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Nature Reviews. Microbiology Jul 2023Crimean-Congo haemorrhagic fever (CCHF) is a severe tick-borne illness with a wide geographical distribution and case fatality rates of 30% or higher. Caused by... (Review)
Review
Crimean-Congo haemorrhagic fever (CCHF) is a severe tick-borne illness with a wide geographical distribution and case fatality rates of 30% or higher. Caused by infection with the CCHF virus (CCHFV), cases are reported throughout Africa, the Middle East, Asia and southern and eastern Europe. The expanding range of the Hyalomma tick vector is placing new populations at risk for CCHF, and no licensed vaccines or specific antivirals exist to treat CCHF. Furthermore, despite cases of CCHF being reported annually, the host and viral determinants of CCHFV pathogenesis are poorly understood. CCHFV can productively infect a multitude of animal species, yet only humans develop a severe illness. Within human populations, subclinical infections are underappreciated and may represent a substantial proportion of clinical outcomes. Compared with other members of the Bunyavirales order, CCHFV has a more complex genomic organization, with many viral proteins having unclear functions in viral pathogenesis. In recent years, improved animal models have led to increased insights into CCHFV pathogenesis, and several antivirals and vaccines for CCHFV have shown robust efficacy in preclinical models. Translation of these insights and candidate therapeutics to the clinic will hopefully reduce the morbidity and mortality caused by CCHFV.
Topics: Animals; Humans; Hemorrhagic Fever Virus, Crimean-Congo; Hemorrhagic Fever, Crimean; Vaccines; Antiviral Agents; Models, Animal
PubMed: 36918725
DOI: 10.1038/s41579-023-00871-9 -
Cell Research Feb 2024Crimean-Congo hemorrhagic fever virus (CCHFV) is the most widespread tick-born zoonotic bunyavirus that causes severe hemorrhagic fever and death in humans. CCHFV enters...
Crimean-Congo hemorrhagic fever virus (CCHFV) is the most widespread tick-born zoonotic bunyavirus that causes severe hemorrhagic fever and death in humans. CCHFV enters the cell via clathrin-mediated endocytosis which is dependent on its surface glycoproteins. However, the cellular receptors that are required for CCHFV entry are unknown. Here we show that the low density lipoprotein receptor (LDLR) is an entry receptor for CCHFV. Genetic knockout of LDLR impairs viral infection in various CCHFV-susceptible human, monkey and mouse cells, which is restored upon reconstitution with ectopically-expressed LDLR. Mutagenesis studies indicate that the ligand binding domain (LBD) of LDLR is necessary for CCHFV infection. LDLR binds directly to CCHFV glycoprotein Gc with high affinity, which supports virus attachment and internalization into host cells. Consistently, a soluble sLDLR-Fc fusion protein or anti-LDLR blocking antibodies impair CCHFV infection into various susceptible cells. Furthermore, genetic knockout of LDLR or administration of an LDLR blocking antibody significantly reduces viral loads, pathological effects and death following CCHFV infection in mice. Our findings suggest that LDLR is an entry receptor for CCHFV and pharmacological targeting of LDLR may provide a strategy to prevent and treat Crimean-Congo hemorrhagic fever.
Topics: Animals; Humans; Mice; Endocytosis; Glycoproteins; Hemorrhagic Fever Virus, Crimean-Congo; Hemorrhagic Fever, Crimean; Receptors, LDL; Virus Internalization
PubMed: 38182887
DOI: 10.1038/s41422-023-00917-w -
Antiviral Research Mar 2022Human infection with Crimean-Congo hemorrhagic fever virus (CCHFV), a tick-borne pathogen in the family Nairoviridae, can result in a spectrum of outcomes, ranging from... (Review)
Review
Human infection with Crimean-Congo hemorrhagic fever virus (CCHFV), a tick-borne pathogen in the family Nairoviridae, can result in a spectrum of outcomes, ranging from asymptomatic infection through mild clinical signs to severe or fatal disease. Studies of CCHFV immunobiology have investigated the relationship between innate and adaptive immune responses with disease severity, attempting to elucidate factors associated with differential outcomes. In this article, we begin by highlighting unanswered questions, then review current efforts to answer them. We discuss in detail current clinical studies and research in laboratory animals on CCHF, including immune targets of infection and adaptive and innate immune responses. We summarize data about the role of the immune response in natural infections of animals and humans and experimental studies in vitro and in vivo and from evaluating immune-based therapies and vaccines, and present recommendations for future research.
