Analysis of the network of IFN-associated molecules in Dengue fever patients

• Grant number: 21/03675-5
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: May 01, 2021
• End date: April 30, 2022
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Otávio Cabral Marques
• Grantee: Júlia Nakanishi Usuda
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 18/18886-9 - Systemic and integrative analysis of the immune response to Zika and Dengue viral infections, AP.JP

Abstract

Notably, anti-cytokine autoantibodies have been linked to the development of opportunistic infections. Among them, anti-IFN-gamma neutralizing autoantibodies can increase the susceptibility to mycobacterial infections, while anti-IFN-alpha are associated with the development of viral infections (e.g., chickenpox, cytomegalovirus, and adenovirus) and cancer. However, the concentration of anti-IFN-alpha autoantibodies in patients who develop dengue fever remain to be characterized.The recognition of viruses by APCs induces the production of various proinflammatory cytokines such as interferon (IFN) alpha/beta, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and mechanisms of phagocytic/microbicidal activity, representing the initial stage of virus dispersion control. In particular, the signaling via type I IFN (e.g., IFN-alpha), which binds to the IFN1R receptor, activates the signal transducers and activators of transcription (STAT) 1 and STAT2. Through this pathway, type I IFNs stimulate several antiviral functions. Among these, they induce a resistance state in the host cells through the action of enzymes such as an OAS1-dependent RNase L (2'-5'-Oligoadenylate Synthetase 1) that catalyzes the degradation of viral RNA. We work with the hypothesis that patients who develop infections by this arbovirus may have a high concentration of anti-IFN type I neutralizing autoantibodies.Furthermore, global and systemic characteristics such as deregulated gene networks, signaling pathways, and gene signatures specific to the IFN response in DENV infections remain to be characterized. Thus, the complete sequencing of the transcriptome through the RNAseq technique has allowed a significant and rapid advance of the systemic understanding of these questions regarding the immune response.In this context, the objective of this project is to characterize the serum concentration and neutralizing function of anti-IFN-alpha autoantibodies in patients with dengue fever. In addition, due to the current limitations imposed by the pandemic that may impact the development of other researches unrelated to COVID19, we will perform in parallel a transcriptional analysis of cohorts of patients infected with dengue in order to characterize networks of molecules associated with IFN that are involved in the response against the DENV.