Global guideline for the diagnosis and management of cryptococcosis: an initiative of the ECMM and ISHAM in cooperation with the ASM.

Cryptococcosis is a major worldwide disseminated invasive fungal infection. Cryptococcosis, particularly in its most lethal manifestation of cryptococcal meningitis, accounts for substantial mortality and morbidity. The breadth of the clinical cryptococcosis syndromes, the different patient types at-risk and affected, and the vastly disparate resource settings where clinicians practice pose a complex array of challenges. Expert contributors from diverse regions of the world have collated data, reviewed the evidence, and provided insightful guideline recommendations for health practitioners across the globe. This guideline offers updated practical guidance and implementable recommendations on the clinical approaches, screening, diagnosis, management, and follow-up care of a patient with cryptococcosis and serves as a comprehensive synthesis of current evidence on cryptococcosis. This Review seeks to facilitate optimal clinical decision making on cryptococcosis and addresses the myriad of clinical complications by incorporating data from historical and contemporary clinical trials. This guideline is grounded on a set of core management principles, while acknowledging the practical challenges of antifungal access and resource limitations faced by many clinicians and patients. More than 70 societies internationally have endorsed the content, structure, evidence, recommendation, and pragmatic wisdom of this global cryptococcosis guideline to inform clinicians about the past, present, and future of care for a patient with cryptococcosis.

Effect of urbanization on the trace element concentrations in the kidney, liver and spines of the European hedgehog (Erinaceus europaeus).

Urbanized environments may be suitable for some wild species, like the European hedgehog (Erinaceus europaeus). However, the (sub)urban areas are source of several pollutants, such as trace elements (TEs). The main objective of our study is to investigate the role of the European hedgehog as a potential bioindicator species for seven TEs (As, Cd, Cr, Cu, Ni, Pb, Zn) in a big urban agglomeration. We analyzed the kidney, liver and spines of 50 European hedgehogs. Moreover, we carried out geographic information system (GIS) with 31 individuals to examine the effects of human pressure (human density and urbanization) on TE concentrations in tissues. We detected the 7 TEs in all tissues. Trace elements, especially Pb and Zn, in the liver, kidney and spines seem to be influenced by human density and urbanization.

Aspergillosis in a colony of Humboldt penguins (Spheniscus humboldti) in a french zoological park: evaluation of environmental exposure.

Aspergillosis is a major health problem in captive penguins due to the inhalation and the development of airborne spores of opportunistic environmental molds of the genus Aspergillus. Diagnosis is often delayed and treatments, based on the use of azole antifungals, are not fully effective. This study assesses the risk of exposure to Aspergillus sp. and determines the environmental reservoirs in the direct environment of a colony of Humboldt penguins (Spheniscus humboldti) in a zoological park in Paris, and the risk of contamination with resistant isolates. Every 15 days between February and May 2022, environmental samples (air and subtract from the nests, pond water, pigeon and penguin droppings) were carried out in the penguin enclosure as well as clinical samples (one-time non-invasive sampling on chicks), and screened for Aspergillus sp. conidia. From 191 environmental samples, 264 strains of Aspergillus including 221 strains of A. fumigatus were isolated, mostly from ambient air, in the nests, and pond water. No "at risk" areas in the penguin environment have been highlighted, nor an increased risk because of the proximity with urban wild birds. However, the load of airborne Aspergillus in the nests increased significantly with outdoor temperature. Of the 221 strains isolated, we identified only one azole-resistant strain, displaying the TR34/L98H mutation in the cyp51A gene. This low prevalence of resistant strains may probably be partly explained by the urban location of the zoological park, surrounded by kilometers of urban areas without agricultural activities.

Development of a primary cell model derived from porcine dorsal soft palate for foot-and-mouth disease virus research and diagnosis.