Topics: Animals; Hemorrhagic Fever Virus, Crimean-Congo; Hemorrhagic Fever, Crimean; Ticks
PubMed: 35026307
DOI: 10.1016/j.antiviral.2022.105244 -
Emerging Infectious Diseases Feb 2023Crimean-Congo hemorrhagic fever (CCHF) is a viral infectious disease for which distribution of the main vector, Hyalomma spp. ticks, is expanding. We analyzed all 10... (Review)
Review
Crimean-Congo hemorrhagic fever (CCHF) is a viral infectious disease for which distribution of the main vector, Hyalomma spp. ticks, is expanding. We analyzed all 10 cases of CCHF diagnosed in Spain during 2013-2021; case-patient median age was 56.5 years, and 7 were men. We identified CCHF virus genotypes III and V. Six case-patients acquired the infection in urban areas. Sixty percent of patients were infected in summer and 40% in spring. Two patients met criteria for hemophagocytic syndrome. Seven patients survived. The epidemiologic pattern of CCHF in Spain is based on occasional cases with an elevated mortality rate. Genotype III and, to a less extent also genotype V, CCHF circulates in humans in a common geographic area in Spain. Those data suggest that the expansion pathways are complex and may change over time. Physicians should remain alert to the possibility of new CCHF cases.
Topics: Animals; Male; Humans; Middle Aged; Female; Hemorrhagic Fever, Crimean; Hemorrhagic Fever Virus, Crimean-Congo; Spain; Ticks; Ixodidae
PubMed: 36692301
DOI: 10.3201/eid2902.220677 -
Antiviral Research Nov 2022Crimean-Congo hemorrhagic fever (CCHF) is a medically relevant tick-borne viral disease caused by the Bunyavirus, Crimean-Congo hemorrhagic fever virus (CCHFV). CCHFV is...
Crimean-Congo hemorrhagic fever (CCHF) is a medically relevant tick-borne viral disease caused by the Bunyavirus, Crimean-Congo hemorrhagic fever virus (CCHFV). CCHFV is endemic to Asia, the Middle East, South-eastern Europe, and Africa and is transmitted in enzootic cycles among ticks, mammals, and birds. Human infections are mostly subclinical or limited to mild febrile illness. Severe disease may develop, resulting in multi-organ failure, hemorrhagic manifestations, and case-fatality rates up to 30%. Despite the widespread distribution and life-threatening potential, no treatments have been approved for CCHF. Antiviral inhibitory peptides, which antagonize viral entry, are licensed for clinical use in certain viral infections and have been experimentally designed against human pathogenic bunyaviruses, with in vitro and in vivo efficacies. We designed inhibitory peptides against CCHFV with and without conjugation to various polyethylene glycol and sterol groups. These additions have been shown to enhance both cellular uptake and antiviral activity. Peptides were evaluated against pseudotyped and wild-type CCHFV via neutralization tests, Nairovirus fusion assays, and cytotoxicity profiling. Four peptides neutralized CCHFV with two of these peptides shown to inhibit viral fusion. This work represents the development of experimental countermeasures for CCHF, describes a nairovirus immunofluorescence fusion assay, and illustrates the utility of pseudotyped CCHFV for the screening of entry antagonists at low containment settings for CCHF.
Topics: Animals; Antiviral Agents; Hemorrhagic Fever Virus, Crimean-Congo; Hemorrhagic Fever, Crimean; Humans; Mammals; Orthobunyavirus; Peptides; Polyethylene Glycols; Sterols
PubMed: 36049554
DOI: 10.1016/j.antiviral.2022.105401 -
The Indian Journal of Medical Research Nov 2009Ganjam virus (GANV), a member of genus Nairovirus of family Bunyavirdae is of considerable veterinary importance in India. Though, predominantly tick borne, GANV was... (Review)
Review
Ganjam virus (GANV), a member of genus Nairovirus of family Bunyavirdae is of considerable veterinary importance in India. Though, predominantly tick borne, GANV was also isolated from mosquitoes, man and sheep. Neutralizing and complement fixing antibodies to GANV have been detected in animal and human sera collected from different parts of the country. Thirty three strains of GANV have been isolated from India, mainly from Haemaphysalis ticks. The virus replicated in certain vertebrate and mosquito cell lines and found pathogenic to laboratory animals. One natural infection and five laboratory-acquired infections in men were also reported. GANV is antigenically related to Nairobi sheep disease virus (NSDV) of Africa, which is highly pathogenic for sheep and goats causing 70-90 per cent mortality among the susceptible population. Recent molecular studies have demonstrated that GANV is an Asian variant of NSDV and both these viruses are related to the dreaded Crimean Congo haemorrhagic fever (CCHF) group viruses. The versatility of the virus to replicate in different arthropod species, its ability to infect sheep, goat and man makes it an important zoonotic agent.
Topics: Animals; Bunyaviridae Infections; Female; Goats; Humans; India; Male; Mice; Nairobi Sheep Disease; Nairobi sheep disease virus; Sheep; Ticks; Virus Replication; Zoonoses
PubMed: 20090098
DOI: No ID Found -
The Journal of General Virology Aug 2020Members of the family produce enveloped virions with three single-stranded RNA segments comprising 17.1 to 22.8 kb in total. These viruses are maintained in... (Review)
Review
Members of the family produce enveloped virions with three single-stranded RNA segments comprising 17.1 to 22.8 kb in total. These viruses are maintained in arthropods and transmitted by ticks to mammals or birds. Crimean-Congo hemorrhagic fever virus is tick-borne and is endemic in most of Asia, Africa, Southern and Eastern Europe whereas Nairobi sheep disease virus, which is also tick-borne, causes lethal haemorrhagic gastroenteritis in small ruminants in Africa and India. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family , which is available at ictv.global/report/nairoviridae.
