Usutu virus (USUV) is an emerging arbovirus that was first isolated in South Africa in 1959. ThisFlavivirusis maintained in the environment through a typical enzootic cycle involving mosquitoes and birds. USUV has spread to a large part of the European continent over the two decades mainly leading to substantial avian mortalities with a significant recrudescence of bird infections recorded throughout Europe within the few last years. USUV infection in humans is considered to be most often asymptomatic or to cause mild clinical signs. Nonetheless, a few cases of neurological complications such as encephalitis or meningoencephalitis have been reported. USUV and West Nile virus (WNV) share many features, like a close phylogenetic relatedness and a similar ecology, with co-circulation frequently observed in nature. However, USUV has been much less studied and in-depth comparisons of the biology of these viruses are yet rare. In this review, we discuss the main body of knowledge regarding USUV and compare it with the literature on WNV, addressing in particular virological and clinical aspects, and pointing data gaps.

The recent Zika virus (ZIKV) epidemic has highlighted the poor knowledge on its physiopathology. Recent studies showed that ZIKV of the Asian lineage, responsible for this international outbreak, causes neuropathology in vitro and in vivo. However, two African lineages exist and the virus is currently found circulating in Africa. The original African strain was also suggested to be neurovirulent but its laboratory usage has been criticized due to its multiple passages. In this study, we compared the French Polynesian (Asian) ZIKV strain to an African strain isolated in Central African Republic and show a difference in infectivity and cellular response between both strains in human neural stem cells and astrocytes. Consistently, this African strain led to a higher infection rate and viral production, as well as stronger cell death and anti-viral response. Our results highlight the need to better characterize the physiopathology and predict neurological impairment associated with African ZIKV.

Mosquito-borne West Nile virus (WNV) infection is benign in most individuals but can cause encephalitis in <1% of infected individuals. We show that ∼35% of patients hospitalized for WNV disease (WNVD) in six independent cohorts from the EU and USA carry auto-Abs neutralizing IFN-α and/or -ω. The prevalence of these antibodies is highest in patients with encephalitis (∼40%), and that in individuals with silent WNV infection is as low as that in the general population. The odds ratios for WNVD in individuals with these auto-Abs relative to those without them in the general population range from 19.0 (95% CI 15.0–24.0, P value <10–15) for auto-Abs neutralizing only 100 pg/ml IFN-α and/or IFN-ω to 127.4 (CI 87.1–186.4, P value <10–15) for auto-Abs neutralizing both IFN-α and IFN-ω at a concentration of 10 ng/ml. These antibodies block the protective effect of IFN-α in Vero cells infected with WNV in vitro. Auto-Abs neutralizing IFN-α and/or IFN-ω underlie ∼40% of cases of WNV encephalitis.

Zika virus (ZIKV) is a small enveloped positive-sense single-stranded RNA virus belonging to the genus Flavivirus of the Flaviviridae family that has reemerged in recent years as a human pathogen with epidemic potential. To date, the ongoing epidemic in the Americas has led to tens of thousands of confirmed cases in Brazil alone (Pan American Health Organization Zika-Epidemiological Report, 2 March 2017). More concerning are the reports of severe neurological disorders such as Guillain-Barre ´syndrome and congenital Zika syndrome (microcephaly and other neurodevelopmental defects), which led the World Health Organization to declare the ZIKV epidemic as a Public Health Emergency of International Concern in 2016. Phylogenetic analyses show that ZIKV can be classified into 2 main lineages: the African lineage and the Asian lineage, the latter of which is responsible for the recent epidemics. Because recent ZIKV infections were associated with the development of congenital and neurological disorders, a key question was raised as to whether Asian-lineage ZIKV strains were phenotypically different from the African lineage strains. It is well described that mutations acquired during Flavivirus evolution can alter their virulence and/or tropism [1]. ZIKV is primarily transmitted by the mosquito species Aedes aegypti and Aedes albopictus. Several studies show that vector transmission can differ between ZIKV strains, as the overall ZIKV infection prevalence and transmission rates of African strains may be higher in A. aegypti than Asian strains [2], suggesting that viral adaptation may have occurred-similar to a single mutation in the chikungunya virus envelope protein that affected vector specificity and epidemic potential. During the recent outbreak, it became clear that ZIKV is sometimes able to cause a prolonged infection. Numerous studies showed that Asian-lineage strains isolated in South America replicate at low levels in tissues months after the initial infection. For example, viral genome can be found in stillborn babies who were infected early during gestation [3], weeks after initial infection in sperm, and in rhesus monkeys, ZIKV can be found in the cerebral spinal fluid (CSF) 42 days after infection, weeks after the virus was cleared from the blood [4]. However, to date, no data are available on the ability of African-lineage strains to cause prolonged infections, but early studies in 2016 suggested that an African ZIKV strain was highly pathogenic and led to cell death; when the first reports on a potential link between microcephaly and ZIKV emerged, laboratories started to study the effect of ZIKV on human neural precursor cells (hNPCs)/human neural stem cells (hNSCs) with MR766, the most available strain at the time (Fig 1 and Table 1). These first studies showed strong tropism and deleterious effects on NSC homeostasis and growth (e.g., [5]). However, some inconsistencies between this rather strong virulence and the long-term developmental effects associated with ZIKV infections led researchers to question the biological validity of this strain, which has been

Infection with Usutu virus (USUV) has been recently associated with neurologic disorders, such as encephalitis or meningoencephalitis, in humans. These findings indicate that USUV is a potential health threat. We report an acute human infection with USUV in France putatively associated with a clinical diagnosis of idiopathic facial paralysis.

West Nile Virus (WNV) and Usutu Virus (USUV) are both neurotropic mosquito-borne viruses belonging to the Flaviviridae family. These closely related viruses mainly follow an enzootic cycle involving mosquitoes as vectors and birds as amplifying hosts, but humans and other mammals can also be infected through mosquito bites. WNV was first identified in Uganda in 1937 and has since spread globally, notably in Europe, causing periodic outbreaks associated with severe cases of neuroinvasive diseases such as meningitis and encephalitis. USUV was initially isolated in 1959 in Swaziland and has also spread to Europe, primarily affecting birds and having a limited impact on human health. There has been a recent expansion of these viruses’ geographic range in Europe, facilitated by factors such as climate change, leading to increased human exposure. While sharing similar biological traits, ecology, and epidemiology, there are significant distinctions in their pathogenicity and their impact on both human and animal health. While WNV has been more extensively studied and is a significant public health concern in many regions, USUV has recently been gaining attention due to its emergence in Europe and the diversity of its circulating lineages. Understanding the pathophysiology, ecology, and transmission dynamics of these viruses is important to the implementation of effective surveillance and control measures. This perspective provides a brief overview of the current situation of these two viruses in Europe and outlines the significant challenges that need to be addressed in the coming years.