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International Health Sep 2023Lassa fever is a viral haemorrhagic fever endemic to eight West African countries. Symptomatic disease is expected to occur in 20% of those infected and transmission...
BACKGROUND
Lassa fever is a viral haemorrhagic fever endemic to eight West African countries. Symptomatic disease is expected to occur in 20% of those infected and transmission typically occurs from viral spillover from rodent hosts. The combination of limited access to diagnostics and healthcare means the true burden of this disease is unknown.
METHODS
The case fatality rate among confirmed, probable and possible cases of Lassa fever in endemic regions is expected to be ≈15%. Here, annual reported cases and deaths have been used to estimate the case fatality rate, using three subsets of available data, to understand the scale of underreporting of severe human cases.
RESULTS
The literature review produced 38 records of cases and fatalities, comprising 5230 reported cases and 1482 reported deaths in seven countries. The estimated case fatality rate ranges from 16.5 to 25.6% (standard deviation 11.5-32.2). The expected number of severe cases between 2012 and 2022 is 8995, with current reported numbers 58% of what is expected.
CONCLUSION
This analysis highlights current uncertainty and systemic underreporting of the morbidity and mortality burden of Lassa fever in its endemic region and must be considered when discussing the epidemiology of this neglected tropical disease.
Topics: Humans; Lassa Fever; Lassa virus; Africa, Western; Health Facilities
PubMed: 36413115
DOI: 10.1093/inthealth/ihac076 -
Virology Oct 2023Lujo virus (LUJV), which belongs to Mammarenavirus, family Arenaviridae, has emerged as a pathogen causing severe hemorrhagic fever with high mortality. Currently, there...
Lujo virus (LUJV), which belongs to Mammarenavirus, family Arenaviridae, has emerged as a pathogen causing severe hemorrhagic fever with high mortality. Currently, there are no effective treatments for arenaviruses, including LUJV. Here, we screened chemical compound libraries of Food and Drug Administration (FDA)-approved drugs and G protein-coupled receptor-associated drugs to identify effective antivirals against LUJV targeting cell entry using a vesicular stomatitis virus-based pseudotyped virus bearing the LUJV envelope glycoprotein (GP). Cannabinoid receptor 1 (CB1) antagonists, such as rimonabant, AM251 and AM281, have been identified as robust inhibitors of LUJV entry. The IC of rimonabant was 0.26 and 0.53 μM in Vero and Huh7 cells, respectively. Analysis of the cell fusion activity of the LUJV GP in the presence of CB1 inhibitors revealed that these inhibitors suppressed the fusion activity of the LUJV GP. Moreover, rimonabant, AM251 and AM281 reduced the infectivity of authentic LUJV in vitro, suggesting that the antiviral activity of CB1 antagonists against LUJV is mediated, at least in part, by inhibition of the viral entry, especially, membrane fusion. These findings suggest promising candidates for developing new therapies against LUJV infections.
Topics: Humans; Chlorocebus aethiops; Animals; Lujo virus; Rimonabant; Arenaviridae Infections; Arenaviridae; Virus Internalization; Receptors, Cannabinoid; Vero Cells
PubMed: 37633192
DOI: 10.1016/j.virol.2023.109867 -
BMC Veterinary Research Nov 2023Wenzhou virus (WENV), a member of the Mammarenavirus genus in the Arenaviridae family, has been detected in wild rodents from eight provinces in China, including...
BACKGROUND
Wenzhou virus (WENV), a member of the Mammarenavirus genus in the Arenaviridae family, has been detected in wild rodents from eight provinces in China, including Zhejiang, Shandong, Hainan, Xinjiang, Hunan, Guangdong, Yunnan, and Jiangxi provinces, and some countries from Southeast Asia. The IgG-antibodies of WENV have been detected in both healthy populations and patients with unknown fever and respiratory symptoms. However, the potential harmfulness of WENV to humans has been underestimated due to mild symptoms after infection, similar to respiratory diseases. Thus, it is imperative to enhance the surveillance of WENV in wild rodents, particularly Rattus norvegicus, and continuously monitor its prevalence.