Foot-and-mouth disease (FMD) is a highly contagious viral disease of cloven-hoofed animals that has a significant socio-economic impact. One concern associated with this disease is the ability of its etiological agent, the FMD virus (FMDV), to persist in its hosts through underlying mechanisms that remain to be elucidated. While persistence has been described in cattle and small ruminants, it is unlikely to occur in pigs. One of the factors limiting the progress in understanding FMDV persistence and, in particular, differential persistence is the lack of suitable in vitro models. A primary bovine cell model derived from the dorsal soft palate, which is the primary site of replication and persistence of FMDV in cattle, has been developed, and it seemed relevant to develop a similar porcine model. Cells from two sites of FMDV replication in pigs, namely, the dorsal soft palate and the oropharyngeal tonsils, were isolated and cultured. The epithelial character of the cells from the dorsal soft palate was then assessed by immunofluorescence. The FMDV-sensitivity of these cells was assessed after monolayer infection with FMDV O/FRA/1/2001 Clone 2.2. These cells were also grown in multilayers at the air-liquid interface to mimic a stratified epithelium susceptible to FMDV infection. Consistent with what has been shown in vivo in pigs, our study showed no evidence of persistence of FMDV in either the monolayer or multilayer model, with no infectious virus detected 28 days after infection. The development of such a model opens up new possibilities for the study and diagnosis of FMDV in porcine cells.

Penicillium and Talaromyces spp. emerging pathogens in dogs since 1990s.

Penicillium and Talaromyces spp. are environmental saprophytic molds rarely encountered as infectious agents in humans and animals. This article summarizes the clinical features, treatment, and outcomes of proven infections caused by Penicillium or Talaromyces in four dogs in France. Two dogs had disseminated infections, while the other two had a localized form. All dogs had positive histopathological results showing the presence of hyaline septate hyphae and a positive fungal culture with typical Penicillium conidiophores. Talaromyces georgiensis (n = 1), Penicillium labradorum (n = 2), and Penicillium from section Ramosa series Raistrickiorum (n = 1), were identified based on Internal Transcribed Spacer (ITS) Sanger sequencing. The dogs were initially treated with ketoconazole or itraconazole. Second-line treatment was initiated in three dogs, but after several relapses, the prognosis remained poor. Since the 1990s, 18 cases of Penicillium or Talaromyces infections in dogs have been described worldwide. This series of four reports brings new cases to those already reported in the literature, which are probably underestimated in the world.

Penicillium and Talaromyces spp. are molds found in the environment that rarely cause infections in humans and animals. This article summarizes the clinical features and treatment of proven infections caused by Penicillium or Talaromyces species in four dogs in France.

SARS-CoV-2-related bat virus behavior in human-relevant models sheds light on the origin of COVID-19.

Bat sarbecovirus BANAL-236 is highly related to SARS-CoV-2 and infects human cells, albeit lacking the furin cleavage site in its spike protein. BANAL-236 replicates efficiently and pauci-symptomatically in humanized mice and in macaques, where its tropism is enteric, strongly differing from that of SARS-CoV-2. BANAL-236 infection leads to protection against superinfection by a virulent strain. We find no evidence of antibodies recognizing bat sarbecoviruses in populations in close contact with bats in which the virus was identified, indicating that such spillover infections, if they occur, are rare. Six passages in humanized mice or in human intestinal cells, mimicking putative early spillover events, select adaptive mutations without appearance of a furin cleavage site and no change in virulence. Therefore, acquisition of a furin site in the spike protein is likely a pre-spillover event that did not occur upon replication of a SARS-CoV-2-like bat virus in humans or other animals. Other hypotheses regarding the origin of the SARS-CoV-2 should therefore be evaluated, including the presence of sarbecoviruses carrying a spike with a furin cleavage site in bats.

High Nasal Nitric Oxide, Cilia Analyses, and Genotypes in a Retrospective Cohort of Children with Primary Ciliary Dyskinesia.

