Cooperation between TLR4 and IL-1R signaling pathways in the regulation of immune response during human and murine L. infantum infection

• Grant number: 17/04347-6
• Support Opportunities: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): October 01, 2017
• Effective date (End): May 15, 2022
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Vanessa Carregaro Pereira
• Grantee: Laís Amorim Sacramento
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases, AP.CEPID
• Associated scholarship(s): 19/12991-8 - Role of IL-1 in the intestinal mucosal integrity and microbiota alterations during visceral leishmaniasis, BE.EP.PD

Abstract

The regulation of intensity and magnitude of immune responses in infectious process need to be precisely orchestrated in order to promote the control of the pathogens and prevent the development of immunopathology. The visceral leishmaniases (VL) is a chronic disease and potentially fatal, if not properly treated. Patient with severe VL present a clinical condition called "cytokine storm", characterized by elevated amounts of pro- and anti-inflammatory mediators systemically. However, the mechanisms involved in the exacerbation of the immune response and/or failure to limit it are unclear. The TLRs signaling pathways act in an integrated way to initiate or regulate the adaptive immune response. We demonstrated the role of TLR9 and TLR2 in the induction of protective immune response against L. infantum infection. On the other hand, the TLR4/TRIF-IRF signaling in dendritic cells (DCs) restricts the development of Th1 and Th17 cells through a mechanism dependent on type 1 IFN and IL-10. In addition, our preliminary data demonstrated that the IL-1 cytokine inhibit T CD4+ producing IFN³ and it absence (IL-1±-/-) induces an intestinal microbiota translocation during infection. Since TLR4 pathway share molecules components with IL-1R signaling pathway, such as IRF1 for example, our goals are: Investigate if the IL-1R and TLR4 signaling regulate the immune response in a coordinated way; Understand the role of IL-1± in the intestinal barrier integrity during VL and finally, evaluate the expression and function of TLRs in patients with severe VL.

Scientific publications

(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)

SACRAMENTO, LAIS AMORIM; BENEVIDES, LUCIANA; MARUYAMA, SANDRA REGINA; TAVARES, LUCAS; FUKUTANI, KIYOSHI FERREIRA; FRANCOZO, MARCELA; SPARWASSER, TIM; CUNHA, FERNANDO QUEIROZ; ALMEIDA, ROQUE PACHECO; DA SILVA, JOAO SANTANA; et al. TLR4 abrogates the Th1 immune response through IRF1 and IFN-beta to prevent immunopathology during L. infantum infection. PLOS PATHOGENS, v. 16, n. 3, MAR 2020. (15/12526-2, 13/08216-2, 17/04347-6, 12/14524-9)