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Recent outbreaks of viral hemorrhagic fevers (VHFs), including Ebola virus disease (EVD) and Lassa fever (LF), highlight the urgent need for sensitive, deployable tests to diagnose these devastating human diseases. Here we develop CRISPR-Cas13a-based (SHERLOCK) diagnostics targeting Ebola virus (EBOV) and Lassa virus (LASV), with both fluorescent and lateral flow readouts. We demonstrate on laboratory and clinical samples the sensitivity of these assays and the capacity of the SHERLOCK platform to handle virus-specific diagnostic challenges. We perform safety testing to demonstrate the efficacy of our HUDSON protocol in heat-inactivating VHF viruses before SHERLOCK testing, eliminating the need for an extraction. We develop a user-friendly protocol and mobile application (HandLens) to report results, facilitating SHERLOCK’s use in endemic regions. Finally, we successfully deploy our tests in Sierra Leone and Nigeria in response to recent outbreaks. Outbreaks of viral hemorrhagic fevers highlight the need for sensitive, field-deployable diagnostics. Here the authors present a CRISPR-based SHERLOCK platform with field protocol and mobile app for Ebola and Lassa fever outbreaks.

The 2018 Nigerian Lassa fever season saw the largest ever recorded upsurge of cases, raising concerns over the emergence of a strain with increased transmission rate. To understand the molecular epidemiology of this upsurge, we performed, for the first time at the epicenter of an unfolding outbreak, metagenomic nanopore sequencing directly from patient samples, an approach dictated by the highly variable genome of the target pathogen. Genomic data and phylogenetic reconstructions were communicated immediately to Nigerian authorities and the World Health Organization to inform the public health response. Real-time analysis of 36 genomes and subsequent confirmation using all 120 samples sequenced in the country of origin revealed extensive diversity and phylogenetic intermingling with strains from previous years, suggesting independent zoonotic transmission events and thus allaying concerns of an emergent strain or extensive human-to-human transmission.

Strengthened in-country sequencing generated 28 Lassa virus genomes from human clinical cases in Guinea, expanding knowledge of Lassa fever in the country. Phylogeographic analysis revealed cross-border exchange between Liberia and the N'Zérékoré region and a Sierra Leone introduction into Guéckédou. Enhanced genomic surveillance is crucial to guide public health.

Two patients with Lassa fever are described who are the first human cases treated with a combination of ribavirin and favipiravir. Both patients survived but developed transaminitis and had prolonged detectable virus RNA in blood and semen, suggesting that the possibility of sexual transmission of Lassa virus should be considered.

Recent occurrences of filoviruses and the arenavirus Lassa virus (LASV) in overlapping endemic areas of Africa highlight the need for a prophylactic vaccine that would confer protection against all of these viruses that cause lethal hemorrhagic fever (HF). We developed a quadrivalent formulation of VesiculoVax that contains recombinant vesicular stomatitis virus (rVSV) vectors expressing filovirus glycoproteins and that also contains a rVSV vector expressing the glycoprotein of a lineage IV strain of LASV. Cynomolgus macaques were vaccinated twice with the quadrivalent formulation, followed by challenge 28 days after the boost vaccination with each of the 3 corresponding filoviruses (Ebola, Sudan, Marburg) or a heterologous contemporary lineage II strain of LASV. Serum IgG and neutralizing antibody responses specific for all 4 glycoproteins were detected in all vaccinated animals. A modest and balanced cell-mediated immune response specific for the glycoproteins was also detected in most of the vaccinated macaques. Regardless of the level of total glycoprotein-specific immune response detected after vaccination, all immunized animals were protected from disease and death following lethal challenges. These findings indicate that vaccination with attenuated rVSV vectors each expressing a single HF virus glycoprotein may provide protection against those filoviruses and LASV most commonly responsible for outbreaks of severe HF in Africa.