Rationale: Although children with primary ciliary dyskinesia (PCD) typically have low nasal nitric oxide (nNO), some children with indisputable PCD may have unexplained high nNO concentrations. Objectives: To look for relationships between nNO measures and genetic findings (and cilia motility or ultrastructure when available) in children with PCD with known genotypes. Methods: We retrospectively studied 73 children with PCD (median age, 9.5 [range, 2.1-18.2] yr). nNO was the mean value of a plateau reached while the velum was closed (nNO-VC; threshold, 77 nl ⋅ min-1) or was calculated as the average of five peaks obtained during tidal breathing (threshold, 40 nl ⋅ min-1). Ciliary beat was classified as either motile (including dyskinetic pattern) or immotile, depending on whether motility was present or absent in all cilia, or as a mixture of motile and immotile cilia. Genotypes were classified as pathogenic mutations in genes known to be associated with high nNO (mild genotype), biallelic truncating mutations in other genes (severe mutations), or putative hypomorphic pathogenic mutations (missense, single amino acid deletion, or moderate splicing mutations) in at least one allele believed to be possibly associated with residual production of a functional protein. Results: nNO was above the discriminant threshold in 16 of 73 (21.9%) children (11 nNO-VC and 5 nNO during tidal breathing). High nNO was less frequent in children with severe mutations (2 of 42) than in those with mild genotypes (7 of 10) or at least one hypomorphic mutation (7 of 21) (P < 0.0001). Median (interquartile range) nNO-VC values (n = 60) were significantly different in the three genotype groups: severe mutations, 18 (10-26) nl ⋅ min-1 (n = 36); possible residual functional protein production (putative hypomorphic mutations), 23 (16-68) nl ⋅ min-1 (n = 17); and mild genotypes, 139 (57-216) nl ⋅ min-1 (n = 7) (P = 0.0002). The higher the cilia motility, the higher the nNO-VC (16 [10-23], 23 [17-56], and 78 [45-93] nl ⋅ min-1 in patients with immotile, dyskinetic motile and immotile, and dyskinetic motile cilia, respectively; P < 0.0001), while nNO values were scattered across different ultrastructure defects (P = 0.07). Conclusions: In children with PCD, high nNO values were linked not only to specific genes but also to potentially hypomorphic mutations in other genes (with possible functional protein production). nNO values increased with the proportion of motile cilia.

Pathogenesis of recent Lassa virus isolates from lineages II and VII in cynomolgus monkeys.

The area of Lassa virus (LASV) circulation is expanding, with the emergence of highly pathogenic new LASV lineages. Benin recently became an endemic country for LASV and has seen the emergence of a new LASV lineage (VII). The first two outbreaks in 2014 and 2016 showed a relatively high mortality rate compared to other outbreaks. We infected cynomolgus monkeys with two strains belonging to lineage II and lineage VII that were isolated from deceased patients during the 2016 outbreak in Benin. The lineage VII strain (L7) caused uniform mortality. Death was associated with uncontrolled viral replication, unbalanced inflammatory responses characterized by increased concentrations of pro- and anti-inflammatory mediators, and the absence of efficient immune responses, resembling the pathogenesis associated with the prototypic Josiah strain in monkeys. The lineage II strain (L2) showed apparently lower virulence than its counterpart, with a prolonged time to death and a lower mortality rate. Prolonged survival was associated with better control of viral replication, a moderate inflammatory response, and efficient T-cell responses. Transcriptomic analyses also highlighted important differences in the immune responses associated with the outcome. Both strains caused strong inflammation in several organs. Notably, meningitis and encephalitis were observed in the cerebral cortex and cerebellum in all monkeys, independently of the outcome. Due to their apparently high pathogenicity, emerging strains from lineage VII should be considered in preclinical vaccine testing. Lineage II would also be beneficial in pathogenesis studies to study the entire spectrum of Lassa fever severity.

In Vivo Efficacy of Voriconazole in a Galleria mellonella Model of Invasive Infection Due to Azole-Susceptible or Resistant Aspergillus fumigatus Isolates.

Aspergillus fumigatus is an environmental filamentous fungus responsible for life-threatening infections in humans and animals. Azoles are the first-line treatment for aspergillosis, but in recent years, the emergence of azole resistance in A. fumigatus has changed treatment recommendations. The objective of this study was to evaluate the efficacy of voriconazole (VRZ) in a Galleria mellonella model of invasive infection due to azole-susceptible or azole-resistant A. fumigatus isolates. We also sought to describe the pharmacokinetics of VRZ in the G. mellonella model. G. mellonella larvae were infected with conidial suspensions of azole-susceptible and azole-resistant isolates of A. fumigatus. Mortality curves were used to calculate the lethal dose. Assessment of the efficacy of VRZ or amphotericin B (AMB) treatment was based on mortality in the lethal model and histopathologic lesions. The pharmacokinetics of VRZ were determined in larval hemolymph. Invasive fungal infection was obtained after conidial inoculation. A dose-dependent reduction in mortality was observed after antifungal treatment with AMB and VRZ. VRZ was more effective at treating larvae inoculated with azole-susceptible A. fumigatus isolates than larvae inoculated with azole-resistant isolates. The concentration of VRZ was maximal at the beginning of treatment and gradually decreased in the hemolymph to reach a Cmin (24 h) between 0.11 and 11.30 mg/L, depending on the dose. In conclusion, G. mellonella is a suitable model for testing the efficacy of antifungal agents against A. fumigatus.

