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A 62-year-old patient was hospitalized in Geneva, Switzerland, with an atypical manifestation of West Nile virus infection. Initially, he sought care for febrile diarrhea and vomiting; his condition deteriorated and hemophagocytic lymphohistiocytosis and meningoencephalitis developed. Corticosteroids improved his condition. We used high-throughput sequencing and ophthalmologic findings to diagnose West Nile virus.

People infected with West Nile virus often experience cognitive side effects including memory loss through unknown mechanisms; mice and humans infected with the virus experience a loss in hippocampal presynaptic terminals, which can be reversed by disrupting complement or microglia in mice. Cognitive abnormalities associated with West Nile virus A majority of West Nile virus (WNV) sufferers experience cognitive signs and symptoms, including memory dysfunction, but the mechanisms driving these impairments are largely unknown. Robyn Klein and colleagues demonstrate an enhancement of complement-mediated synaptic pruning in the hippocampus following WNV infection. This pruning required microglia and resembled developmental pruning by the same mechanism. Disruption of complement or microglia during infection protected animals from the WNV-induced memory deficits. Over 50% of patients who survive neuroinvasive infection with West Nile virus (WNV) exhibit chronic cognitive sequelae 1 , 2 . Although thousands of cases of WNV-mediated memory dysfunction accrue annually 3 , the mechanisms responsible for these impairments are unknown. The classical complement cascade, a key component of innate immune pathogen defence, mediates synaptic pruning by microglia during early postnatal development 4 , 5 . Here we show that viral infection of adult hippocampal neurons induces complement-mediated elimination of presynaptic terminals in a murine WNV neuroinvasive disease model. Inoculation of WNV-NS5-E218A, a WNV with a mutant NS5(E218A) protein 6 , 7 leads to survival rates and cognitive dysfunction that mirror human WNV neuroinvasive disease. WNV-NS5-E218A-recovered mice (recovery defined as survival after acute infection) display impaired spatial learning and persistence of phagocytic microglia without loss of hippocampal neurons or volume. Hippocampi from WNV-NS5-E218A-recovered mice with poor spatial learning show increased expression of genes that drive synaptic remodelling by microglia via complement. C1QA was upregulated and localized to microglia, infected neurons and presynaptic terminals during WNV neuroinvasive disease. Murine and human WNV neuroinvasive disease post-mortem samples exhibit loss of hippocampal CA3 presynaptic terminals, and murine studies revealed microglial engulfment of presynaptic terminals during acute infection and after recovery. Mice with fewer microglia ( Il34 −/− mice with a deficiency in IL-34 production) or deficiency in complement C3 or C3a receptor were protected from WNV-induced synaptic terminal loss. Our study provides a new murine model of WNV-induced spatial memory impairment, and identifies a potential mechanism underlying neurocognitive impairment in patients recovering from WNV neuroinvasive disease.

We report 2 cases of donor-derived West Nile virus infection in kidney transplant recipients in France. Both recipients had mild disease develop and recovered without sequelae. A more proactive screening strategy in France, particularly during periods of highest risk for West Nile virus circulation, would help reduce risk for donor-derived infections.