Viral hemorrhagic Lassa fever (LF), caused by Lassa virus (LASV), is a significant public health concern endemic in West Africa with high morbidity and mortality rates, limited treatment options, and potential for international spread. Despite advances in interrogating its epidemiology and clinical manifestations, the molecular mechanisms driving pathogenesis of LASV and other arenaviruses remain incompletely understood. This review synthesizes current knowledge regarding the role of LASV host-virus interactions in mediating the pathogenesis of LF, with emphasis on interactions between viral and host proteins. Through investigation of these critical protein–protein interactions, we identify potential therapeutic targets and discuss their implications for development of medical countermeasures including antiviral drugs. This review provides an update in recent literature of significant LASV host-virus interactions important in informing the development of targeted therapies and improving clinical outcomes for LF patients. Knowledge gaps are highlighted as opportunities for future research efforts that would advance the field of LASV and arenavirus pathogenesis.

An increase in Lassa fever cases was identified in Nigeria this year. In this analysis of the infecting viruses, the predominant mode of transmission appeared to be multiple insertions from local rodent populations rather than sustained person-to-person spread.

Lassa fever is a severe viral hemorrhagic fever caused by a zoonotic virus that repeatedly spills over to humans from its rodent reservoirs. It is currently not known how climate and land use changes could affect the endemic area of this virus, currently limited to parts of West Africa. By exploring the environmental data associated with virus occurrence using ecological niche modelling, we show how temperature, precipitation and the presence of pastures determine ecological suitability for virus circulation. Based on projections of climate, land use, and population changes, we find that regions in Central and East Africa will likely become suitable for Lassa virus over the next decades and estimate that the total population living in ecological conditions that are suitable for Lassa virus circulation may drastically increase by 2070. By analysing geotagged viral genomes using spatially-explicit phylogeography and simulating virus dispersal, we find that in the event of Lassa virus being introduced into a new suitable region, its spread might remain spatially limited over the first decades. It is currently unknown how climate and land use changes could affect the endemic area of Lassa virus, a zoonotic pathogen responsible for Lassa fever. Here, the authors show that by 2070, new regions in Africa will likely become ecologically suitable for Lassa virus, drastically increasing the population living in conditions favourable for virus circulation.

Identifying genes under local adaptation is an essential step to understand the mechanisms of adaptive evolution. Pathogen-mediated selection is expected to enhance host fitness by favouring resistance to locally prevalent pathogens. However, such pathogen-driven adaptation has been documented in only a few natural systems. Here, we sequenced the Major Histocompatibility Complex Class I region (MHC-I) of 739 Mastomys natalensis captured in Guinea and Nigeria, where the rodent is reservoir to two distinct Lassa virus (LASV) lineages. As predicted, the MHC-I profiles of the two countries, while showing overlap, did not cluster together. Moreover, different MHC-I alleles were associated with active or past infection measured as PCR-positive or IgG-positive, respectively, in each population. MHC-I allele ManaMHC-I*017 showed a diametric response, with individuals carrying this allele less likely to be found with an ongoing LASV infection in Guinea while more likely in Nigeria. Similarly, individuals with ManaMHC-I*069 were less likely to have a positive antibody test in Guinea but the same allele had little effect on IgG detection in Nigeria, suggesting that an individual’s fitness depends on its immunogenetic repertoire. Together, these findings encapsulate a genetically characterised case of local adaptation in a wild virus–rodent system. Moreover, we hypothesise that aside from differences in virus diversity, genetic variation within regional LASV lineages contributes to the marked differences in host immunogenetic diversity.

Lassa virus (LASV) causes Lassa fever; mortality rates are higher in pregnant women, and fetal infection and death are possible. Sexual transmission after recovery from Lassa fever has occurred. Using virus strains that are lethal (Josiah) or nonlethal (NJ2015) in guinea pigs, we characterized LASV-associated pathology and reproductive tissue tropism in male and female animals. Uterus, ovary, and epididymis were the earliest and most affected tissues; perivascular lymphocytic inflammation was prominent at lethal timepoints and persisted in survivors after clinical disease. LASV-Josiah RNA was detected in reproductive tissues by 4 days postinfection (dpi). Virus localized by immunohistochemistry and in situ hybridization predominantly within vascular smooth muscle and interstitial mesenchymal cells and was widespread in reproductive tissues in lethal infections (12-25 dpi) but not detected in survivors (41-42 dpi). Using a physiologically relevant model, we describe reproductive tissue targets to further elucidate LASV infection and effects on reproductive health and virus transmission.