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Flaviviruses are vector-borne RNA viruses that can emerge unexpectedly in human populations and cause a spectrum of potentially severe diseases including hepatitis, vascular shock syndrome, encephalitis, acute flaccid paralysis, congenital abnormalities and fetal death. This epidemiological pattern has occurred numerous times during the last 70 years, including epidemics of dengue virus and West Nile virus, and the most recent explosive epidemic of Zika virus in the Americas. Flaviviruses are now globally distributed and infect up to 400 million people annually. Of significant concern, outbreaks of other less well-characterized flaviviruses have been reported in humans and animals in different regions of the world. The potential for these viruses to sustain epidemic transmission among humans is poorly understood. In this Review, we discuss the basic biology of flaviviruses, their infectious cycles, the diseases they cause and underlying host immune responses to infection. We describe flaviviruses that represent an established ongoing threat to global health and those that have recently emerged in new populations to cause significant disease. We also provide examples of lesser-known flaviviruses that circulate in restricted areas of the world but have the potential to emerge more broadly in human populations. Finally, we discuss how an understanding of the epidemiology, biology, structure and immunity of flaviviruses can inform the rapid development of countermeasures to treat or prevent human infections as they emerge. Flaviviruses, a group of vector-borne RNA viruses that includes dengue virus, West Nile virus, Zika virus and several lesser-known species, often emerge in human populations and cause epidemics. Here, Pierson and Diamond review the basic biology of these viruses, their life cycles, the diseases they cause and available therapeutic options. They also discuss the global distribution of flaviviruses, with a focus on lesser-known species that have the potential to emerge more broadly in human populations.

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.

Key Points Flaviviruses are a genus within the Flaviviridae family with a single-stranded, positive-sense RNA genome. Many representatives of the genus, such as dengue, West Nile and Zika viruses, are associated with pathogenic effects in humans. Infections with flaviviruses cause symptoms of varying severity, ranging from flu-like illnesses and fevers to potentially lethal haemorrhagic fevers. Neurological complications include encephalitis (for West Nile virus) or microcephaly and Guillain–Barré syndrome (for Zika virus). Vaccine development for humans was successful for some members of the genus, but no specific, pharmacological antiviral agent has reached the market. Drugs with broad-spectrum antiviral activity would be particularly desirable to tackle outbreaks of emerging or neglected flaviviruses. Molecular targets with promising prospects for broad-spectrum relevance include viral proteins, such as the viral protease or polymerase, and host targets exploited by these viruses, including α-glucosidase and mechanisms involved in nucleoside biosynthesis. Flaviviruses, including dengue and Zika viruses, are of substantial public health concern. Klein and colleagues review the development of broad-spectrum antiviral agents that would target many of the known and potentially unknown flaviviruses. The benefits and caveats of molecules that target either viral proteins or host mechanisms exploited by these viruses are discussed. Infections with flaviviruses, such as dengue, West Nile virus and the recently re-emerging Zika virus, are an increasing and probably lasting global risk. This Review summarizes and comments on the opportunities for broad-spectrum agents that are active against multiple flaviviruses. Broad-spectrum activity is particularly desirable to prepare for the next flaviviral epidemic, which could emerge from as-yet unknown or neglected viruses. Potential molecular targets for broad-spectrum antiflaviviral compounds include viral proteins, such as the viral protease or polymerase, and host targets that are exploited by these viruses during entry and replication, including α-glucosidase and proteins involved in nucleoside biosynthesis. Numerous compounds with broad-spectrum antiviral activity have already been identified by target-specific or phenotypic assays. For other compounds, broad-spectrum activity can be anticipated because of their mode of action and molecular targets.

