Abstract
BackgroundViral encephalitis is a common cause of lethal infections in humans, and several different viruses are documented to be responsible. Rocio virus is a flavivirus that causes a severe lethal encephalitis syndrome in humans and also mice, providing an interesting model to study the CNS compartmentalized immune response. Interleukin 33 (IL-33), a member of the IL-1 family, is an immunomodulatory cytokine that is highly expressed in the CNS. However, the role of IL-33 on viral encephalitis remains unclear. Therefore, we aimed to explore how the IL-33/ST2 axis regulates the local immune response during Rocio virus infection.MethodsWild-type (WT), ST2 (ST2−/−), and nitric oxide synthase-deficient mice (iNOS−/−) and Stat6 (Stat6−/−)-deficient mice were infected with different concentrations of the Rocio virus by intraperitoneal route, the cytokine mRNA level in CNS was analyzed by qPCR, and cellular immunophenotyping was performed on infected mice by the flow cytometry of isolated CNS mononuclear cells.ResultsWe have shown that the mRNA expression of IL-33 and ST2 receptors is increased in the CNS of Rocio virus-infected WT mice and that ST2−/− mice showed increased susceptibility to infection. ST2 deficiency was correlated with increased tissue pathology, cellular infiltration, and tumor necrosis factor alpha (TNF-α) and interferon-gamma (IFN-γ) mRNA levels and higher viral load in the CNS, compared with wild-type mice. The increased Th1 cytokine levels released in the CNS acted on infiltrating macrophages, as evidenced by flow cytometry characterization of cellular infiltrates, inducing the expression of iNOS, contributing to brain injury. Moreover, iNOS−/− mice were more resistant to Rocio virus encephalitis, presenting a lower clinical score and reduced mortality rate, despite the increased tissue pathology.ConclusionsWe provide evidences of a specific role for IL-33 receptor signaling in nitric oxide induction through local IFN-γ modulation, suggesting that nitric oxide overproduction might have an important role in the progression of experimental viral encephalitis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0628-1) contains supplementary material, which is available to authorized users.
Highlights
Viral encephalitis is a common cause of lethal infections in humans, and several different viruses are documented to be responsible
BALB/c mice are susceptible to ROCV infection First, we assessed the susceptibility of BALB/c by infecting these animals with different concentrations of the Rocio virus (ROCV) by intraperitoneal (i.p.) route
There are no differences on weight change on mice infected with 1.106 or 1.105 plaqueforming unit (PFU) (Fig. 1b); higher titer-infected mice displayed an earlier development of encephalitis signals, as determined by clinical score (Fig. 1c)
Summary
Viral encephalitis is a common cause of lethal infections in humans, and several different viruses are documented to be responsible. Infection with ROCV leads to a wide range of symptoms including, but not restrict to, the following: fever, headache, anorexia, nausea, vomiting, myalgia, and malaise. The pathology of this viral infection in humans ranges from asymptomatic to acute encephalitis [1]. Previous studies from our group demonstrated that ROCV infects and induces in BALB/c mice damage of the central nervous system (CNS), characterized by neuronal degeneration and apoptosis with detectable levels of inflammatory cytokines and massive cellular infiltration [2]. These cells produce high amounts of interferon-gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α), among other cytokines, which contribute to the degeneration and death of neurons with extensive tissue damage [2]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