RESULTS
From 2017 to 2021, a total of 390 wild rodents were collected from six provinces in the eastern and southern coastal areas, containing nine species of rats. Samples of each tissue were collected, and PCR amplified for identification. Four R. norvegicus samples were detected to be WENV-positive. No genomic sequence of WENV was detected in Rattus flavipectus, Rattus losea, Suncus murinus, Apodemus agrarius, Mus musculus, Microtus fortis, Micromys minutus, and Niviventer niviventer from Jiangsu, Zhejiang, Fujian, Hainan, Guangdong and Guangxi provinces. Three genomic sequences were identified to be WENV by phylogenetic analysis. The full-length sequences of HAIKOU-40 were amplified in R. norvegicus from Hainan, which showed a close relationship to Wufeng/ WFS, sharing 84.5-89.4% homology at the nucleotide level and 91.6-98.9% homology at the amino acid level. Phylogenetic analysis revealed that HAIKOU-40 formed an Asia-specific cluster with all WENVs and Loie River mammarenavirus (LORV), provisionally named Asian ancestry. This cluster has diverged earlier from the remaining mammarenavirus. The sequences obtained in Xiamen, Fujian province showed more than 90% nucleotide identities with WENV, which may be a strain of WENV. Additionally, the sequence of Wuxi-87 which was a positive sequence detected in Wuxi, Jiangsu province exhibited 83% nucleotide identity with Lassa virus (LASV). Further efforts will be made to isolate and identify this virus strain, verify the relationship between Wuxi-87 and LASV, and confirm whether R. norvegicus is a new host of LASV.
CONCLUSIONS
In this study, we conducted a systematic examination of the prevalence of WENV among rodents on the southeast coast of China. Additionally, we characterized the genome of a newly discovered WENV strain, that confirmed the role of R. norvegicus in the transmission of WENV. This highlights the importance of investigating the prevalence of WENV in both wild rodents and humans.
Topics: Mice; Rats; Humans; Animals; Rodentia; Arenavirus; Phylogeny; China; Genomics; Nucleotides
PubMed: 38031051
DOI: 10.1186/s12917-023-03798-8 -
Pediatric Research Jan 2024Lymphocytic choriomeningitis virus (LCMV) is a prevalent pathogen, whose natural host and reservoir is the wild mouse. Humans can be infected when they contact the... (Review)
Review
Lymphocytic choriomeningitis virus (LCMV) is a prevalent pathogen, whose natural host and reservoir is the wild mouse. Humans can be infected when they contact the secretions of mice. Most infections of postnatal humans result in mild illness. However, the consequences can be severe when the infection occurs during pregnancy, as the virus crosses the placenta to infect the fetus. LCMV infection of the human fetus can lead to severe neuropathologic effects, including microencephaly, hydrocephalus, focal destructive lesions, and cerebellar hypoplasia. Outcomes among children with congenital LCMV are variable, but most are permanently and severely disabled. The neonatal rat inoculated with LCMV models human prenatal infection. The rat model has demonstrated that effects of LCMV depend on host age at the time of infection. Some effects, including encephalomalacia and neuronal migration disturbances, are immune-mediated and depend on the actions of T-lymphocytes. Other effects, including cerebellar hypoplasia, are virus-mediated and do not depend on T-lymphocytes. Cerebellar neuronal migration disturbances are caused by immune-mediated corruption of Bergmann glia structure. The rat pup inoculated with LCMV is a superb animal model for human congenital infection. All neuropathologic effects observed in human congenital LCMV infection can be recapitulated in the rat model. IMPACT: Lymphocytic choriomeningitis virus (LCMV) is a prevalent human pathogen that can cause serious neurologic birth defects when the infection occurs during pregnancy. The effects of the virus on the developing brain depend strongly on the age of the host at the time of infection. Some of the pathologic effects of LCMV are immune-mediated and are driven by T-lymphocytes, while other pathologic effects are due to the virus itself.
Topics: Humans; Pregnancy; Female; Child; Animals; Rats; Mice; Lymphocytic choriomeningitis virus; Brain; Lymphocytic Choriomeningitis; Cerebellum; Mice, Inbred C57BL; Developmental Disabilities; Nervous System Malformations
PubMed: 38182822
DOI: 10.1038/s41390-023-02985-5 -
Virology Nov 2023Arenaviruses are highly pathogenic viruses that pose a serious public health threat. Chapare virus (CHAV) and Machupo virus (MACV), two New World arenaviruses, cause...