It has been 20 years since West Nile virus first emerged in the Americas, and since then, little progress has been made to control outbreaks caused by this virus. After its first detection in New York in 1999, West Nile virus quickly spread across the continent, causing an epidemic of human disease and massive bird die-offs. Now the virus has become endemic to the United States, where an estimated 7 million human infections have occurred, making it the leading mosquito-borne virus infection and the most common cause of viral encephalitis in the country. To bring new attention to one of the most important mosquito-borne viruses in the Americas, we provide an interactive review using Nextstrain: a visualization tool for real-time tracking of pathogen evolution (nextstrain.org/WNV/NA). Nextstrain utilizes a growing database of more than 2,000 West Nile virus genomes and harnesses the power of phylogenetics for students, educators, public health workers, and researchers to visualize key aspects of virus spread and evolution. Using Nextstrain, we use virus genomics to investigate the emergence of West Nile virus in the U S, followed by its rapid spread, evolution in a new environment, establishment of endemic transmission, and subsequent international spread. For each figure, we include a link to Nextstrain to allow the readers to directly interact with and explore the underlying data in new ways. We also provide a brief online narrative that parallels this review to further explain the data and highlight key epidemiological and evolutionary features (nextstrain.org/narratives/twenty-years-of-WNV). Mirroring the dynamic nature of outbreaks, the Nextstrain links provided within this paper are constantly updated as new West Nile virus genomes are shared publicly, helping to stay current with the research. Overall, our review showcases how genomics can track West Nile virus spread and evolution, as well as potentially uncover novel targeted control measures to help alleviate its public health burden.

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.

Humans and equines are two dead-end hosts of the mosquito-borne West Nile virus (WNV) with similar susceptibility and pathogenesis. Since the introduction of WNV vaccines into equine populations of the United States of America (USA) in late 2002, there have been only sporadic cases of WNV infection in equines. These cases are generally attributed to unvaccinated and under-vaccinated equines. In contrast, due to the lack of a human WNV vaccine, WNV cases in humans have remained steadily high. An average of 115 deaths have been reported per year in the USA since the first reported case in 1999. Therefore, the characterization of protective immune responses to WNV and the identification of immune correlates of protection in vaccinated equines will provide new fundamental information about the successful development and evaluation of WNV vaccines in humans. This review discusses the comparative epidemiology, transmission, susceptibility to infection and disease, clinical manifestation and pathogenesis, and immune responses of WNV in humans and equines. Furthermore, prophylactic and therapeutic strategies that are currently available and under development are described. In addition, the successful vaccination of equines against WNV and the potential lessons for human vaccine development are discussed.

West Nile virus is a mosquito-borne flavivirus which has been posing continuous challenges to public health worldwide due to the identification of new lineages and clades and its ability to invade and establish in an increasing number of countries. Its current distribution, genetic variability, ecology, and epidemiological pattern in the African continent are only partially known despite the general consensus on the urgency to obtain such information for quantifying the actual disease burden in Africa other than to predict future threats at global scale. References were searched in PubMed and Google Scholar electronic databases on January 21, 2020, using selected keywords, without language and date restriction. Additional manual searches of reference list were carried out. Further references have been later added accordingly to experts' opinion. We included 153 scientific papers published between 1940 and 2021. This review highlights: (i) the co-circulation of WNV-lineages 1, 2, and 8 in the African continent; (ii) the presence of diverse WNV competent vectors in Africa, mainly belonging to the Culex genus; (iii) the lack of vector competence studies for several other mosquito species found naturally infected with WNV in Africa; (iv) the need of more competence studies to be addressed on ticks; (iv) evidence of circulation of WNV among humans, animals and vectors in at least 28 Countries; (v) the lack of knowledge on the epidemiological situation of WNV for 19 Countries and (vii) the importance of carrying out specific serological surveys in order to avoid possible bias on WNV circulation in Africa. This study provides the state of art on WNV investigation carried out in Africa, highlighting several knowledge gaps regarding i) the current WNV distribution and genetic diversity, ii) its ecology and transmission chains including the role of different arthropods and vertebrate species as competent reservoirs, and iii) the real disease burden for humans and animals. This review highlights the needs for further research and coordinated surveillance efforts on WNV in Africa.