Global guideline for the diagnosis and management of the endemic mycoses: an initiative of the European Confederation of Medical Mycology in cooperation with the International Society for Human and Animal Mycology.

The global burden of the endemic mycoses (blastomycosis, coccidioidomycosis, emergomycosis, histoplasmosis, paracoccidioidomycosis, sporotrichosis, and talaromycosis) continues to rise yearly and these infectious diseases remain a leading cause of patient morbidity and mortality worldwide. Management of the associated pathogens requires a thorough understanding of the epidemiology, risk factors, diagnostic methods and performance characteristics in different patient populations, and treatment options unique to each infection. Guidance on the management of these infections has the potential to improve prognosis. The recommendations outlined in this Review are part of the "One World, One Guideline" initiative of the European Confederation of Medical Mycology. Experts from 23 countries contributed to the development of these guidelines. The aim of this Review is to provide an up-to-date consensus and practical guidance in clinical decision making, by engaging physicians and scientists involved in various aspects of clinical management.

A single-shot Lassa vaccine induces long-term immunity and protects cynomolgus monkeys against heterologous strains.

A safe and protective Lassa virus vaccine is crucially needed in Western Africa to stem the recurrent outbreaks of Lassa virus infections in Nigeria and the emergence of Lassa virus in previously unaffected countries, such as Benin and Togo. Major challenges in developing a Lassa virus vaccine include the high diversity of circulating strains and their reemergence from 1 year to another. To address each of these challenges, we immunized cynomolgus monkeys with a measles virus vector expressing the Lassa virus glycoprotein and nucleoprotein of the prototypic Lassa virus strain Josiah (MeV-NP). To evaluate vaccine efficacy against heterologous strains of Lassa virus, we challenged the monkeys a month later with heterologous strains from lineage II or lineage VII, finding that the vaccine was protective against these strains. A second cohort of monkeys was challenged 1 year later with the homologous Josiah strain, finding that a single dose of MeV-NP was sufficient to protect all vaccinated monkeys. These studies demonstrate that MeV-NP can generate both long-lasting immune responses and responses that are able to protect against diverse strains of Lassa virus.

Aspergillosis in Wild Birds.

The ubiquitous fungi belonging to the genus Aspergillus are able to proliferate in a large number of environments on organic substrates. The spores of these opportunistic pathogens, when inhaled, can cause serious and often fatal infections in a wide variety of captive and free-roaming wild birds. The relative importance of innate immunity and the level of exposure in the development of the disease can vary considerably between avian species and epidemiological situations. Given the low efficacy of therapeutic treatments, it is essential that breeders or avian practitioners know the conditions that favor the emergence of Aspergillosis in order to put adequate preventive measures in place.

Systemic viral spreading and defective host responses are associated with fatal Lassa fever in macaques.

Lassa virus (LASV) is endemic in West Africa and induces a viral hemorrhagic fever (VHF) with up to 30% lethality among clinical cases. The mechanisms involved in control of Lassa fever or, in contrast, the ensuing catastrophic illness and death are poorly understood. We used the cynomolgus monkey model to reproduce the human disease with asymptomatic to mild or fatal disease. After initial replication at the inoculation site, LASV reached the secondary lymphoid organs. LASV did not spread further in nonfatal disease and was rapidly controlled by balanced innate and T-cell responses. Systemic viral dissemination occurred during severe disease. Massive replication, a cytokine/chemokine storm, defective T-cell responses, and multiorgan failure were observed. Clinical, biological, immunological, and transcriptomic parameters resembled those observed during septic-shock syndrome, suggesting that similar pathogenesis is induced during Lassa fever. The outcome appears to be determined early, as differentially expressed genes in PBMCs were associated with fatal and non-fatal Lassa fever outcome very early after infection. These results provide a full characterization and important insights into Lassa fever pathogenesis and could help to develop early diagnostic tools.

X-rays minibeam radiation therapy at a conventional irradiator: Pilot evaluation in F98-glioma bearing rats and dose calculations in a human phantom.

Minibeam radiation therapy (MBRT) is a type of spatial fractionated radiotherapy that uses submillimetric beams. This work reports on a pilot study on normal tissue response and the increase of the lifespan of glioma-bearing rats when irradiated with a tabletop x-ray system. Our results show a significant widening of the therapeutic window for brain tumours treated with MBRT: an important proportion of long-term survivals (60%) coupled with a significant reduction of toxicity when compared with conventional (broad beam) irradiations. In addition, the clinical translation of the minibeam treatment at a conventional irradiator is evaluated through a possible human head treatment plan.

