Impact of infection-induced immunological scarring on the long-term host metabolic homeostasis

• Grant number: 15/25364-0
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: May 01, 2016
• End date: April 30, 2021
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Denise Morais da Fonseca
• Grantee: Denise Morais da Fonseca
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Marcela Davoli Ferreira ; Momtchilo Russo ; Niels Olsen Saraiva Câmara ; Yasmine Belkaid
• Associated research grant(s): 21/06881-5 - Gut-lung axis: understanding the immune dialogue between barrier tissues in the development of disease, AP.JP2
• Associated scholarship(s): 20/11408-4 - Study of stromal-leukocyte interactions for acetylcholine effects on immunological homeostasis in the mesentery, BP.IC; 19/12691-4 - Gut-lung axis: contribution of diet and intestinal microbiota to the regulation of lung mucosa-associated immune system, BP.DR; 19/14026-8 - Contribution of short chain fatty acids to the development of non-classical metabolic syndrome after acute intestinal infection, BP.MS; + associated scholarships 19/07771-9 - Analysis of the development of glucose intolerance and insulin resistance post-immunological scar induced by acute intestinal infection, BP.IC; 18/15981-0 - Effect of anti-inflammatory cholinergic pathway in the metabolic changes following high fat diets, BP.MS; 18/00458-0 - Development of an experimental model of environmental Enteropathy, BP.MS; 17/14209-0 - The role of neuroimmune interactions in the development of the "immunological scar" after acute intestinal infection., BP.PD; 17/02298-8 - Analysis of lipid metabolism after immunological scar induced by acute gastrointestinal infection, BP.MS; 16/08385-7 - Impact of infection-induced immunological scarring on the long-term host metabolic homeostasis, BP.JP - associated scholarships

Abstract

The immune system deals with highly diverse infectious challenges in a manner that both promotes the control of invading agents and restores tissue homeostasis. At barrier tissues, sites of constant microbial exposure, tissue-specific immunity requires defined structural components that have immunologic and neuroendocrine detectors providing signal for the spatial segregation from the microbiota and infectious agents. This process ensures the maintenance of organ function and enables the balance between tolerance to environmental antigens and regulated protective immunity. These balanced processes are essential for the preservation of tissue integrity and function, and the microbiota plays an important role in this process. Inflammatory disorders affecting barrier sites are complex diseases that develop as a result of a breakdown in tissue homeostasis and the subsequent failure to regulate immunity against environmental or microbial antigens. In the past few years, metabolic disorders, such as obesity, diabetes, cardiovascular diseases and metabolic syndromes, have been included in the categories of complex diseases trigged by several endogenous and exogenous stressors. Indeed, it has been shown that there is an important crosstalk between the immune system and gut microorganisms during the development of obesity, metabolic syndromes and type 2 diabetes. However, the role of the microbiota and the functional impact of infections in such diseases are not fully understood. This is largely due to the complexity of the microbiota components and the bidirectional involvement of different host physiological systems in the maintenance of intestinal homeostasis, such as the immune and the neuroendocrine systems. For instance, the gut microbiota plays an essential role in nutrient absorption, changes in the diet impact the microbiota composition, and both microbiota and diet interfere with the function of the immune and endocrine systems. In this context, gastrointestinal infections can disturb homeostasis beyond the gut tissue, causing long-term consequences to distal sites and systems. Recently, we have shown that a single episode of acute gastrointestinal infection with Yersinia pseudotuberculosis can lead to the development of immunological scaring causing irreversible long-term consequences to tissue specific immunity. Notably, this immunological scar is characterized by the disruption of gut-immune system dialog, loss of compartmentalization of the microbiota and remodeling of the mesentery, including adipose tissue and associated lymphoid tissue. Since the intestinal tract and the associated lymphatic system are deeply affected in this context, we hypothesized that acute infections that promote mesentery remodeling could also impact the host metabolic homeostasis and trigger metabolic disorders. Therefore, in this project we will take advantage of the experimental of Yersinia-induced immunological scar to understand the crosstalk between microbiota-immune-neuroendocrine systems following acute infections in the development of metabolic disorders. The results obtained in this project will open a new framework to comprehend the pathogenesis of multifactorial / complex diseases triggered by infections at the barrier tissues. (AU)

Scientific publications

(8)

(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)

HENRIQUE, MARESSA O.; NETO, LEILA S.; ASSIS, JOSIANE B.; BARROS, MICHELE S.; CAPURRO, MARGARETH L.; LEPIQUE, ANA P.; FONSECA, DENISE M.; SA-NUNES, ANDERSON. Evaluation of inflammatory skin infiltrate following Aedes aegypti bites in sensitized and non-sensitized mice reveals saliva-dependent and immune-dependent phenotypes. IMMUNOLOGY, v. 158, n. 1, p. 47-59, SEP 2019. (09/09892-6, 15/25364-0)

