The control of infectious diseases remains a global priority, with zoonoses occupying a special place among them. They continue to pose a major threat to human and animal populations, particularly in low- and middle-income countries (LMICs). Controlling zoonoses requires complex measures, which are being developed with increasing precision using the "One Health" approach, but are still far from being mastered on the ground. One of the main challenges in managing these diseases is the lack of coordination between the human and animal health sectors and the communities that they serve, which often results in late detection of epidemics and limited control. The integration of community health workers and community animal health workers into health systems for the surveillance and response to zoonoses is now a necessity in order to improve information for target populations, early detection of cases, and prophylactic, therapeutic, or sanitary response. This model, already in place in some countries, offers a path towards more resilient and responsive public and animal health infrastructures in the regions most affected by zoonotic diseases and, as a result, limits the spread and transmission of these diseases to other countries.

BackgroundIn the Amazonian region, vampire bats are the primary reservoir of rabies virus, causing sporadic and lethal human rabies cases that often remain unnoticed. Managing human cases in this region is challenging and further complicated by atypical clinical forms and the potential exposure to various toxic compounds, particularly among gold miners.MethodsWe carried out clinical, electrical, biological and histological analysis of concurrent cases of progressive motor neuronopathy and fatal encephalitis in a context of regular exposure to bat bites of gold miners living in a small and remote gold mine camp in Amazonia, in French Guiana, South America.FindingsWe analyzed a spatio-temporal cluster of three suspected rabies cases in 2024 with a fatal outcome, with concomitant onset of acute bilateral lower-limb paralysis without demyelination, two of which occurred presumably two weeks after a bat-bite. Electroneuromyography suggested the involvement of the anterior horn of the spinal cord, as described in furious forms of rabies. None of the cases exhibited other cardinal signs of the furious form. Confirmation of rabies was obtained for them on sera and brain biopsies collected ante- and post-mortem respectively.InterpretationThe concurrent occurrence of disease, the axonal motor neuropathy mimicking the motor form of Guillain Barré syndrome in the context of paralytic rabies, lead to diagnostic-wandering. This underscores the importance of thinking about vampire bat rabies virus in the presence of any atypical neurological picture in patients living in exposed areas in Latin America.

Rabies is a complex disease that has defied efforts to develop an effective treatment. Although it can be successfully prevented through vector control or pre- or post-exposure prophylaxis, no therapeutic options exist for symptomatic rabies, and the disease is still responsible for about 59 000 human deaths each year. Following our successful attempts to use the human monoclonal antibodies RVC20 and RVC58 for intracerebroventricular treatment of rabies, we report here on the effects of these mAbs when administered intravenously to symptomatic rabid mice. Only a small proportion of mAbs was detected to cross the blood-brain barrier, yet this limited amount sufficiently cleared the viral infection and was enough to cure the infected animals. Remarkably, these mAbs were more effective at preventing rabies-related death when used individually rather than when used as a cocktail. RVC58 achieved an 80% survival rate, likely due to its distinct binding topography, potent viral neutralization, and enhanced FcγR engagement in the presence of virions. The significance of this work is that the use of a single mAb could substantially lower the costs and improve treatment accessibility in under-resourced settings, potentially contributing to improved equity of global health. These findings establish intravenous mAb therapy as a promising therapeutic approach for symptomatic rabies and provide a foundation for clinical development of an accessible treatment option. Highlights ### Competing Interest Statement S.K., H.B., and G.D.M. have received funding through sponsored research awards from Vir Biotechnology Inc. related to the work described in this paper. F.B and D.C. are employees of Vir Biotechnology Inc. and may hold shares in Vir Biotechnology Inc. D.C., H.B., and G.D.M. hold a patent for the mAbs used in this study (PCT/EP2019/078439). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Rabies continues to kill over 60,000 people per year despite life-saving vaccines and post-exposure treatments, and costs billions of dollars in prevention and treatment. Preventing rabies deaths and reducing the global economic burden of the virus will require both developing a monoclonal antibody cocktail to replace human serum in treatment and improving rabies vaccines to elicit long-lasting protection. Here, we solve nine cryo-EM structures of neutralizing monoclonal antibodies in complex with the rabies virus surface glycoprotein (RABV-G). The nine structures span three known antigenic sites plus two new antigenic sites, not previously mapped. We further find that these two new sites are the targets of antibodies with the desired broad neutralization of rabies as well as other emerging lyssaviruses. Across the mAb panel, fusion inhibition and binding affinity correlate best with neutralization. Together, these results provide a roadmap for structure-guided vaccine and therapeutic antibody design for rabies and related lyssaviruses.