Mosquito-borne arboviruses, including Usutu virus (USUV) and West Nile virus (WNV), are emerging threats in Europe, with changes in climate, land use shifts, and increasing global connectivity influencing their dynamics. Understanding how these viruses emerge and establish in new regions is critical for mitigating risks and improving public and wildlife health preparedness. Here, we present a seven-year study (2016–2022, inclusive) documenting the emergence and spread of USUV and WNV in the Netherlands. We established a nationwide sampling framework integrating live birds sampling by volunteer ringers, dead birds referrals by citizen scientists and zoos, and mosquito trapping. Samples were analyzed using molecular, genomic, and serological methods. USUV was first detected in the Netherlands in 2016, caused major outbreaks in birds until 2018 and resurged in 2022. The dominant, enzootic lineage, Africa 3, co-circulated with sporadic introductions of lineage Europe 3. The first localized WNV lineage 2 outbreak occurred in live birds and mosquitoes in 2020, followed by a detection in a bird in 2022 and serological evidence of continued circulation, suggesting WNV is in an early stage of establishment. Our findings were crucial in detecting a human WNV outbreak, underscoring the value of integrated wildlife studies in detecting emerging threats to public health. Arboviruses are climate sensitive, and their global distributions are changing. Here, the authors describe results of a One Health study programme to investigate the occurrence of Usutu and West Nile Virus in the Netherlands, a previously non-endemic area.

Usutu virus is a zoonotic arbovirus that causes massive mortality in blackbirds. Using a unique longitudinal dataset on the kinetics of virus-specific antibodies in naturally infected wild blackbirds (Turdus merula), we found that individual birds may remain seropositive for >1 year and that reinfection can occur despite low-level virus neutralizing antibodies.

Usutu virus (USUV) is an emerging arbovirus that was first isolated in South Africa in 1959. This Flavivirus is 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.

Usutu virus (USUV) is a mosquito-borne flavivirus circulating in Western Europe that causes die-offs of mainly common blackbirds ( Turdus merula ). In the Netherlands, USUV was first detected in 2016, when it was identified as the likely cause of an outbreak in birds. In this study, dead blackbirds were collected, screened for the presence of USUV and submitted to Nanopore-based sequencing. Genomic sequences of 112 USUV were obtained and phylogenetic analysis showed that most viruses identified belonged to the USUV Africa 3 lineage, and molecular clock analysis evaluated their most recent common ancestor to 10 to 4 years before first detection of USUV in the Netherlands. USUV Europe 3 lineage, commonly found in Germany, was less frequently detected. This analyses further suggest some extent of circulation of USUV between the Netherlands, Germany and Belgium, as well as likely overwintering of USUV in the Netherlands.

Usutu virus (USUV) is an emerging zoonotic flavivirus in Europe and the first zoonotic mosquito-borne virus to be confirmed in animal hosts in the United Kingdom (UK). Repeated detection of USUV in the years following its initial detection in 2020 indicated that the virus is overwintering in the UK and should now be considered endemic within southeast England. Surveillance of avian hosts and mosquito vectors has been insufficient to elucidate the mechanism by which USUV has persisted through temperate winters. Through enhanced targeted vector surveillance at the index site between 2021 and 2024 inclusive, we detected USUV RNA in host-seeking adult female Culex pipiens s.l. as well as in adults reared from field-caught larvae. This is, to our knowledge, the first description of vertical transmission of USUV in an arthropod vector that should consequently be considered a viable mechanism for the persistence of USUV in temperate areas.

Most areas of the globe are endemic for at least one flavivirus, putting billions at risk for infection. This diverse group of viral pathogens causes a range of manifestations in humans from asymptomatic infection to hemorrhagic fever to encephalitis to birth defects and even death. Many flaviviruses are transmitted by mosquitos and have expanded in geographic distribution in recent years, with dengue virus being the most prevalent, infecting approximately 400 million people each year. The explosive emergence of Zika virus in Latin America in 2014 refocused international attention on this medically important group of viruses. Meanwhile, yellow fever has caused major outbreaks in Africa and South America since 2015 despite a reliable vaccine. There is no vaccine for Zika yet, and the only licensed dengue vaccine performs suboptimally in certain contexts. Further lessons are found when considering the experience with Japanese encephalitis virus, West Nile virus, and tickborne encephalitis virus, all of which now have protective vaccination in human or veterinary populations. Thus, vaccination is a mainstay of public health strategy for combating flavivirus infections; however, numerous challenges exist along the path from development to delivery of a tolerable and effective vaccine. Nevertheless, intensification of investment and effort in this area holds great promise for significantly reducing the global burden of disease attributable to flavivirus infection.

Long-term serologic surveillance of red-legged partridges suggests emergence of Bagaza virus in Portugal in 2021, associated with disease outbreaks in this species. Results also reveal sporadic circulation of Usutu virus and endemic circulation of West Nile virus, highlighting the role of red-legged partridges in the transmission and maintenance cycle and as sentinels of orthoflaviviruses.