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Investigation of the immunological mechanisms involved in the resistance to long-term induced immunosuppression in pediatric sepsis

Grant number: 18/23079-5
Support Opportunities:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): March 01, 2019
Effective date (End): February 29, 2020
Field of knowledge:Biological Sciences - Immunology - Applied Immunology
Principal Investigator:Fernando de Queiroz Cunha
Grantee:David Fernando Colon Morelo
Supervisor: Bernardo Simões Franklin
Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Research place: Universität Bonn, Germany  
Associated to the scholarship:16/11405-0 - Immuno-molecular mechanisms involved in the resistance to the development of immunosuppression in neonatal sepsis, BP.DR


Sepsis is a life-threatening multi-organ dysfunction caused by a dysregulated host response to infection. Sepsis-surviving patients commonly develop a late immunosuppression which is associated with increased susceptibility to secondary infections. The mechanisms involved in this immunosuppressive state include increased IL-33 production in the lung tissue homogenates and bronchial lavage (BAL) fluids and the expansion of M2-like macrophages as well as regulatory T lymphocytes (Tregs). Preliminary data from our lab demonstrate that pediatric sepsis survivors do not develop post-sepsis immunosuppression. These observations suggest that the sepsis-induced immunosuppression could be influenced by age. We have found that this "resistance" was associated with a downregulation of Foxp3 and Tgfb1 genes on spleen tissue homogenates of infants and a reduced expansion and proliferative capacity of these cells when compared to Tregs isolated from adult septic survivors. Further, we observed that the inability of infants Tregs to expand was related to a lower stability of Foxp3 expression on these cells. Epigenetic modifications, such as DNA demethylation in the Foxp3 locus by the DNA methyltransferase (Dnmt1), plays an important role in the stability of Foxp3 expression and consequently in Tregs-lineage stabilization. We found that adult post-septic adult, but not infant mice showed a significative downregulation of Dnmt1 in the spleen, suggesting a previously unappreciated role of epigenetic modification in the sepsis-induced immunoparalysis in adult mice. We further show that the IL-33/M2-like macrophages axis, which is induced during acute sepsis, is a determining factor for the development of post-sepsis-induced immunosuppression in adult mice. Hence, we investigated the role of the axis IL-33/type 2 cytokines/M2 macrophages in post-sepsis infant mice. We showed that sepsis-surviving infant mice present a significative reduction in the expansion of M2-like macrophages (F4/80+CD206+ cells), which was associated with impaired production of IL-33. Finally, in a cohort of post-septic patients we found that, contrary to adult survivors, serum IL-33 levels and the peripheral expansion of Tregs was not changed in surviving pediatric patients. We thus propose to investigate:1. Which are the cellular sources of IL-33 that maintain M2-like macrophage repertoire that drives post-septic immunosuppression in surviving adult mice? 2. What are the mechanisms involved in the reduced infant Tregs stability?3. What is the impact of the reduced Tregs stability on the resistance of sepsis-induced immunosuppression in infant mice? 4. How epigenetic modifications at the Foxp3 locus are involved in this phenomenon? Hence, the main aim of this project is to investigate the molecular mechanisms involved in the resistance to long-term induced immunosuppression in pediatric sepsis. This project will reveal new underlying mechanisms involved in the post-septic-induced immunosuppression and may allow the discovery of new possible therapeutic targets to treat sepsis immunosuppression. (AU)

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