Mecanismos envolvendo ativação de receptores do tipo toll9 e formação de espécies reativas na resistência do hospedeiro à infecção pelo vírus da dengue

Abstract

Dengue is one of the most important arboviruses that affect humans and it is a serious global health problem. The disease is caused by dengue virus which is divided into four serotypes (DENV-1, DENV-2, DENV-3, DENV-4). The disease usually manifests in two forms: the classic fever and the dengue hemorrhagic fever / dengue shock syndrome. The installation of an abnormal inflammatory response and mass release of proinflammatory cytokines and reactive species appears to be involved in the progression of classic disease to the more severe forms of the disease, but many of these components also seem to be essential for controlling the infection. In this work, we found that even in dengue fever, there is a systemical inflammatory process installed followed by cell death and mitochondrial DNA release in serum. This process could lead the activation of its putative receptor TLR9 during infection by DENV-3, resulting in the induction of IFN-I and IL-1. Additionally, pathways that induce the production of IFN- are activated with consequent generation of reactive oxygen and nitrogen species. Here, we elucidated a more comprehensive effect for IFN- to exert its effects during infection by DENV: the upregulation of the expression of gp91phox with consequent production of superoxide. During the illness, superoxide should react with NO, resulting in ONOO-, to exert a more effective antiviral action. Thus, the virus-host interaction generates a sequence of processes, by which viral replication should be rapidly controlled, in part, by processes involving inflammation and cell death with consequent release of mitochondrial DNA, TLR9 activation and production of reactive species. The actions of ONOO- and the activation of TLR9 seem to be the main mechanisms by which the host resists to infection and contains the disease progression during dengue.