Encefalite de Saint Louis: caracterização dos papéis dos interferons em um modelo de infecção em camundongos

Abstract

Flaviviruses are a genre of closely-related viral pathogens, which emerged or reemerged in the last decades in Brazil and in the world. Flaviviruses such as St. Louis encephalitis virus (SLEV) can cause encephalitis, a severe disease that may lead to death or neurological sequelae. St. Louis encephalitis pathogenesis is poorly understood, which delays the development of a specific treatment or vaccine, in similar way to Zika and Dengue. To address this problem, we developeda mice model of SLEV infection to study mechanisms involved in resistance to infection and disease. The model consists in the intracranial (i.c.) inoculation of the SLEV strain BeH 355964in mice, a strain isolated from a human patient in Brazil. Inoculated mice die from infection, presenting with SLEV replication, inflammation and brain damage, which are consistent with encephalitis. The correlation of SLEV replication and mortality after infection brought us to the study of IFNs, which are typically associated to the control of viral replication. We infected ABR-/- and IFN-/- mice, which lack type I IFN receptors or lack type II IFN, respectively, to find that ABR-/- mice are very susceptible to infection, in contrast to IFN-/- mice, which are slightly resistant. Further study of disease parameters showed that type I IFNs are essential for the control of SLEV replication, through the increase of ISG expression in the brain, notably RIG-I. RIG-I is a molecule known to participate in innate immune responses to RNA viruses. In contrast, absence of IFN (type II IFN) resulted in the reduction of viral load in the brain, due to high basal levels of RIG-I expression presented by IFN-/- mice in the brain. SLEV caused the expression of type III IFN only in the brains of IFN-/- mice, indicating that IFN type II and III interact in ways that are not yet understood, in the context of infection. We conclude that our SLEV infection model is a useful tool for the study of St. Louis encephalitis. This infection model allows for the study of mechanisms of disease pathogenesis and or resistance, such as antiviral responses against a flavivirus in the brain. Thus, this animal model will help to generate applicable knowledge to St. Louis encephalitis and to related flaviviral diseases, such as Zika.