Topics: Animals; Genome, Viral; Humans; Nairovirus; RNA Viruses
PubMed: 32840475
DOI: 10.1099/jgv.0.001485 -
Nature Communications Sep 2021The increasing burden of tick-borne orthonairovirus infections, such as Crimean-Congo hemorrhagic fever, is becoming a global concern for public health. In the present...
The increasing burden of tick-borne orthonairovirus infections, such as Crimean-Congo hemorrhagic fever, is becoming a global concern for public health. In the present study, we identify a novel orthonairovirus, designated Yezo virus (YEZV), from two patients showing acute febrile illness with thrombocytopenia and leukopenia after tick bite in Hokkaido, Japan, in 2019 and 2020, respectively. YEZV is phylogenetically grouped with Sulina virus detected in Ixodes ricinus ticks in Romania. YEZV infection has been confirmed in seven patients from 2014-2020, four of whom were co-infected with Borrelia spp. Antibodies to YEZV are found in wild deer and raccoons, and YEZV RNAs have been detected in ticks from Hokkaido. In this work, we demonstrate that YEZV is highly likely to be the causative pathogen of febrile illness, representing the first report of an endemic infection associated with an orthonairovirus potentially transmitted by ticks in Japan.
Topics: Adult; Animals; Antibodies, Viral; Fever; Genome, Viral; Humans; Ixodes; Japan; Leukocyte Count; Male; Middle Aged; Nairovirus; Phylogeny; RNA, Viral; Virion
PubMed: 34545081
DOI: 10.1038/s41467-021-25857-0 -
Frontiers in Cellular and Infection... 2023Increased human activities around the globe and the rapid development of once rural regions have increased the probability of contact between humans and wild animals. A... (Review)
Review
Increased human activities around the globe and the rapid development of once rural regions have increased the probability of contact between humans and wild animals. A majority of bunyaviruses are of zoonotic origin, and outbreaks may result in the substantial loss of lives, economy contraction, and social instability. Many bunyaviruses require manipulation in the highest levels of biocontainment, such as Biosafety Level 4 (BSL-4) laboratories, and the scarcity of this resource has limited the development speed of vaccines for these pathogens. Meanwhile, new technologies have been created, and used to innovate vaccines, like the mRNA vaccine platform and bioinformatics-based antigen design. Here, we summarize current vaccine developments for three different bunyaviruses requiring work in the highest levels of biocontainment: Crimean-Congo Hemorrhagic Fever Virus (CCHFV), Rift Valley Fever Virus (RVFV), and Hantaan virus (HTNV), and provide perspectives and potential future directions that can be further explored to advance specific vaccines for humans and livestock.
Topics: Animals; Humans; Rift Valley fever virus; Hemorrhagic Fever Virus, Crimean-Congo; Vaccines; Hemorrhagic Fever, Crimean
PubMed: 37274315
DOI: 10.3389/fcimb.2023.1174030 -
Journal of Virology Dec 2015The nairoviruses include assorted tick-borne bunyaviruses that are emerging as causative agents of infectious diseases among humans and animals. As negative-sense...
UNLABELLED
The nairoviruses include assorted tick-borne bunyaviruses that are emerging as causative agents of infectious diseases among humans and animals. As negative-sense single-stranded RNA (-ssRNA) viruses, nairoviruses encode nucleoprotein (NP) that encapsidates the genomic RNA and further forms ribonucleoprotein (RNP) complex with viral RNA-dependent RNA polymerase (RdRp). We previously revealed that the monomeric NP encoded by Crimean-Congo hemorrhagic fever virus (CCHFV) presents a racket-shaped structure and shows unusual DNA-specific endonuclease activity. To examine the structural and biological variation of nairovirus-encoded NPs, here, we systematically solved the crystal structures of NPs encoded by various nairoviruses, including Hazara virus (HAZV), Kupe virus (KUPV), and Erve virus (ERVEV). Combined with biochemical analysis, our results generate a clearer picture to aid in the understanding of the functional diversity of nairovirus-encoded NPs and the formation of nairovirus RNPs.
IMPORTANCE
Nairoviruses comprise several tick-borne bunyaviruses that are emerging as causative agents of infectious diseases among humans and animals; however, little is known of the nairovirus genome assembly and transcription mechanisms. Based on the previous study of CCHFV NP reported by different research groups, we systematically investigate here the structural and functional diversity among three different nairoviruses. This work provides important information on nairovirus nucleoprotein function and the formation of RNPs.
Topics: Crystallography; DNA Primers; DNA, Complementary; Electrophoretic Mobility Shift Assay; Genetic Variation; Models, Molecular; Nairovirus; Nucleoproteins; X-Ray Diffraction
PubMed: 26246561
DOI: 10.1128/JVI.01680-15