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Dengue fever is the most important arbovirosis for public health, with more than 5 million cases worldwide in 2023. Mosnodenvir is the first anti-dengue compound with very high preclinical pan-serotype activity, currently undergoing phase 2 clinical evaluation. Here, by analyzing dengue virus (DENV) genomes from the 2023-2024 epidemic in the French Caribbean Islands, we show that they all exhibit mutation NS4B:V91A, previously associated with a marked decrease in sensitivity to mosnodenvir in vitro. Using antiviral activity tests on four clinical and reverse-genetic strains, we confirm a marked decrease in mosnodenvir sensitivity for DENV-2 ( > 1000 fold). Finally, combining phylogenetic analysis and experimental testing for resistance, we find that virus lineages with low sensitivity to mosnodenvir due to the V91A mutation likely emerged multiple times over the last 30 years in DENV-2 and DENV-3. These results call for increased genomic surveillance, in particular to track lineages with resistance mutations. These efforts should allow to better assess the activity profile of DENV treatments in development against circulating strains. Dengue is a major public health threat in the Americas including the French Caribbean Islands, in which an epidemic has been ongoing since August 2023. Here, the authors investigate the genetic composition of the strain responsible for the epidemic and find evidence that it is resistant to the main dengue antiviral in current development.

Chikungunya virus (CHIKV) is a re-emerging alphavirus that is transmitted to humans by mosquito bites and causes musculoskeletal and joint pain 1 , 2 . Despite intensive investigations, the human cellular factors that are critical for CHIKV infection remain unknown, hampering the understanding of viral pathogenesis and the development of anti-CHIKV therapies. Here we identified the four-and-a-half LIM domain protein 1 (FHL1) 3 as a host factor that is required for CHIKV permissiveness and pathogenesis in humans and mice. Ablation of FHL1 expression results in the inhibition of infection by several CHIKV strains and o’nyong-nyong virus, but not by other alphaviruses and flaviviruses. Conversely, expression of FHL1 promotes CHIKV infection in cells that do not normally express it. FHL1 interacts directly with the hypervariable domain of the nsP3 protein of CHIKV and is essential for the replication of viral RNA. FHL1 is highly expressed in CHIKV-target cells and is particularly abundant in muscles 3 , 4 . Dermal fibroblasts and muscle cells derived from patients with Emery–Dreifuss muscular dystrophy that lack functional FHL1 5 are resistant to CHIKV infection. Furthermore,  CHIKV infection  is undetectable in Fhl1-knockout mice. Overall, this study shows that FHL1 is a key factor expressed by the host that enables CHIKV infection and identifies the interaction between nsP3 and FHL1 as a promising target for the development of anti-CHIKV therapies. FHL1 is a key factor expressed by humans and mice that is required for chikungunya virus infection and is therefore a promising target for the development of therapies against chikungunya virus.

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.

Dengue virus (DENV) transmission in Bolivia has historically been restricted to tropical lowland regions, where the primary vector Ae. aegypti is endemic. In recent years, however, the vector has expanded into high-altitude areas. In 2024, Cochabamba, located at ~ 2,550 m above sea level, experienced its largest recorded dengue outbreak. We analyzed data from 9,576 suspected dengue cases reported between January and July 2024, of which 5,923 were laboratory-confirmed. A subset of DENV-positive samples underwent whole-genome sequencing and phylogenetic analysis. Dengue cases were detected in municipalities located at elevations up to 2,719 m, with the highest number reported in Cochabamba city (4,104/5,923, 69.3%; 2,558 m) and the highest incidence observed in Capinota (839 cases per 100,000 population; 2,386 m). Molecular analyses indicated predominant circulation of DENV-2 genotype II clade F.1.1.2. Phylogenetic reconstruction identified two distinct clades closely related to viruses previously detected in southern Brazil, suggesting multiple independent introductions into the department in late 2023. However, the limited availability of genomic data from Bolivia and neighboring countries limits precise identification of the outbreak’s origin. This study provides the first characterization of the 2024 dengue outbreak in Cochabamba, an exceptional event of substantial DENV circulation at high altitude, likely facilitated by the expanding geographic range of Ae. aegypti , potentially driven by climate change.

Serological surveys are essential to quantify immunity in a population but serological cross-reactivity often impairs estimates of the seroprevalence. Here, we show that modeling helps addressing this key challenge by considering the important cross-reactivity between Chikungunya (CHIKV) and O’nyong-nyong virus (ONNV) as a case study. We develop a statistical model to assess the epidemiology of these viruses in Mali. We additionally calibrate the model with paired virus neutralization titers in the French West Indies, a region with known CHIKV circulation but no ONNV. In Mali, the model estimate of ONNV and CHIKV prevalence is 30% and 13%, respectively, versus 27% and 2% in non-adjusted estimates. While a CHIKV infection induces an ONNV response in 80% of cases, an ONNV infection leads to a cross-reactive CHIKV response in only 22% of cases. Our study shows the importance of conducting serological assays on multiple cross-reactive pathogens to estimate levels of virus circulation. O’nyong nyong and Chikungunya virus are arboviruses present in Africa but their prevalence is unknown, partly due to high antibody cross-reactivity with one another. Here, the authors develop a statistical model that accounts for cross-reactivity to characterise circulation of both viruses from seroprevalence surveys.

