Implicação do fator RasGEF1b na regulação da expressão da quimiocina Cxcl1 e neutrofilia durante a infecção pelo vírus H1N1 em camundongos

Abstract

The influenza virus is one of the most common causes of respiratory infections, and is one of the main problems affecting public health worldwide, causing a high mortality rate. During infection, the Toll-like receptor 7 (TLR7) expressed on epithelial, dendritic cells and macrophages recognizes the influenza A virus (IAV) due to its ability to detect single-stranded RNA (ssRNA) of viral origin. The production of cytokines and chemokines as well as the expression of intracellular signaling molecules caused during an IAV infection mediated by TLR7 significantly impact the body's response. The Ras-associated guanine nucleotide exchange factor domain family member 1b (RasGEF1b) has dominant and caused expression in macrophages stimulated with inflamed TLR agonists. Only recently, its function has begun to be revealed in the immune response. Expression profiling of specific affected genes revealed that RasGEF1b deficiency in macrophages affected only a few genes responsible for LPS. In particular, one gene with impaired expression was Cxcl1, which encodes the chemokine KC/Cxcl1 that is critical for neutrophil recruitment to inflammatory sites, mainly in bacterial and viral infections. These observations led us to suggest that RasGEF1b plays a role in the immune response by regulating chemokine expression. Thus, we aimed to evaluate the physiological role of RasGEF1b on Cxcl1 expression in the TLR7-mediated immune response and during IAV infection. Rasgef1bfl/fl;vav-icre mice (with gene recombination in hematopoietic tissue) and Rasgef1bfl/fl;CMV-cre mice (with somatic gene recombination) were used for infection with the A/PR8/34 virus or stimulation with R848, respectively, and subsequent study of phenotype, expression and production of relevant molecules in the response against the virus. We also demonstrated that Rasgef1bfl/fl;vav-icre mice have significantly increased survival during an Influenza infection. These studies provide new knowledge about a host factor in the TLR7-mediated immune response through IAV infection and that may provide insights for the development of therapeutic interventions so permitted for our IAV infections.