Scott C. Weaver

SARS-CoV-2 Omicron variants emerged in 2022 with >30 novel mutations in the spike alone. While most studies focus on receptor binding domain changes, mutations in the C-terminus of S1 (CTS1), adjacent to the furin cleavage site, have largely been ignored. Here, we examine three Omicron mutations in CTS1: H655Y, N679K, and P681H. Generating a SARS-CoV-2 triple mutant (YKH), we find that the mutant increases spike processing, consistent with prior reports for H655Y/P681H. In addition, the YKH mutant induces attenuated disease, but augments viral loads in male golden Syrian hamsters. Next, we generate a single N679K mutant, finding it reduces viral replication in Calu3 human respiratory cells and induces less disease in male golden Syrian hamsters. Mechanistically, the N679K mutant has increased spike processing but also reduces spike in purified virions; spike decreases are further exacerbated in infected Calu3 cell lysates. Importantly, exogenous spike expression reveals that N679K reduces overall spike protein in the context of the epidemic strain. Although a loss-of-function mutation, transmission competition demonstrates that N679K confers a replication advantage in the upper airway, potentially impacting transmissibility. Together, the data show that N679K reduces overall spike protein during Omicron infection, which has implications for infection, immunity, and transmission.

Alphaviruses are arthropod-borne viruses that recognize cellular receptors in both vertebrate hosts and mosquito vectors to complete their transmission cycle, yet how they maintain recognition of receptors across evolutionarily divergent host species remains unresolved. Among alphaviruses, chikungunya virus (CHIKV), which is primarily vectored in urban settings by Aedes species mosquitoes, is the most widespread, and causes explosive outbreaks that can involve hundreds of thousands to millions of cases annually. The cell adhesion protein Lachesin is a mosquito-specific cellular receptor for CHIKV and multiple other arthritogenic alphaviruses. The envelope E2–E1 glycoproteins of these alphaviruses broadly recognize Lachesin orthologs from diverse mosquito species, but not other insects or arachnids. Lachesin genetic manipulation to prevent mosquito virus infection without interfering with endogenous receptor function could have a major impact for CHIKV control. Here, we determined high-resolution cryo-electron microscopy (cryo-EM) structures of alphaviruses bound to Aedes albopictus Lachesin. Comparative analysis of Lachesin-bound CHIKV, Semliki Forest virus (SFV), and Middelburg virus (MIDV) revealed that these three genetically divergent viruses use a similar surface to recognize Lachesin domain 1, but with reorganized E2–E1 glycoprotein contact residues. We show that a soluble Ae. albopictus Lachesin receptor decoy protein blocks the E2–E1-mediated entry of CHIKV and other arthritogenic alphaviruses into mammalian cells with greater breadth than a vertebrate receptor MXRA8 decoy and protects against lethal SFV challenge and CHIKV pathogenesis in murine models. Additionally, we identified a naturally occurring single residue Lachesin polymorphism that is found in some Anopheles (malaria vector) mosquitoes, and fully ablates CHIKV E2–E1 recognition, informing strategies for mosquito-targeted genetic interventions that could prevent mosquito vector infection and virus transmission. These findings define distinct determinants of receptor binding in mosquitoes and humans for arthritogenic alphaviruses, with implications for countermeasure development and outbreak preparedness.