Topological data analysis reveals genotype-phenotype relationships in primary ciliary dyskinesia.

BACKGROUND: Primary ciliary dyskinesia (PCD) is a heterogeneous inherited disorder caused by mutations in approximately 50 cilia-related genes. PCD genotype-phenotype relationships have mostly arisen from small case series because existing statistical approaches to investigating relationships have been unsuitable for rare diseases. METHODS: We applied a topological data analysis (TDA) approach to investigate genotype-phenotype relationships in PCD. Data from separate training and validation cohorts included 396 genetically defined individuals carrying pathogenic variants in PCD genes. To develop the TDA models, 12 clinical and diagnostic variables were included. TDA-driven hypotheses were subsequently tested using traditional statistics. RESULTS: Disease severity at diagnosis, measured by forced expiratory volume in 1 s (FEV1) z-score, was significantly worse in individuals with CCDC39 mutations (compared to other gene mutations) and better in those with DNAH11 mutations; the latter also reported less neonatal respiratory distress. Patients without neonatal respiratory distress had better preserved FEV1 at diagnosis. Individuals with DNAH5 mutations were phenotypically diverse. Cilia ultrastructure and beat pattern defects correlated closely to specific causative gene groups, confirming these tests can be used to support a genetic diagnosis. CONCLUSIONS: This large scale, multi-national study presents PCD as a syndrome with overlapping symptoms and variations in phenotype according to genotype. TDA modelling confirmed genotype-phenotype relationships reported by smaller studies (e.g. FEV1 worse with CCDC39 mutation) and identified new relationships, including FEV1 preservation with DNAH11 mutations and diversity of severity with DNAH5 mutations.

Central nervous system candidiasis beyond neonates: Lessons from a nationwide study.

Though candidiasis is the most frequent invasive fungal infection, Candida spp. central nervous system (CNS) infections are rare but severe. To further describe clinico-patho-radiological presentations of this entity, we report a retrospective study from January 2005 to December 2018 including patients aged ≥ 28 days with proven or probable CNS candidiasis in France. Twenty-four patients were included. Seventeen patients (70%) had CNS localization secondary to disseminated candidiasis (10 with hematologic malignancies [HM]; the seven other patients had infective endocarditis [IE]). Among patients with HM, seven previously had lumbar puncture for intrathecal chemotherapy, the three others had IE. Among patients with disseminated infection, magnetic resonance imaging (MRI) evidenced meningitis (17%), micro-abscesses (58%), or vascular complications (67%). Seven patients (30%) had isolated CNS involvement related to neurosurgery (n = 2), CARD9 deficiency (n = 2), intravenous drug use, diabetes mellitus, or no identified predisposing condition (n = 1 each). All evaluated patients with isolated CNS involvement had meningitis on cerebrospinal fluid (CSF) and intracranial hypertension. For the latter patients, MRI evidenced meningitis (71%) or abscesses (57%). Among all patients, cerebrospinal fluid (CSF) culture grew Candida spp. in 31% of cases. CSF ßDGlucan or mannan Ag were positive in respectively 86% and 80% of cases. Mortality attributed to CNS candidiasis was 42%: 53% in case of disseminated infection (70% for HM) and 14% in case of localized infection. CNS candidiasis are isolated or occur during disseminated infection in patients with HM and lumbar puncture for intrathecal chemotherapy or during IE. Clinical, radiological finding and outcome highly vary according to CNS localized versus disseminated candidiasis. LAY SUMMARY: Candida is a yeast and is the most common cause of fungal infections worldwide. Candida central nervous system (CNS) infections are rare, severe, and poorly described. We report a retrospective study from January 2005 to December 2018 including patients aged ≥ 28 days with proven or probable CNS candidiasis in France. Twenty-four patients were included (14 men, median age 51 years). Seventeen patients had CNS localization secondary to disseminated candidiasis from blood to CNS (10 with hematologic malignancies [HM], the seven other patients had infective endocarditis [IE]). Seven patients had isolated CNS involvement related to neurosurgery (n = 2), CARD9 deficiency (n = 2), intravenous drug use (n = 1), diabetes mellitus (n = 1), or no identified risk factor (n = 1).During Candida CNS infections, brain lesions were meningitis abscesses or vascular complications. Cerebrospinal fluid (CSF) culture grew Candida spp. in 31% of cases. Forty-two percent of patients died from infection: 53% in case of disseminated infection (70% for HM) and 14% in case of localized infection.