Rapid emergence of most vector-borne diseases (VBDs) may be associated with range expansion of vector populations. Culex quinquefasciatus Say 1823 is a potential vector of West Nile virus, Saint Louis encephalitis virus, and lymphatic filariasis. We estimated the potential distribution of Cx. quinquefasciatus under both current and future climate conditions. The present potential distribution of Cx. quinquefasciatus showed high suitability across low-latitude parts of the world, reflecting the current distribution of the species. Suitable conditions were identified also in narrow zones of North Africa and Western Europe. Model transfers to future conditions showed a potential distribution similar to that under present-day conditions, although with higher suitability in southern Australia. Highest stability with changing climate was between 30°S and 30°N. The areas present high agreement among diverse climate models as regards distributional potential in the future, but differed in anticipating potential for distribution in North and Central Africa, southern Asia, central USA, and southeastern Europe. Highest disparity in model predictions across representative concentration pathways (RCPs) was in Saudi Arabia and Europe. The model predictions allow anticipation of changing distributional potential of the species in coming decades.

West Nile virus (WNV) is a mosquito-borne flavivirus primarily transmitted by Culex species and maintained in a bird–mosquito–bird cycle. Though WNV is not considered endemic to Indonesia, sporadic molecular and serological findings suggest possible under-recognized circulation. To examine this possibility, we conducted a cross-sectional serosurvey of 569 archived serum and plasma samples collected between 2021 and 2023 from non-febrile individuals, including blood donors in Papua and community-based participants in Kalimantan. Samples were initially screened using a commercial WNV IgM Enzyme Linked Immunosorbent Assay (ELISA), IgM-positive and equivocal samples were further tested with IgM ELISAs against closely related flaviviruses, including dengue virus (DENV), Japanese encephalitis virus (JEV), and Zika virus (ZIKV). WNV-reactive IgM was initially detected in 9 (1.58%) samples, with 7 (1.23%) additional equivocal results. After additional testing, the WNV IgM seroprevalence was 0.35%, while 1.76% showed cross-reactivity to other flaviviruses. These cases spanned regions including North Kalimantan and Papua, where evidence of WNV-related exposure was previously reported. Detection of WNV-reactive IgM in asymptomatic individuals suggests potential silent or undetected circulation of WNV in Indonesia. Given diagnostic cross-reactivity and IgM persistence, further studies using molecular tools, plaque reduction neutralization test (PRNT), IgG testing, and entomological data are needed to clarify WNV epidemiology and inform surveillance strategies in the region.

Key Points West Nile virus (WNV) continues to pose a significant public health risk throughout most of the world. In the United States, WNV is endemic and the leading cause of mosquito-borne encephalitis. Currently there is no approved vaccine or therapy to prevent or limit WNV infection in humans. Mosquitoes have innate immune programmes, similar to those of mammalian hosts, that function to limit viral replication and spread. In addition, mosquito salivary factors enhance WNV replication, dissemination and virus-induced disease. WNV can cross the blood–brain barrier by one of several routes, including passive transport through the endothelium, infection of the olfactory neurons, transport by infected immune cells, inflammation-induced disruption of blood–brain barrier integrity, and direct axonal retrograde transport from infected peripheral neurons. Both innate and adaptive immune responses are required for controlling WNV replication and protection against a lethal disease outcome. Type I interferons are crucial for eliciting cell-intrinsic immune defences and priming adaptive immune responses during WNV infection. In particular, the RIG-I-like receptor and Toll-like receptor signalling pathways are essential for triggering interferons and immune defences in response to WNV infection. Here, Suthar, Diamond and Gale review recent insights into West Nile virus pathogenesis and the host immune responses that this virus activates. Given the continuing spread of the virus in the Western hemisphere, a better understanding of these host–virus interactions is crucial and should facilitate the development of effective vaccines and therapeutics. West Nile virus (WNV) is an emerging neurotropic flavivirus that is transmitted to humans through the bite of an infected mosquito. WNV has disseminated broadly in the Western hemisphere and now poses a significant public health risk. The continuing spread of WNV, combined with the lack of specific therapeutics or vaccines to combat or prevent infection, imparts a pressing need to identify the viral and host processes that control the outcome of and immunity to WNV infection. Here, we provide an overview of recent research that has revealed the virus–host interface controlling WNV infection and immunity.