The 2015–17 Zika virus (ZIKV) epidemic in the Americas subsided faster than expected and evolving population immunity was postulated to be the main reason. Herd immunization is suggested to occur around 60–70% seroprevalence, depending on demographic density and climate suitability. However, herd immunity was only documented for a few cities in South America, meaning a substantial portion of the population might still be vulnerable to a future Zika virus outbreak. The aim of our study was to determine the vulnerability of populations to ZIKV by comparing the environmental suitability of ZIKV transmission to the observed seroprevalence, based on published studies. Using a systematic search, we collected seroprevalence and geospatial data for 119 unique locations from 37 studies. Extracting the environmental suitability at each location and converting to a hypothetical expected seroprevalence, we were able to determine the discrepancy between observed and expected. This discrepancy is an indicator of vulnerability and divided into three categories: high risk, low risk, and very low risk. The vulnerability was used to evaluate the level of risk that each location still has for a ZIKV outbreak to occur. Of the 119 unique locations, 69 locations (58%) fell within the high risk category, 47 locations (39%) fell within the low risk category, and 3 locations (3%) fell within the very low risk category. The considerable heterogeneity between environmental suitability and seroprevalence potentially leaves a large population vulnerable to future infection. Vulnerability seems to be especially pronounced at the fringes of the environmental suitability for ZIKV (e.g. Sao Paulo, Brazil). The discrepancies between observed and expected seroprevalence raise the question: “why did the ZIKV epidemic stop with large populations unaffected?”. This lack of understanding also highlights that future ZIKV outbreaks currently cannot be predicted with confidence.

Alphaviruses comprise over 30 identified species spread worldwide and carry a large global health burden. With vector expansion occurring in and around Europe, it is anticipated this burden will increase. Therefore, regular assessment of the diagnostic capabilities in Europe is important, e.g., by conducting external quality assessments (EQAs). Here we evaluated molecular detection of alphaviruses in expert European laboratories by conducting an EQA in March 2022. Molecular panels included 15 samples: nine alphaviruses, Barmah Forest virus (BFV), chikungunya virus (CHIKV), Eastern equine encephalitis virus (EEEV), Mayaro virus (MAYV), o’nyong-nyong virus (ONNV), Ross River virus (RRV), Sindbis virus (SINV), Venezuelan equine encephalitis virus (VEEV), and Western equine encephalitis virus (WEEV) and four negative control samples. Alphavirus detection was assessed among 23 laboratories in 16 European countries. Adequate capabilities were lacking for several viruses, and approximately half of the laboratories (11/23) relied on pan-alphavirus assays with varying sensitivity and specificity. Only 46% of laboratories characterized all EQA samples correctly. Correct result rates were > 90% for CHIKV, RRV and SINV, but laboratories lacked specificity for ONNV and MAYV and sensitivity for VEEV, BFV, and EEEV. Only two alphaviruses causing human disease circulate or have circulated in Europe, CHIKV and SINV. Molecular detection was satisfactory with both CHIKV and SINV, but < 50% correct for the entire alphaviruses panel. With continued imported cases, and a growing global concern about climate change and vector expansion, focus on progress toward rapid, accurate alphavirus diagnostics in Europe is recommended, as well as regular EQAs to monitor quality.

West Nile Virus (WNV) and Usutu virus (USUV) circulate through complex cryptic transmission cycles involving mosquitoes as vectors, birds as amplifying hosts and several mammal species as dead-end hosts. Both viruses can be transmitted to humans through mosquito bites, which can lead to neuroinvasive and potentially fatal disease. Notably, WNV can also be transmitted through blood donations and organ transplants. The high proportion of asymptomatic infections caused by these viruses and their cryptic enzootic circulation make their early detection in the environment challenging. Viral surveillance in France still heavily relies on human and animal surveillance, i . e . late indicators of viral circulation. Entomological surveillance is a method of choice for identifying virus circulation ahead of the first human and animal cases and to reveal their genetic identity, but performing molecular screening of vectors is expensive, and time-consuming. Here we show substantial WNV and USUV co-circulation in Atlantic seaboard of France between July and August 2023 using a non-invasive MX (Molecular Xenomonitoring) method that use trapped mosquito excreta. MX offers significant advantages over traditional entomological surveillance: it is cost-effective and efficient, enabling viral RNA screening from a community of trapped mosquitoes via their excreta, which can be transported at room temperature. Additionally, MX extends the longevity of trapped mosquitoes, enhancing virus detection and simplifying logistics, and is easy to implement without requiring specialized skills. At the crossroads between entomological and environmental surveillance, MX can detect the circulation of zoonotic pathogens in the environment before cases are observed in humans and horses, enabling the timely alerts to health policy makers, allowing them to take suitable control measures.

The mosquito-borne alphavirus o'nyong-nyong virus (ONNV) has proven its potential to cause major human outbreaks. On the African continent, ONNV causes unspecific febrile illness and co-circulates with the close relative chikungunya virus (CHIKV). The true scale of ONNV burden is poorly understood in Africa, because of the scarce availability of molecular in-house and commercial assays, strong cross-reactivity between ONNV and CHIKV in serological assays and a lack of surveillance. We designed a new RT-qPCR assay targeting the E1 gene for the detection of ONNV that can be used in monoplex or in duplex format, combined with a previously published CHIKV monoplex assay targeting the nsp1. The lower limit of detection with 95% positivity rate was determined to be <10 RNA copies/µL in monoplex and duplex format for both ONNV and CHIKV. Both monoplex assays and the duplex assay proved to be linear within the tested range of approximately 10 to 10 RNA copies/µl, and showed 100% specificity against a wide panel of arbovirus supernatants as well as several other pathogens in clinical samples. Testing of CHIKV positive serum and ONNV-spiked plasma samples confirmed the suitability of the assays in a clinical setting. The new assays provide a robust tool for molecular ONNV as well as ONNV/CHIKV simultaneous detection and may contribute to clarify the true burden of the two viruses, to improve arbovirus surveillance and to strengthen epidemics preparedness in Africa.