"Chronic Disseminated Aspergillosis," a Novel Fungal Immune Reconstitution Inflammatory Syndrome.

We report a case of chronic hepatosplenic aspergillosis following immune reconstitution complicating colic aspergillosis in an AIDS patient with multicentric Castleman disease. Symptoms mimicked the clinical presentation of chronic disseminated candidiasis and responded to corticosteroid. This emerging entity enlarges the spectrum of fungal immune reconstitution inflammatory syndrome in the HIV setting.

Spatially Modulated Proton Minibeams Results in the Same Increase of Lifespan as a Uniform Target Dose Coverage in F98-Glioma-Bearing Rats.

Proton minibeam radiation therapy (pMBRT) is a new approach in proton radiotherapy, by which a significant increase in the therapeutic index has already been demonstrated in RG2 glioma-bearing rats. In the current study we investigated the response of other types of glioma (F98) and performed a comparative evaluation of tumor control effectiveness by pMBRT (with different levels of dose heterogeneity) versus conventional proton therapy. The results of our study showed an equivalent increase in the lifespan for all evaluated groups (conventional proton irradiation and pMBRT) and no significant differences in the histopathological analysis of the tumors or remaining brain tissue. The reduced long-term toxicity observed with pMBRT in previous evaluations at the same dose suggests a possible use of pMBRT to treat glioma with less side effects while ensuring the same tumor control achieved with standard proton therapy.

An unanticipated tumor-suppressive role of the SUMO pathway in the intestine unveiled by Ubc9 haploinsufficiency.

Sumoylation is an essential posttranslational modification in eukaryotes that has emerged as an important pathway in oncogenic processes. Most human cancers display hyperactivated sumoylation and many cancer cells are remarkably sensitive to its inhibition, thus supporting application of chemical sumoylation inhibitors in cancer treatment. Here we show, first, that transformed embryonic fibroblasts derived from mice haploinsufficient for Ubc9, the essential and unique gene encoding the SUMO E2 conjugating enzyme, exhibit enhanced proliferation and transformed phenotypes in vitro and as xenografts ex vivo. To then evaluate the possible impact of loss of one Ubc9 allele in vivo, we used a mouse model of intestinal tumorigenesis. We crossed Ubc9+/- mice with mice harboring a conditional ablation of Apc either all along the crypt-villus axis or only in Lgr5+ crypt-based columnar (CBC) cells, the cell compartment that includes the intestinal stem cells proposed as cells-of-origin of intestinal cancer. While Ubc9+/- mice display no overt phenotypes and no globally visible hyposumoylation in cells of the small intestine, we found, strikingly, that, upon loss of Apc in both models, Ubc9+/- mice develop more (>2-fold) intestinal adenomas and show significantly shortened survival. This is accompanied by reduced global sumoylation levels in the polyps, indicating that Ubc9 levels become critical upon oncogenic stress. Moreover, we found that, in normal conditions, Ubc9+/- mice show a moderate but robust (15%) increase in the number of Lgr5+ CBC cells when compared to their wild-type littermates, and further, that these cells display higher degree of stemness and cancer-related and inflammatory gene expression signatures that, altogether, may contribute to enhanced intestinal tumorigenesis. The phenotypes of Ubc9 haploinsufficiency discovered here indicate an unanticipated tumor-suppressive role of sumoylation, one that may have important implications for optimal use of sumoylation inhibitors in the clinic.

A combination of two human monoclonal antibodies cures symptomatic rabies.

Rabies is a neglected disease caused by a neurotropic Lyssavirus, transmitted to humans predominantly by the bite of infected dogs. Rabies is preventable with vaccines or proper post-exposure prophylaxis (PEP), but it still causes about 60,000 deaths every year. No cure exists after the onset of clinical signs, and the case-fatality rate approaches 100% even with advanced supportive care. Here, we report that a combination of two potent neutralizing human monoclonal antibodies directed against the viral envelope glycoprotein cures symptomatic rabid mice. Treatment efficacy requires the concomitant administration of antibodies in the periphery and in the central nervous system through intracerebroventricular infusion. After such treatment, recovered mice presented good clinical condition, viral loads were undetectable, and the brain inflammatory profile was almost normal. Our findings provide the unprecedented proof of concept of an antibody-based therapeutic approach for symptomatic rabies.