Arthritogenic alphaviruses cause acute febrile illnesses associated with rash and arthritis when they are transmitted to humans through the bite of infected mosquitoes. Among these, chikungunya virus (CHIKV), transmitted primarily through the bite of infected Aedes aegypti and Aedes albopictus mosquitoes, causes explosive outbreaks involving hundreds of thousands to millions of cases, with recent re-emergence in several global regions. While several cellular receptors that mediate alphavirus entry into mammalian cells have been identified, their mosquito counterparts remained unknown, largely due to a lack of functional genomics tools for these invertebrate species. Here, we established a CRISPR-based genetic screening platform in Aedes albopictus cells and used it to identify Lachesin, a conserved invertebrate cell adhesion molecule, as a receptor for CHIKV and multiple related alphaviruses including Semliki Forest virus (SFV), o’nyong-nyong virus (ONNV), Mayaro virus (MAYV), and Ross River virus (RRV). Lachesin depletion using RNA interference, anti-Lachesin antibody treatment, and soluble forms of Lachesin blocked CHIKV and SFV E2–E1 glycoprotein-mediated infection of mosquito cells. We show that alphavirus E2–E1 glycoproteins bind the first immunoglobulin domain of Lachesin, facilitating attachment and internalization of virus-like particles. Orthologs from divergent mosquito genera, but not from arachnids or other arthropods, also serve as alphavirus receptors, suggesting that cellular receptor binding is not the main obstacle to arthritogenic alphavirus vector host expansion. Our findings enhance understanding of the mechanisms of alphavirus emergence and vector competence and could aid in the development of broadly active, entry-targeted therapeutics against multiple alphaviruses that threaten public health.

Limitations in global access to research and health care capacity undermine equity, sustainability, and resilience, particularly in resource-limited settings. Molecular diagnostics and biologic therapeutics are set to revolutionize medicine; however, our dependence on centralized biomanufacturing and cold chain logistics restricts access to these benefits. These constraints reflect a chronic and unmet global challenge. Here, with research teams in North and South America and Asia, we challenge the top-down paradigm by advancing community-driven solutions that empower underserved populations to participate in the bioeconomy, producing what they need, when, and where they need it. Our approach leverages low-burden biomanufacturing—built on cell-free protein synthesis and open-source hardware—to enable local, on-demand production of high-value bioproducts, including growth factors, vaccines, and diagnostic enzymes, demonstrating performance comparable to commercial gold standards. Implemented at 10 sites worldwide, this platform supported patient trials targeting globally relevant pathogens. Together, these efforts lay the foundation for a globally inclusive biomanufacturing ecosystem, where innovation goes beyond geographic boundaries.

: Chikungunya, a debilitating mosquito-borne disease caused by chikungunya virus, has surged dramatically in the past two decades. Chikungunya outbreaks can intensify rapidly, with infections posing a significant endemic health burden in tropical/subtropical areas and for travelers. Health professionals require timely and accurate outbreak information to adequately protect travelers and assess chikungunya risk. However, detection is often insufficient in the areas most susceptible to outbreaks, leading to diagnostic and reporting delays. Consequently, travelers are often unaware of increased chikungunya infection risk at their destination. We assessed chikungunya surveillance and reporting resources, and we developed expert recommendations for traveler health protection. Because data-reporting cadences, reliability, and availability vary, we organized structured activities and convened an expert panel to compare these resources and evaluate their strengths and weaknesses. We provide a synthesis of the expert panel discussion and provide recommendations on how to improve chikungunya surveillance and risk communication to travelers. Assessing outbreak risk requires using multiple local and international reporting resources because no single resource contains all of the necessary information. The panelists identified several challenges regarding chikungunya surveillance and outbreak reporting: inadequate chikungunya surveillance infrastructure and diagnostic capacity; varying case definitions; limited understanding of the local health care context; inadequate awareness of chikungunya in health care settings; and restricted or delayed access to real-time surveillance data. As chikungunya risk increases worldwide, greater attention and resources are needed to improve timely, sensitive, and specific diagnostic testing and rapid communication to health care workers and travelers, particularly in resource-poor regions where outbreaks occur.

