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Zika virus (ZIKV), a member of the Flaviviridae family, is an important human pathogen that has caused epidemics in Africa, Southeast Asia, and the Americas. No licensed treatments for ZIKV disease are currently available. Favipiravir (T-705; 6-fluoro-3-hydroxy-2-pyrazinecarboxamide) and ribavirin (1-(β-D-Ribofuranosyl)-1H-1,2,4-triazole-3-carboxamide) are nucleoside analogs that have exhibited antiviral activity against a broad spectrum of RNA viruses, including some flaviviruses. In this study, we strengthened evidence for favipiravir and ribavirin inhibition of ZIKV replication in vitro. Testing in IFNAR−/− mice revealed that daily treatments of favipiravir were sufficient to provide protection against lethal ZIKV challenge in a dose-dependent manner but did not completely abrogate disease. Ribavirin, on the other hand, had no beneficial effect against ZIKV infection in this model and under the conditions examined. Combined treatment of ribavirin and favipiravir did not show improved outcomes over ribavirin alone. Surprisingly, outcome of favipiravir treatment was sex-dependent, with 87% of female but only 25% of male mice surviving lethal ZIKV infection. Since virus mutations were not associated with outcome, a sex-specific host response likely explains the observed sex difference. [ABSTRACT FROM AUTHOR]

Ebola virus is a continuing threat to human populations, causing a virulent hemorrhagic fever disease characterized by dysregulation of both the innate and adaptive host immune responses. Severe cases are distinguished by an early, elevated pro-inflammatory response followed by a pronounced lymphopenia with B and T cells unable to mount an effective anti-viral response. The precise mechanisms underlying the dysregulation of the host immune system are poorly understood. In recent years, focus on host-derived miRNAs showed these molecules to play an important role in the host gene regulation arsenal. Here, we describe an investigation of RNA biomarkers in the fatal Ebola virus disease (EVD) cynomolgus macaque model. We monitored both host mRNA and miRNA responses in whole blood longitudinally over the disease course in these non-human primates (NHPs). Analysis of the interactions between these classes of RNAs revealed several miRNA markers significantly correlated with downregulation of genes; specifically, the analysis revealed those involved in dysregulated immune pathways associated with EVD. In particular, we noted strong interactions between the miRNAs hsa-miR-122-5p and hsa-miR-125b-5p with immunological genes regulating both B and T-cell activation. This promising set of biomarkers will be useful in future studies of severe EVD pathogenesis in both NHPs and humans and may serve as potential prognostic targets. [ABSTRACT FROM AUTHOR]

Crimean-Congo hemorrhagic fever virus (CCHFV) is an arthropod-borne virus (arbovirus), mainly transmitted by ticks, belonging to the genus Orthonairovirus (family Nairoviridae, order Bunyavirales). CCHFV causes a potentially severe, or even fatal, human disease, and it is widely distributed in Africa, Asia, eastern Europe and, more recently, in South-western Europe. Until a few years ago, no cases of Crimean-Congo hemorrhagic fever (CCHF) had been reported in western Europe, with the exception of several travel-associated cases. In 2010, the CCHFV was reported for the first time in South-western Europe when viral RNA was obtained from Hyalomma lusitanicum ticks collected from deer in Cáceres (Spain). Migratory birds from Africa harboring CCHFV-infected ticks and flying to Spain appear to have contributed to the establishment of the virus (genotype III, Africa-3) in this country. In addition, the recent findings in a patient and in ticks from deer and wild boar of viral sequences similar to those from eastern Europe (genotype V, Europe-1), raise the possibility of the introduction of CCHFV into Spain through the animal trade, although the arrival by bird routes cannot be ruled out (Africa-4 has been also recently detected). The seropositive rates of animals detected in regions of South-western Spain suggest an established cycle of tick-host-tick in certain areas, and the segment reassortment detected in the sequenced virus from one patient evidences a high ability to adaptation of the virus. Different ixodid tick genera can be vectors and reservoirs of the virus, although Hyalomma spp. are particularly relevant for its maintenance. This tick genus is common in Mediterranean region but it is currently spreading to new areas, partly due to the climate change and movement of livestock or wild animals. Although to a lesser extent, travels with our pets (and their ticks) may be also a factor to be considered. As a consequence, the virus is expanding from the Balkan region to Central Europe and, more recently, to Western Europe where different genotypes are circulating. Thus, seven human cases confirmed by molecular methods have been reported in Spain from 2016 to August 2020, three of them with a fatal outcome. A One Health approach is essential for the surveillance of fauna and vector populations to assess the risk for humans and animals. We discuss the risk of CCHFV causing epidemic outbreaks in Western Europe. [ABSTRACT FROM AUTHOR]