Arenaviruses are highly pathogenic viruses that pose a serious public health threat. Chapare virus (CHAV) and Machupo virus (MACV), two New World arenaviruses, cause hemorrhagic fevers with case fatality rates of up to 45%. Research on therapeutic drug targets and vaccines for these viruses is limited because biosafety level 4 containment is required for handling them. In this study, we developed reverse genetics systems, including minigenomes and recombinant viruses, that will facilitate the study of these pathogens. The minigenome system is based on the S segment of CHAV or MACV genomes expressing the fluorescent reporter gene ZsGreen (ZsG). We also generated recombinant CHAV and MACV with and without the ZsG reporter gene. As a proof-of-concept study, we used both minigenomes and recombinant viruses to test the inhibitory effects of previously reported antiviral compounds. The new reverse genetics system described here will facilitate future therapeutic studies for these two life-threatening arenaviruses.
Topics: Arenaviruses, New World; Reverse Genetics
PubMed: 37774602
DOI: 10.1016/j.virol.2023.109888 -
Cell Reports. Medicine Feb 2024Lassa fever (LF) is an acute viral illness that causes thousands of deaths annually in West Africa. There are currently no Lassa virus (LASV) vaccines or antivirals...
Lassa fever (LF) is an acute viral illness that causes thousands of deaths annually in West Africa. There are currently no Lassa virus (LASV) vaccines or antivirals approved for human use. Recently, we showed that combinations of broadly neutralizing human monoclonal antibodies (BNhuMAbs) known as Arevirumab-2 or Arevirumab-3 protected up to 100% of cynomolgus macaques against challenge with diverse lineages of LASV when treatment was initiated at advanced stages of disease. This previous work assessed efficacy against parenteral exposure. However, transmission of LASV to humans occurs primarily by mucosal exposure to virus shed from Mastomys rodents. Here, we describe the development of a lethal intranasal exposure macaque model of LF. This model is employed to show that Arevirumab cocktails rescue 100% of macaques from lethal LASV infection when treatment is initiated 8 days after LASV exposure. Our work demonstrates BNhuMAbs have utility in treating LASV infection acquired through mucosal exposure.
Topics: Animals; Humans; Lassa virus; Lassa Fever; Macaca fascicularis; Immunotherapy; Antibodies, Monoclonal
PubMed: 38280377
DOI: 10.1016/j.xcrm.2024.101392 -
The Journal of Infectious Diseases Apr 2024Hepatitis B Virus (HBV) is a major driver of infectious disease mortality. Curative therapies are needed and ideally should induce CD8 T cell-mediated clearance of...
Alternating Arenavirus Vector Immunization Generates Robust Polyfunctional Genotype Cross-Reactive Hepatitis B Virus-Specific CD8 T-Cell Responses and High Anti-Hepatitis B Surface Antigen Titers.
Hepatitis B Virus (HBV) is a major driver of infectious disease mortality. Curative therapies are needed and ideally should induce CD8 T cell-mediated clearance of infected hepatocytes plus anti-hepatitis B surface antigen (HBsAg) antibodies (anti-HBs) to neutralize residual virus. We developed a novel therapeutic vaccine using non-replicating arenavirus vectors. Antigens were screened for genotype conservation and magnitude and genotype reactivity of T cell response, then cloned into Pichinde virus (PICV) vectors (recombinant PICV, GS-2829) and lymphocytic choriomeningitis virus (LCMV) vectors (replication-incompetent, GS-6779). Alternating immunizations with GS-2829 and GS-6779 induced high-magnitude HBV T cell responses, and high anti-HBs titers. Dose schedule optimization in macaques achieved strong polyfunctional CD8 T cell responses against core, HBsAg, and polymerase and high titer anti-HBs. In AAV-HBV mice, GS-2829 and GS-6779 were efficacious in animals with low pre-treatment serum HBsAg. Based on these results, GS-2829 and GS-6779 could become a central component of cure regimens.
Topics: Mice; Animals; Hepatitis B Surface Antigens; Hepatitis B virus; Arenavirus; Hepatitis B; Hepatitis B Vaccines; Hepatitis B Antibodies; Immunization; CD8-Positive T-Lymphocytes; Genotype; Antigens, Surface
PubMed: 37602681
DOI: 10.1093/infdis/jiad340 -
PLoS Neglected Tropical Diseases Sep 2023Numerous arenaviruses have been identified throughout the Americas and a subset of these viruses cause viral hemorrhagic fever in humans. This study compared the...