Oropouche virus (OROV) is an arbovirus endemic to the Amazon region since the 1950s that re-emerged in late 2023, causing a major epidemic across Central and South America. Here we investigated the transmission dynamics of the 2023–2024 epidemic in Manaus City (Amazonas state, Brazil), a major metropolitan hub in the Amazon, and estimated OROV infections across Latin America and the Caribbean. OROV re-emergence in Manaus resulted in an increase of IgG seroprevalence from 11.4% in November 2023 to 25.7% in November 2024. The neutralizing capacity of OROV-specific IgG antibodies from individuals collected before and after the re-emergence demonstrated a median plaque reduction neutralization test 50% titer of 640 against both the historical and contemporary OROV isolates. A historical reconstruction of OROV circulation in Manaus indicated a continuous low-level transmission with two major outbreaks of comparable seasonality and magnitude in 1980–1981 and 2023–2024. We estimate approximately 336,000 OROV infections in the Amazon region under a scenario of continuous endemic transmission without major outbreaks and over 9.4 million OROV infections during major outbreaks from 1960 to 2025. Collectively, our findings provide a comprehensive assessment of OROV transmission in Manaus and contribute to a better understanding of the OROV burden.

Introduction Colombia’s tropical climate and low-altitude cities create an ideal environment where mosquito-borne diseases can thrive. During 2013-2014, dengue was the most diagnosed cause of febrile syndrome. However, other viruses like Venezuelan equine encephalitis (VEEV), Mayaro (MAYV), and chikungunya viruses (CHIKV) were also present, and their true prevalence was likely underestimated due to limited surveillance. Methods We conducted a cross-sectional study involving 90 febrile patients from the Urabá region. For each patient, we collected both acute and convalescent serum samples, which were analyzed to detect antibodies against VEEV, CHIKV, and MAYV. Additionally, we attempted virus isolation from the acute-phase serum samples. Results We found that antibodies against VEEV were present in 28.3% of samples, CHIKV antibodies were detected in 5%, and MAYV antibodies in 1.7%. Notably, one patient tested positive for CHIKV even before the first outbreak was recognized in Colombia in 2014. Furthermore, we isolated and fully sequenced VEEV, and our analysis revealed a close phylogenetic relationship with subtype ID Panamanian strains. Conclusion This study highlights the need to consider arboviruses beyond just dengue (DENV), when evaluating febrile illness in Colombia. The detection of VEEV and CHIKV, even before they were officially recognized as significant public health threats in this region, underscores the need for enhanced surveillance and diagnostic capabilities.

Mosquito-borne diseases such as malaria and dengue threaten billions of people and cause the death of hundreds of thousands annually. Recent studies have revealed that many mosquito species regularly engage in high-altitude wind-borne migration, but its epidemiological significance remains unclear. The hypothesis that high-flying mosquitoes spread pathogens over long distances has not been directly tested. Here, we report that high-flying mosquitoes are commonly infected with arboviruses, protozoans, and helminths and provide a insights into this pathogen–vector aerial network. A total of 1,017 female mosquitoes intercepted on nets suspended from helium balloons at 120 to 290 m above ground over Mali and Ghana were screened for infection with arboviruses, Haemosporida, and filariae. The mosquitoes collected at altitude comprised 61 species, across 10 genera, dominated by Culex , Aedes, and Anopheles . Infection and infectiousness (capacity to transmit a pathogen to another host inferred based on disseminated infection) rates of migrant mosquitoes were 7.2% and 4.4% with Plasmodium spp., 1.6% and 0.6% with filariae, and 3.5% and 1.1% with flaviviruses, respectively. Twenty-one mosquito-borne pathogens were identified, including Dengue, West Nile, and M’Poko viruses, 15 avian Plasmodium species including Plasmodium matutinum , and three filariids, including Pelecitus sp. Confirmed head–thorax (disseminated) infections of multiple pathogens in Culex perexiguus , Mansonia uniformis , and Anopheles squamosus reveal that pathogens carried by high-altitude wind-borne mosquitoes are capable of infecting hosts far from their departure location. This high-altitude traffic of sylvatic pathogens (circulating in wild animals) may be key to their maintenance among enzootic foci as well as initiating outbreaks at distant locations.