Lassa fever (LF) is a viral hemorrhagic disease found in Sub-Saharan Africa and is responsible for up to 300,000 cases and 5000 deaths annually. LF is highly endemic in Sierra Leone, particularly in its Eastern Province. Kenema Government Hospital (KGH) maintains one of only a few LF isolation facilities in the world with year-round diagnostic testing. Here we focus on space-time trends for LF occurring in Sierra Leone between 2012 and 2019 to provide a current account of LF in the wake of the 2014–2016 Ebola epidemic. Data were analyzed for 3277 suspected LF cases and classified as acute, recent, and non-LF or prior LF exposure using enzyme-linked immunosorbent assays (ELISAs). Presentation rates for acute, recent, and non-LF or prior LF exposure were 6.0% (195/3277), 25.6% (838/3277), and 68.4% (2244/3277), respectively. Among 2051 non-LF or prior LF exposures, 33.2% (682/2051) tested positive for convalescent LF exposure. The overall LF case-fatality rate (CFR) was 78.5% (106/135). Both clinical presentations and confirmed LF cases declined following the Ebola epidemic. These declines coincided with an increased duration between illness onset and clinical presentation, perhaps suggesting more severe disease or presentation at later stages of illness. Acute LF cases and their corresponding CFRs peaked during the dry season (November to April). Subjects with recent (but not acute) LF exposure were more likely to present during the rainy season (May to October) than the dry season (p < 0.001). The findings here suggest that LF remains endemic in Sierra Leone and that caseloads are likely to resume at levels observed prior to the Ebola epidemic. The results provide insight on the current epidemiological profile of LF in Sierra Leone to facilitate LF vaccine studies and accentuate the need for LF cohort studies and continued advancements in LF diagnostics. [ABSTRACT FROM AUTHOR]

Arenaviruses such as Lassa virus cause arenavirus hemorrhagic fever (AVHF), but protective vaccines and effective antiviral therapy remain unmet medical needs. Our prior work has revealed that inducible nitric oxide synthase (iNOS) induction by IFN-γ represents a key pathway to microvascular leak and terminal shock in AVHF. Here we hypothesized that Ruxolitinib, an FDA-approved JAK inhibitor known to prevent IFN-γ signaling, could be repurposed for host-directed therapy in AVHF. We tested the efficacy of Ruxolitinib in MHC-humanized (HHD) mice, which develop Lassa fever-like disease upon infection with the monkey-pathogenic lymphocytic choriomeningitis virus strain WE. Anti-TNF antibody therapy was tested as an alternative strategy owing to its expected effect on macrophage activation. Ruxolitinib but not anti-TNF antibody prevented hypothermia and terminal disease as well as pleural effusions and skin edema, which served as readouts of microvascular leak. As expected, neither treatment influenced viral loads. Intriguingly, however, and despite its potent disease-modifying activity, Ruxolitinib did not measurably interfere with iNOS expression or systemic NO metabolite levels. These findings suggest that the FDA-approved JAK-inhibitor Ruxolitinib has potential in the treatment of AVHF. Moreover, our observations indicate that besides IFN-γ-induced iNOS additional druggable pathways contribute essentially to AVHF and are amenable to host-directed therapy. [ABSTRACT FROM AUTHOR]

Ebola virus (EBOV) is a negative-sense RNA virus that can infect humans and nonhuman primates with severe health consequences. Development of countermeasures requires a thorough understanding of the interaction between host and pathogen, and the course of disease. The goal of this study was to further characterize EBOV disease in a uniformly lethal rhesus macaque model, in order to support development of a well-characterized model following rigorous quality standards. Rhesus macaques were intramuscularly exposed to EBOV and one group was euthanized at predetermined time points to characterize progression of disease. A second group was not scheduled for euthanasia in order to analyze survival, changes in physiology, clinical pathology, terminal pathology, and telemetry kinetics. On day 3, sporadic viremia was observed and pathological evidence was noted in lymph nodes. By day 5, viremia was detected in all EBOV exposed animals and pathological evidence was noted in the liver, spleen, and gastrointestinal tissues. These data support the notion that EBOV infection in rhesus macaques is a rapid systemic disease similar to infection in humans, under a compressed time scale. Biomarkers that correlated with disease progression at the earliest stages of infection were observed thereby identifying potential "trigger-to-treat" for use in therapeutic studies. [ABSTRACT FROM AUTHOR]

Filoviruses are zoonotic, negative-sense RNA viruses, most of which are capable of causing severe disease in humans and nonhuman primates, often with high case fatality rates. Among these viruses, those belonging to the Ebolavirus genus—particularly Ebola virus, Sudan virus, and Bundibugyo virus—represent some of the most pathogenic to humans. Taï Forest virus (TAFV) is thought to be among the least pathogenic ebolaviruses; however, only a single non-fatal case has been documented in humans, in 1994. With the recent success of the ferret as a lethal model for a number of ebolaviruses, we set out to evaluate its suitability as a model for TAFV. Our results demonstrate that, unlike other ebolaviruses, TAFV infection in ferrets does not result in lethal disease. None of the intramuscularly inoculated animals demonstrated any overt signs of disease, whereas the intranasally inoculated animals exhibited mild to moderate weight loss during the early stage of infection but recovered quickly. Low levels of viral RNA were detected in the blood and tissues of several animals, particularly the intranasally inoculated animals, and all animals mounted a humoral immune response, with high titers of GP-specific IgG detectable as early as 14 days post-infection. These data provide additional insight into the pathogenesis of TAFV. [ABSTRACT FROM AUTHOR]