Le contrôle des maladies infectieuses reste une priorité au niveau mondial et parmi celles-ci les zoonoses occupent une place particulière. Elles restent une menace majeure pour les populations humaines et animales, en particulier dans les pays à revenu faible et intermédiaire. Leur contrôle répond à des mesures complexes, développées de manière de plus en plus précises au travers de l’approche « Une seule santé » qui sont encore loin d’être maîtrisées sur le terrain. L’un des principaux défis de la gestion de ces maladies est le manque de coordination entre les secteurs de la santé humaine et animale et les communautés qu’ils desservent, ce qui se traduit souvent par une détection tardive des épidémies et un contrôle limité. L’intégration des agents de santé communautaires et les agents communautaires de santé animale dans les systèmes de santé pour la surveillance et la réponse aux zoonoses constitue aujourd’hui une opportunité pour améliorer l’information des populations cibles, la détection précoces des cas et la réponse prophylactique, thérapeutique ou sanitaire, Ce modèle d’organisation sanitaire, déjà en place dans certains pays, offre une voie vers des infrastructures de santé publique et animale plus résilientes et plus réactives dans les régions les plus touchées par les maladies zoonotiques et par voie de conséquence limite l’expansion et la diffusion vers d’autres pays de ces maladies.

BACKGROUND:The abridged Institut Pasteur du Cambodge (IPC) 3-session intradermal (ID) rabies post-exposure prophylaxis (PEP) regimen has been shown to be as safe and immunogenic as the 4-session regimen previously recommended by WHO. This regimen reduces time, cost, improves adherence and access to PEP for underserved people. Our study aimed to compare long-term and anamnestic immune response after a rabies vaccine booster dose in people previously vaccinated with a 3 or 4-session ID PEP. METHODS:In this prospective, multi-site, comparative immunogenicity study, we measured rabies virus neutralizing antibody in 181 persons that had previously received 3- or 4-session ID PEP, 2, 5, or 10 years earlier in Cambodia or Madagascar, at day 0 and at day 7 after a booster. In addition, RABV-specific T cell response was evaluated in a sub-group of 35 Cambodian participants. RESULTS:All participants had rabies virus neutralizing antibody titers considered adequate (≥ 0.5 IU/mL) on day 7 after the booster dose. The overall geometric mean titer (GMT) of rabies antibody on day 0 and day 7 did not differ significantly between the 2 groups. Furthermore, RABV-specific T cell response was similar regardless of the ID PEP regimen initially received in a sub-group of 35 participants. CONCLUSIONS:In this multisite, real-world study, we showed that the 3-session ID PEP regimen provides robust long-term immunogenicity up to 10 years after initial PEP and ensures the induction of an adequate anamnestic response within 7 days after an additional booster in all participants.

BACKGROUND:Rabies post-exposure prophylaxis (PEP) requires timely appropriate wound management and vaccination (including concomitant rabies immunoglobulin [RIG], depending on vaccination history and wound severity) to ensure rapid increases in rabies virus neutralizing antibody (RVNA) titers, a surrogate marker of protection. In this systematic review and meta-analysis, we assessed factors influencing the immunogenicity of rabies vaccines administered as PEP. METHODS:PubMed, Embase, and The Cochrane Library were systematically searched for randomized controlled trials published in English, French, Spanish, or Portuguese from January 1, 1983 to March 28, 2022 reporting the immunogenicity of rabies vaccines, specifically rabies human diploid cell vaccine (Imovax Rabies), purified Vero cell rabies vaccine (Verorab), and purified chick embryo cell rabies vaccine (RabAvert/Rabipur), as part of PEP in healthy individuals. Pooled RVNA geometric mean titers (GMTs) and seroconversion rates at Day 14 (D14) post-vaccination, determined by rapid fluorescent focus inhibition test, were estimated using random effects meta-analyses. RESULTS:We identified 1040 studies, of which 67 (9689 participants across 140 intervention groups) were included. The pooled RVNA GMT across all vaccines at D14 post-vaccination was 8.19 (95% CI: 6.73-9.98) and did not differ significantly by vaccine, administration route, or RIG use; however, there were significant interlaboratory differences. Meta-regression analysis, including titration year, demonstrated a negative association with log-transformed RVNA GMTs, equating to a 4.18% reduction (95% CI: -5.89 to -2.44) in log-transformed GMTs per year during the period assessed. Across all vaccines assessed, the pooled seroconversion rate by D14 post-vaccination was 98% (95% CI: 97-98; n = 7023; I2 = 64%) and was not impacted by vaccine, administration route, RIG use, test laboratory, or titration year. CONCLUSIONS:Although RVNA GMTs appear to have decreased by titration year, there was no clinically meaningful impact on immunogenicity, and the three licensed rabies vaccines assessed are expected to provide similar protection.