Numerous arenaviruses have been identified throughout the Americas and a subset of these viruses cause viral hemorrhagic fever in humans. This study compared the pathology and viral RNA distribution in Hartley guinea pigs challenged with two human-disease causing New World arenaviruses, Junin virus (JUNV) or Guanarito virus (GTOV). Histopathologic analysis and RNA in situ hybridization revealed similar pathology and viral RNA distribution for both groups of animals challenged with either JUNV or GTOV on days 3, 7, 10 and 12 post exposure (PE). Gross lesions were first observed on day 7 and primarily involved the lungs and liver. The most severe histologic lesions occurred in the lymph nodes, spleen, and thymus and included lymphoid depletion and necrosis which increased in severity over time. Extensive necrosis was also observed in the bone marrow on day 12. Minimal to mild inflammation with and without necrosis was observed in the choroid plexus of the brain, choroid of the eye, intestinal tract, lung and adrenal gland. Significant liver lesions were rare, consisting predominantly of hepatocyte vacuolation. Viral RNA labeling was identified in nearly all organs examined, was often extensive in certain organs and generally increased over time starting on day 7. Our data demonstrate the guinea pig may serve as a useful model to study New World arenavirus infection in humans and for the evaluation and development of medical countermeasures.
Topics: Humans; Guinea Pigs; Animals; Arenaviruses, New World; RNA, Viral; Junin virus; Liver; Brain
PubMed: 37682988
DOI: 10.1371/journal.pntd.0011620 -
Viruses Aug 2023The mammarenavirus Junín (JUNV) is the causative agent of Argentine hemorrhagic fever, a severe disease of public health concern. The most abundant viral protein is the...
The mammarenavirus Junín (JUNV) is the causative agent of Argentine hemorrhagic fever, a severe disease of public health concern. The most abundant viral protein is the nucleoprotein (NP), a multifunctional, two-domain protein with the primary role as structural component of the viral nucleocapsids, used as template for viral polymerase RNA synthesis activities. Here, we report that the C-terminal domain (CTD) of the attenuated Candid#1 strain of the JUNV NP can be purified as a stable soluble form with a secondary structure in line with known NP structures from other mammarenaviruses. We show that the JUNV NP CTD interacts with the viral matrix protein Z in vitro, and that the full-length NP and Z interact with each other in cellulo, suggesting that the NP CTD is responsible for this interaction. This domain comprises an arrangement of four acidic residues and a histidine residue conserved in the active site of exoribonucleases belonging to the DEDDh family. We show that the JUNV NP CTD displays metal-ion-dependent nuclease activity against DNA and single- and double-stranded RNA, and that this activity is impaired by the mutation of a catalytic residue within the DEDDh motif. These results further support this activity, not previously observed in the JUNV NP, which could impact the mechanism of the cellular immune response modulation of this important pathogen.
Topics: Junin virus; Nucleoproteins; Arenaviridae; Catalysis; Exoribonucleases
PubMed: 37766225
DOI: 10.3390/v15091818 -
Viruses Nov 2023Reptarenaviruses cause Boid Inclusion Body Disease (BIBD), a fatal disease of boid snakes with an economic and ecological impact, as it affects both captive and wild...
Reptarenaviruses cause Boid Inclusion Body Disease (BIBD), a fatal disease of boid snakes with an economic and ecological impact, as it affects both captive and wild constrictor snakes. The clinical picture of BIBD is highly variable but often only limited. Intracytoplasmic inclusion bodies (IB), which develop in most cell types including blood cells, are the pathognomonic hallmark of BIBD; their detection represents the diagnostic gold standard of the disease. However, IBs are not consistently present in clinically healthy reptarenavirus carriers, which can, if undetected, lead to and maintain the spread of the disease within and between snake populations. Sensitive viral detection tools are required for screening and control purposes; however, the genetic diversity of reptarenaviruses hampers the reverse transcription (RT) PCR-based diagnostics. Here, we describe a multiplex RT-PCR approach for the molecular diagnosis of reptarenavirus infection in blood samples. The method allows the detection of a wide range of reptarenaviruses with the detection limit reaching 40 copies per microliter of blood. Using 245 blood samples with a reference RT-PCR result, we show that the technique performs as well as the segment-specific RT-PCRs in our earlier studies. It can identify virus carriers and serve to limit reptarenavirus spreading in captive snake collections.
Topics: Animals; Arenaviridae; Arenaviridae Infections; Reverse Transcription; Reverse Transcriptase Polymerase Chain Reaction; Boidae
PubMed: 38140554
DOI: 10.3390/v15122313