY, FLAVIO DA SILVA; FRANTZ, FABIANI GAI. Decitabine Promotes Modulation in Phenotype and Function of Monocytes and Macrophages That Drive Immune Response Regulation. CELLS, v. 10, n. 4, APR 2021. (18/15066-0, 17/05365-8)

CASTRO, RICARDO CARDOSO; GONCALES, RELBER AGUIAR; ZAMBUZI, FABIANA ALBANI; FRANTZ, FABIANI GAI. Notch signaling pathway in infectious diseases: role in the regulation of immune response. Inflammation Research, v. 70, n. 3, FEB 2021. (18/15066-0)

ANTUNES, MATEUS DA SILVA MATIAS; SUGIYAMA, FABRICIA HELOISA CAVICCHIOLI; GRAVINA, HUMBERTO DORIGUETTO; CASTRO, RICARDO CARDOSO; MERCADO, FRANCISCO JAVIER ROMERO; DE LIMA, JULIA OLIVEIRA; FONTANARI, CAROLINE; FRANTZ, FABIANI GAI. COVID-19 inactivated and non-replicating viral vector vaccines induce regulatory training phenotype in human monocytes under epigenetic control. FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY, v. 13, p. 16-pg., 2023-07-14. (18/15066-0)