Mitochondrial outer membrane proteins are exploited by diverse intracellular pathogens, to modulate cell metabolism and innate sensing pathways. Here, we demonstrate that TOMM70-dependent mitochondrial recruitment is required to protect SARS-CoV-2 ORF9b from proteasomal degradation, a dependency conserved across ORF9b homologs from related coronaviruses. ORF9b mitochondrial recruitment requires the E477 residue of TOMM70, a surface distinct from that used by the parasite Toxoplasma gondii to engage host mitochondria. We further show that TOMM70 is not a passive scaffold: its depletion activates interferon-stimulated gene expression independently of infection and remodels host immunity distinctly from ORF9b, establishing the receptor and viral protein as mechanistically separable. Using ORF9b-deficient SARS-CoV-2, we demonstrate that ORF9b is dispensable for viral replication and pathological responses in human respiratory epithelial cells and lungs of infected golden Syrian hamsters. Omics profiling of SARS-CoV-2 infected lungs revealed an induction of pathways related to COVID-19 in the absence of ORF9b. Notably, ORF9b-deficient virus-infected lungs show elevated expression of C15ORF48, a nuclear-encoded mitochondrial protein that substitutes for Complex IV subunit NDUFA4 to attenuate inflammation. Collectively, we propose that ORF9b is a receptor-gated viral protein whose principal measurable consequence during authentic infection is a restraint on inflammatory respiratory-chain remodeling.

Bat rabies in mainland France is mainly caused by European bat lyssavirus 1 (EBLV-1; Lyssavirus hamburg), which is almost exclusively associated with the common serotine bat, Cnephaeus (Eptesicus) serotinus. Two variants, EBLV-1a and EBLV-1b, circulate in France and display largely distinct, parapatric distributions. Because bats are highly sensitive to climatic conditions due to their physiological characteristics, including heterothermy, we investigated the relationship between climate and the geographical distribution of these two variants. Using generalized linear models and species distribution models, we assessed the influence of temperature and precipitation on EBLV-1 occurrence. The distribution of EBLV-1 cases was significantly associated with climatic variables, particularly minimum temperatures during the coldest month, maximum temperatures during the warmest month, and precipitation during the driest period. EBLV-1a was more frequently associated with areas characterized by milder winters and warmer, more humid conditions, whereas EBLV-1b was linked to colder and drier environments. Habitat suitability models predicted limited overlap between the two variants, supporting the existence of distinct climatic niches. These findings suggest that climatic factors contribute to shaping the spatial distribution of EBLV-1 variants and highlight the need for broader scale studies to better understand their ecology and potential response to future climate change.

Background Over the past five decades, nearly 1,500 bat rabies cases have been reported in Europe. The majority of positive cases (with 90% of cases) originated from Germany, followed by The Netherlands, Denmark, Poland, France and Spain. Among the seven lyssaviruses detected in European bats, three different recognized species are circulating in some native bat species in France: EBLV-1, BBLV, and LLEBV, primarily associated with the host species Eptesicus serotinus, Myotis nattereri, and Miniopterus schreibersii, respectively. Case presentation In 2022, we reported an unusual case of EBLV-1 infection in a long-distance migrant bat species, Pipistrellus nathusii. The bat's brain tested positive for the presence of viral antigens using the fluorescent antibody test (FAT) and for viral RNA through molecular techniques (including real-time and end-point pan-lyssavirus RT-PCR). In this study, we determined the nearly complete genome sequence of the virus using next-generation sequencing (PX733926). Molecular clock dating and phylogenetic analysis confirmed that the bat was infected with the EBLV-1a variant, the most common and widely distributed European bat lyssavirus. The virus genome showed 99.88% nucleotide similarity with a strain isolated from a serotine bat in the Lower Saxony region of Germany in 2016 (OU524432). Conclusions This finding is the first of its kind in France and the third in Europe involving a long-distance migrant bat. It may partially explain the extensive geographic distribution of EBLV-1a across Europe, following both east-west and north-south axes.