BHATTACHARJEE, AMRITA; BURR, ANSEN H. P.; OVERACRE-DELGOFFE, ABIGAIL E.; TOMETICH, JUSTIN T.; YANG, DEYI; HUCKESTEIN, BRYDIE R.; LINEHAN, JONATHAN L.; SPENCER, SEAN P.; HALL, JASON A.; HARRISON, OLIVER J.; et al. nvironmental enteric dysfunction induces regulatory T cells that inhibit local CD4+T cell responses and impair oral vaccine efficac. IMMUNITY, v. 54, n. 8, p. 1745+, AUG 10 2021. (15/25364-0)

NASCIMENTO, DANIELE CARVALHO; VIACAVA, PAULA RAMOS; FERREIRA, RAPHAEL GOMES; DAMACENO, MARINA ALVES; PINEROS, ANNIE ROCIO; MELO, PAULO HENRIQUE; DONATE, PAULA BARBIM; TOLLER-KAWAHISA, JULIANA ESCHER; ZOPPI, DANIEL; VERAS, FLAVIO PROTASIO; et al. Sepsis expands a CD39(+) plasmablast population that promotes immunosuppression via adenosine-mediated inhibition of macrophage antimicrobial activity. IMMUNITY, v. 54, n. 9, p. 2024+, SEP 14 2021. (13/08216-2, 15/25974-3, 12/10100-0, 15/25364-0)

MENEZES-SILVA, LUISA; DA FONSECA, DENISE MORAIS. Connecting the dots in type 1 diabetes: The role for gut-pancreas axis. Journal of Leukocyte Biology, v. 106, n. 3, p. 3-pg., 2019-08-01. (16/08385-7, 18/15981-0, 15/25364-0)

NUNES, FERNANDA P. B.; ALBERCA-CUSTODIO, RICARDO WESLEY; GOMES, ELIANE; FONSECA, DENISE M.; YOKOYAMA, NICOLE H.; LABRADA, ALEXIS; RUSSO, MOMTCHILO. TLR9 agonist adsorbed to alum adjuvant prevents asthma-like responses induced by Blomia tropicalis mite extract. Journal of Leukocyte Biology, v. 106, n. 3, p. 12-pg., 2019-07-22. (15/25364-0, 13/24694-1, 16/16602-8, 15/16728-9)

NUNES, FERNANDA P. B.; ALBERCA-CUSTODIO, RICARDO WESLEY; GOMES, ELIANE; FONSECA, DENISE M.; YOKOYAMA, NICOLE H.; LABRADA, ALEXIS; RUSSO, MOMTCHILO. TLR9 agonist adsorbed to alum adjuvant prevents asthma-like responses induced by Blomia tropicalis mite extract. Journal of Leukocyte Biology, v. 106, n. 3, SI, JULY 2019. (15/16728-9, 15/25364-0, 13/24694-1, 16/16602-8)

ALBERCA-CUSTODIO, RICARDO WESLEY; FAUSTINO, LUCAS D.; GOMES, ELIANE; NUNES, FERNANDA PEIXOTO BARBOSA; DE SIQUEIRA, MIRIAN KRYSTEL; LABRADA, ALEXIS; ALMEIDA, RAFAEL RIBEIRO; CAMARA, NIELS OLSEN SARAIVA; DA FONSECA, DENISE MORAIS; RUSSO, MOMTCHILO. Allergen-Specific Immunotherapy With Liposome Containing CpG-ODN in Murine Model of Asthma Relies on MyD88 Signaling in Dendritic Cells. FRONTIERS IN IMMUNOLOGY, v. 11, APR 23 2020. (15/25364-0, 15/16728-9, 14/19906-2, 13/24694-1, 17/05264-7, 16/16602-8)

SIQUEIRA, MIRIAN KRYSTEL DE; ANDRADE-OLIVEIRA, VINICIUS; STACY, APOLLO; GUIMARAES, JOAO PEDRO TORRES; ALBERCA-CUSTODIO, RICARDO WESLEY; CASTOLDI, ANGELA; SANTOS, JAQUELINE MARQUES; DAVOLI-FERREIRA, MARCELA; MENEZES-SILVA, LUISA; TURATO, WALTER MIGUEL; et al. Infection-elicited microbiota promotes host adaptation to nutrient restriction. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v. 120, n. 4, p. 8-pg., 2023-01-24. (21/06881-5, 17/02298-8, 18/15981-0, 15/25364-0, 18/00458-0, 16/08385-7, 18/14562-4, 17/14209-0)