Zika virus (ZIKV) infection is a global health emergency that causes significant neurodegeneration. Neurodegenerative processes may be exacerbated by N-methyl-d-aspartate receptor (NMDAR)-dependent neuronal excitoxicity. Here, we have exploited the hypothesis that ZIKV-induced neurodegeneration can be rescued by blocking NMDA overstimulation with memantine. Our results show that ZIKV actively replicates in primary neurons and that virus replication is directly associated with massive neuronal cell death. Interestingly, treatment with memantine or other NMDAR blockers, including dizocilpine (MK-801), agmatine sulfate, or ifenprodil, prevents neuronal death without interfering with the ability of ZIKV to replicate in these cells. Moreover, in vivo experiments demonstrate that therapeutic memantine treatment prevents the increase of intraocular pressure (IOP) induced by infection and massively reduces neurodegeneration and microgliosis in the brain of infected mice. Our results indicate that the blockade of NMDARs by memantine provides potent neuroprotective effects against ZIKV-induced neuronal damage, suggesting it could be a viable treatment for patients at risk for ZIKV infection-induced neurodegeneration.

In Africa, Old World Primates are involved in the maintenance of sylvatic circulation of ZIKV. However, in Brazil, the hosts for the sylvatic cycle remain unknown. We hypothesized that free-living NHPs might play a role in urban/periurban ZIKV dynamics, thus we undertook an NHP ZIKV investigation in two cities in Brazil. We identified ZIKV-positive NHPs and sequences obtained were phylogenetically related to the American lineage of ZIKV. Additionally, we inoculated four C. penicillata with ZIKV and our results demonstrated that marmosets had a sustained viremia. The natural and experimental infection of NHPs with ZIKV, support the hypothesis that NHPs may be a vertebrate host in the maintainance of ZIKV transmission/circulation in urban tropical settings. Further studies are needed to understand the role they may play in maintaining the urban cycle of the ZIKV and how they may be a conduit in establishing an enzootic transmission cycle in tropical Latin America.

SummaryDengue is a mosquito-borne disease that affects millions of people worldwide yearly. Currently, there is no vaccine or specific treatment available. Further investigation on dengue pathogenesis is required to better understand the disease and to identify potential therapeutic targets. The chemokine system has been implicated in dengue pathogenesis, although the specific role of chemokines and their receptors remains elusive. Here we describe the role of the CC-chemokine receptor CCR5 in Dengue virus (DENV-2) infection. In vitro experiments showed that CCR5 is a host factor required for DENV-2 replication in human and mouse macrophages. DENV-2 infection induces the expression of CCR5 ligands. Incubation with an antagonist prevents CCR5 activation and reduces DENV-2 positive-stranded (+) RNA inside macrophages. Using an immunocompetent mouse model of DENV-2 infection we found that CCR5 À/À mice were resistant to lethal infection, presenting at least 100-fold reduction of viral load in target organs and significant reduction in disease severity. This phenotype was reproduced in wild-type mice treated with CCR5-blocking compounds. Therefore, CCR5 is a host factor required for DENV-2 replication and disease development. Targeting CCR5 might represent a therapeutic strategy for dengue fever. These data bring new insights on the association between viral infections and the chemokine receptor CCR5.

BackgroundFlaviviruses are a genre of closely related viral pathogens which emerged in the last decades in Brazil and in the world. Saint (St.) Louis encephalitis virus (SLEV) is a neglected flavivirus that can cause a severe neurological disease that may lead to death or sequelae. St. Louis encephalitis pathogenesis is poorly understood, which hinders the development of specific treatment or vaccine.MethodsTo address this problem, we developed a model of SLEV infection in mice to study mechanisms involved in the pathogenesis of severe disease. The model consists in the intracranial inoculation of the SLEV strain BeH 355964, a strain isolated from a symptomatic human patient in Brazil, in adult immunocompetent mice.ResultsInoculated mice presented SLEV replication in the brain, accompanied by tissue damage, disease signs, and mortality approximately 7 days post infection. Infection was characterized by the production of proinflammatory cytokines and interferons and by leukocyte recruitment to the brain, composed mainly by neutrophils and lymphocytes. In vitro experiments indicated that SLEV is able to replicate in both neurons and glia and caused neuronal death and cytokine production, respectively.ConclusionsAltogether, intracranial SLEV infection leads to meningoencephalitis in mice, recapitulating several aspects of St. Louis encephalitis in humans. Our study indicates that the central nervous system (CNS) inflammation is a major component of SLEV-induced disease. This model may be useful to identify mechanisms of disease pathogenesis or resistance to SLEV infection.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0837-2) contains supplementary material, which is available to authorized users.

In the 20th century, socioeconomic and environmental changes facilitated the reintroduction of mosquitoes in developing cities, resulting in the reinsertion of mosquito-borne viral diseases and the dispersal of their causative agents on a worldwide scale. Recurrent outbreaks of arboviral diseases are being reported, even in regions without a previous history of arboviral disease transmission. Of note, arboviral infections represented approximately 30% of all emerging vector-borne diseases in the last decade. Therapeutic strategies against infectious viral diseases include the use of different classes of molecules that act directly on the pathogen and/or act by optimizing the host immune response. Drugs targeting the virus usually provide amelioration of symptoms by suppressing and controlling the infection. However, it is limited by the short-window of effectiveness, ineffectiveness against latent viruses, development of drug-resistant mutants and toxic side effects. Disease may also be a consequence of an excessive, uncontrolled or misplaced inflammatory response, treatments that interfere in host immune response are interesting options and can be used isolated or in combination with virus-targeted therapies. The use of host-targeted therapies requires specific knowledge regarding host immune patterns that may trigger dengue virus (DENV), chikungunya virus (CHIKV) or Zika virus (ZIKV) disease.

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St. Louis encephalitis virus (SLEV) is a neglected mosquito-borne flavivirus that causes severe neurological disease in humans. SLEV replication in the central nervous system (CNS) induces the local production of interferons (IFNs), which are attributed to host protection. The antiviral response to SLEV infection in the CNS is not completely understood, which led us to characterize the roles of IFNs using mouse models of St. Louis encephalitis. We infected mice deficient in type I IFN receptor (ABR −/-) or deficient in Type II IFN (IFNγ −/-) and assessed the contribution of each pathway to disease development. We found that type I and II IFNs play different roles in SLEV infection. Deficiency in type I IFN signaling was associated to an early and increased mortality, uncontrolled SLEV replication and impaired ISG expression, leading to increased proinflammatory cytokine production and brain pathology. Conversely, IFNγ −/mice were moderately resistant to SLEV infection. IFNγ deficiency caused no changes to viral load or SLEV-induced encephalitis and did not change the expression of ISGs in the brain. We found that type I IFN is essential for the control of SLEV replication whereas type II IFN was not associated with protection in this model.