How virus-host cell interactions and innate immune antagonism shape neurotropic infection dynamics across diverse brain cell types is largely unknown. To "unmask" and study how innate immune inhibition affects cell-type-specific transcriptional regulation of the human and viral genome, we perform single-cell RNA sequencing of human brain cell co-cultures, comparing an isolate of rabies virus (RABV) to its mutant incapable of antagonizing interferon- and nuclear factor (NF)-κB-dependent responses. RABV gene expression is shaped by host cell type. RABV induces small-scale, cell-type-conserved transcriptional programs that likely support infection by (1) hijacking negative transcriptional feedback of pro-viral factors while (2) reducing anti-viral RNAs. Unexpectedly, disinhibited innate immune signaling increases RABV transcription, most strikingly in an infection-independent "pro-viral" astrocyte subpopulation. Further analysis suggests that pro-viral-like astrocytes are a rare subtype in the human brain and are primed to protect the brain during viral infection in concert with interferon-sensitive microglia recalcitrant to infection.

Following infection with SARS-CoV-2, patients may experience with one or more symptoms that appear or persist over time. Neurological symptoms associated with long COVID include anxiety, depression, and memory impairment. However, the exact underlying mechanisms are not yet fully understood. Using golden hamsters as a model, we provide further evidence that SARS-CoV-2 is neuroinvasive and can persistently infect the brain, as viral RNA and replicative virus are detected in the brainstem 80 days after the initial infection. Infected hamsters exhibit a neurodegenerative signature in the brainstem, characterized by overexpression of innate immunity genes, and altered expression of genes involved in the dopaminergic and glutamatergic synapses, in energy metabolism, and in proteostasis. These infected animals exhibit persistent depression-like behavior, impaired short-term memory, and late-onset signs of anxiety. Finally, we provide evidence that viral and immunometabolic mechanisms coexist in the brainstem of SARS-CoV-2-infected hamsters, contributing to the manifestation of neuropsychiatric and cognitive symptoms.

Viruses in the Mononegavirales order encode a large protein that orchestrates replication, transcription, and the capping of viral RNA. This protein, comprising over 2.000 amino acids, contains an RNA-dependent RNA polymerase, a capping domain, and a methyltransferase (MTase) domain involved in methylating the cap structure. The MTase domain features a conserved K-D-K-E catalytic tetrad -typical of 2′O-methyltransferases-which is essential for methylating viral mRNA caps at both the N7 and 2′O positions. However, the role of these residues in other epitranscriptomic modifications of rabies virus (RABV) RNAs remains poorly characterized. To further explore the role of mRNA cap methylation in the immune evasion strategies of RABV, we investigated the functional contribution of the K-D-K-E motif within the MTase domain, using the Thai isolate as a model. Using reverse genetics, we demonstrated that the mutation K1830R in the K-D-K-E tetrad of the Tha MTase domain induces changes in the methylation landscape of viral mRNAs and, intriguingly, of host mRNAs. In addition, viruses harbouring the K1830R mutation are more sensitive to interferon-α and exhibit a less pathogenic phenotype in vitro and in vivo compared to the wild-type virus. Overall, these results suggest that the regulation of viral and cellular RNA methylation landscapes plays a crucial role in controlling RABV infection. Although the exact role of these epitranscriptomic modifications is not yet fully understood, some of these methylations appear to have proviral effects and enhance viral propagation by allowing RABV to efficiently evade the host’s antiviral response. Importance This study highlights the pivotal role of the K-D-K-E catalytic domain included in the methyltransferase domain of the large protein of Rabies virus, by modelling viral RNAs with epitranscriptomic changes. For the first time, we identify specific methylations on the viral RNA, such as 2’-O and m6A methylations, which seem to enable the virus to mask its RNA and evade detection by the host’s pattern recognition receptors. These epitranscriptomic modifications affect not only viral RNAs but also cellular RNAs, underscoring a complex interplay between viral and host mechanisms. We further demonstrate that RABV harbouring an altered K-D-R-E catalytic domain, exhibit differential methylation patterns correlated with increased sensitivity to IFN and lower pathogenicity. This emphasizes the importance of this domain in virulence and immune evasion. ### Competing Interest Statement The authors have declared no competing interest. ANR- 16-CE11-0031-01 ANR-10-INBS-09

Zoonotic diseases remain a major threat to both human and animal populations, especially in low-income and middle-income countries. A key challenge in managing these diseases is insufficient coordination between human and animal health sectors and the communities they serve, which often results in delayed outbreak detection and minimal disease control. Community health workers and community animal health workers can help fill this gap by identifying suspected cases early and facilitating communication between communities and health services. However, challenges, such as a scarcity of resources, political and social barriers, and quantitative evaluation of performance and impact, have hindered the broader deployment of community health workers and community animal health workers. In this Personal View, we highlight the need to better integrate community health workers and community animal health workers into health systems for zoonotic disease surveillance and response and illustrate how this can be achieved with examples from Cameroon, Chad, Côte d'Ivoire, and Mali. The framework we put forward provides a step-by-step approach on how to effectively integrate community-based zoonotic disease surveillance, response, and awareness, both at scale and in a sustainable manner. Ultimately, this practical framework offers a path to more resilient and responsive public and animal health infrastructures in the regions most affected by zoonotic diseases.

