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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.

The Usutu virus (USUV), a neurotropic mosquito-borne flavivirus discovered in 1959 in South Africa, has spread over the last twenty years across the European continent. This virus follows an enzootic cycle involving mosquitoes and birds. This caused epizootics with significant bird mortality in Europe in 2016 and 2018. It can also occasionally infect humans and other mammals, including horses and bats, which act as incidental or dead-end hosts. The zoonotic risk associated with this succession of avian epizootics in Europe deserves attention, even if, to date, human cases remain exceptional. Human infection is most often asymptomatic or responsible for mild clinical symptoms. However, human Usutu infections have also been associated with neurological disorders, such as encephalitis and meningoencephalitis. One of the major complexities of the study of USUV pathogenesis is the presence of a great diversity of lineages which could co-circulate spatiotemporally. In this review we discuss several aspects of the circulation of Usutu virus in humans in Europe, the neurological disorders associated, involved viral lineages, and the issues and questions raised by their circulation.

The beginning decades of the 21st century have been marked by multiple emergence and re-emergence phenomena of viral diseases [...].The beginning decades of the 21st century have been marked by multiple emergence and re-emergence phenomena of viral diseases [...].

Emerging diseases have posed a constant threat and major challenge to human health throughout our history. From the Black Death in the Middle Ages to the COVID-19 pandemic, these diseases have generated significant human suffering and economic disruption. The emergence of new pathogens, such as Ebola, Zika, SARS-CoV-2 or mpox, has illustrated the potential for these diseases to spread extraordinarily rapidly. Far from dissipating despite remarkable advances in medical science and public health in recent decades, emerging diseases continue to appear and proliferate at an alarming rate. Changes in our environment, produced primarily by human activity and the evolution of human/animal interactions, are likely to be responsible for novel health crises in the future.

Zoonotic diseases account for at least 60% of all infectious diseases and no less than two-thirds of new emerging ones, which underlines the importance of monitoring them as early as possible [...].Zoonotic diseases account for at least 60% of all infectious diseases and no less than two-thirds of new emerging ones, which underlines the importance of monitoring them as early as possible [...].

Among emerging arthropod-borne viruses (arbovirus), West Nile virus (WNV) is a flavivirus that can be associated with severe neuroinvasive infections in humans. In 2018, the European WNV epidemic resulted in over 2000 cases, representing the most important arboviral epidemic in the European continent. Characterization of inflammation and neuronal biomarkers released during WNV infection, especially in the context of neuronal impairments, could provide insight into the development of predictive tools that could be beneficial for patient outcomes. We first analyzed the inflammatory signature in the serum of WNV-infected mice and found increased concentrations of several inflammatory cytokines. We next analyzed serum and cerebrospinal-fluid (CSF) samples from a cohort of patients infected by WNV between 2018 and 2019 in Hungary to quantify a large panel of inflammatory cytokines and neurological factors. We found higher levels of inflammatory cytokines (e.g., IL4, IL6, and IL10) and neuronal factors (e.g., BDNF, GFAP, MIF, TDP-43) in the sera of WNV-infected patients with neuroinvasive disease. Furthermore, the serum inflammatory profile of these patients persisted for several weeks after initial infection, potentially leading to long-term sequelae and having a deleterious effect on brain neurovasculature. This work suggests that early signs of increased serum concentrations of inflammatory cytokines and neuronal factors could be a signature underlying the development of severe neurological impairments. Biomarkers could play an important role in patient monitoring to improve care and prevent undesirable outcomes.

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. Importantly, infections with African strains resulted in more weight loss, mortality, and severe prolonged neurological symptoms compared to Asian strains. [...]induction of type 1 and 2 interferon (IFN) were higher following infection with African strains associated with enhanced levels of inflammatory cytokines such as interleukin 6 (IL6) or tumor necrosis factor (TNF). [...]these systems have limitations, in particular, studying viral pathogenesis using animals lacking a key component of antiviral immunity, which makes it still difficult to derive definitive conclusions regarding ZIKV virulence in humans. [...]many unanswered questions remain, in particular, regarding the mechanisms of host restriction, immune evasion, and inflammatory response as well as the long-term neurodevelopmental implications of congenital infection in humans. [...]the data reviewed here indicate that there are intrinsic differences in the pathogenicity/virulence of African- and Asian-lineage ZIKV strains.

Arthropod-borne viruses or arbovirus, are most commonly associated with acute infections, resulting on various symptoms ranging from mild fever to more severe disorders such as hemorrhagic fever. Moreover, some arboviral infections can be associated with important neuroinflammation that can trigger neurological disorders including encephalitis, paralysis, ophthalmological impairments, or developmental defects, which in some cases, can lead to long-term defects of the central nervous system (CNS). This is well illustrated in Zika virus-associated congenital brain malformations but also in West Nile virus-induced synaptic dysfunctions that can last well beyond infection and lead to cognitive deficits. Here, we summarize clinical and mechanistic data reporting on cognitive disturbances triggered by arboviral infections, which may highlight growing public health issues spanning the five continents.

The “One Health” concept considers that human and animal health, and ecosystems are closely related and aims to make a link between ecology and human and veterinary medicine. Due to the explosion in population growth along with the geographic and climatic conditions (equatorial and/or tropical climate), Africa is becoming a major hotspot for various socio-health issues associated with infectious diseases, including arboviruses. The incontestable advantages of a One Health approach in Africa lie in the fight against pathogens, such as arboviruses, and in the preservation of environmental, animal, and human health to ensure that the increasing high needs of this population are met as well as their protection against potential epidemics. The One Health strategy gives us a glimpse of the difficulties and challenges that the African continent faces. The importance of this approach in Africa is to establish guidelines and strategies for effective solutions and changes in behavior and harmful activities. Overall, the establishment of high-quality global health policies in the framework of the global health standards program would provide healthy and sustainable human–animal–environmental interactions for the welfare of all.

Usutu virus (USUV) is a zoonotic arbovirus infecting mainly wild birds. It is transmitted by ornithophilic mosquitoes, mainly of the genus Culex from birds to birds and to several vertebrate dead-end hosts. Several USUV lineages, differing in their virulence have emerged in the last decades and now co-circulate in Europe, impacting human populations. However, their relative transmission and effects on their mosquito vectors is still not known. We thus compared the vector competence and survival of Culex pipiens mosquitoes experimentally infected with two distinct USUV lineages, EU2 and EU3, that are known to differ in their virulence and replication in vertebrate hosts. Infection rate was variable among blood feeding assays but variations between EU2 and EU3 lineages were consistent suggesting that Culex pipiens was equally susceptible to infection by both lineages. However, EU3 viral load increased with viral titer in the blood meal while EU2 viral load was high at all titers which suggest a greater replication of EU2 than EU3 in mosquito. While their relative transmission efficiencies are similar, at least at low blood meal titer, positive correlation between transmission and blood meal titer was observed for EU3 only. Contrary to published results in vertebrates, EU3 induced a higher mortality to mosquitoes (i.e. virulence) than EU2 whatever the blood meal titer. Therefore, we found evidence of lineage-specific differences in vectorial capacity and virulence to both the vector and vertebrate host which lead to balanced propagation of both viral lineages. These results highlight the need to decipher the interactions between vectors, vertebrate hosts, and the diversity of arbovirus lineages to fully understand transmission dynamics.