Dear Editor, Viruses transmitted by arthropods (arboviruses) are highly diverse,both genetically and in terms of host insect species.

OBJECTIVES:In early 2025, a patient died in the South of France with confirmed rabies following a dog bite while traveling in Morocco to visit relatives. This report summarizes the patient's clinical course and the subsequent public health investigation. METHODS:Demographics, epidemiological, and medical data from the infected patient and from contacts at risk of exposure were retrospectively retrieved from medical files. RESULTS:The patient presented with fever, cardiac and neurological symptoms. Initial clinical presentation mimicking psychiatric disorders and suggesting a myocarditis led to multiple exposures of family members and health care workers (HCWs). Rabies virus was retrieved from saliva, skin biopsy, and post-mortem brain biopsy. A total of 44 potentially exposed persons were identified among family and community contacts and among HCWs who cared for the patient, and received rabies post-exposure prophylaxis (RPEP). Most family members shared food and drinks with the patient, notably during a large family meal with potential mucosal exposure to infected saliva. Several HCWs had a contact with the patient's body fluids without application of standard of isolation precautions. CONCLUSIONS:Recommendations for RPEP in contacts with a human rabies case differ between countries, and practices differ between teams. The dramatic nature of the disease often leads to irrational fear that may compromise the strict application of recommendations. Travelers to North African countries, including those visiting friends and relatives should be informed about the risk for rabies when injured by dogs or cats and about the need to receive an adequate RPEP.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for coronavirus disease 2019 (COVID-19), disrupts the alveolar epithelial barrier and exacerbates airway inflammation, leading to acute respiratory failure. The Envelope (E) protein is key to virulence, notably through its PDZ-binding motif (PBM), which interacts with host PDZ proteins, affecting signaling pathways and pathogenicity. This study investigates the PBM’s role in virulence by generating PBM-deficient mutant viruses and assessing their impact in vitro and in vivo. The mutants showed delayed replication and reduced cytopathic effects in vitro. In vivo, infected hamsters exhibited less weight loss, lower viral loads, and reduced inflammation, indicating attenuated pathogenicity. Histological analysis confirmed milder airway damage. Additionally, PBM-deficient viruses had impaired interactions with tight junction proteins like ZO-1, a PDZ-containing protein essential for epithelial integrity. Although the PBM played a key role in airway pathology, its impact on neuroinvasion was minimal during the acute phase of infection. Thus, the E protein PBM plays a critical role in SARS-CoV-2’s fitness, virulence, and pathogenicity, through the disruption of cell junctions and inflammation, underscoring its potential as a therapeutic target.

Background: Rabies is a vaccine-preventable zoonotic disease which causes thousands of deaths every year, mainly in Asia and Africa, and dogs are the main source of human cases. Although rabies is rare in international travellers, rabies exposure is relatively frequent and the number of travellers seeking post-exposure treatment may rise as international travel continues to increase. We aimed to better understand the characteristics of travellers exposed to rabies abroad, in order to deliver targeted advice and rabies vaccination during pre-travel clinics. Methods: During 2018-2022, we studied all returning travellers who attended a single travel clinic in Paris, France, for animal exposures abroad and requiring rabies post-exposure prophylaxis (n = 2916). Results: During the study period, 2916 returning travellers were included, and 59.7 % of exposures occurred in Southeast Asia (mainly Thailand and Indonesia) and North-Africa. Dogs were predominantly responsible for exposures, but the animals involved varied significantly according to the region visited and the age of the traveller. Monkey exposures were more frequently reported in Asia, and cat exposures in North Africa and among children. Exposures were reported as unprovoked in 22.9 % of cases, and 91 % of travellers had not received antirabies vaccines before travelling. Conclusions: Travellers to rabies endemic countries should benefit from more targeted information based on the region visited, the animals they are likely to encounter, and the age of the travellers. Critically, they should be counselled on the importance of avoiding contact with animals, the long-lasting benefit of pre-travel rabies vaccination, and the need for adequate post-exposure prophylaxis.