![Species in the Phlebovirus genus according to current classification [3]](https://www.researchgate.net/profile/Benjamin-Brennan-2/publication/260645123/figure/tbl1/AS:669706860122115@1536681966211/Species-in-the-Phlebovirus-genus-according-to-current-classification-3_Q320.jpg)
![Phylogeny of representative phleovirus proteins. The analogous protein from Gouleako virus, a mosquito-associated phlebovirus-like virus, was used as the outgroup in each case. Taken from Swei et al. [38•].](https://www.researchgate.net/profile/Benjamin-Brennan-2/publication/260645123/figure/fig1/AS:267514047365176@1440791727631/Phylogeny-of-representative-phleovirus-proteins-The-analogous-protein-from-Gouleako_Q320.jpg)
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Emerging phleboviruses
Abstract and Figures
The Bunyavidae family is the largest grouping of RNA viruses and arguably the most diverse. Bunyaviruses have a truly global distribution and can infect vertebrates, invertebrates and plants. The majority of bunyaviruses are vectored by arthropods and thus have the remarkable capability to replicate in hosts of disparate phylogeny. The family has provided many examples of emerging viruses including Sin Nombre and related viruses responsible for hantavirus cardiopulmonary syndrome in the Americas, first identified in 1993, and Schmallenberg virus which emerged in Europe in 2011, causing foetal malformations in ruminants. In addition, some well-known bunyaviruses like Rift Valley fever and Crimean-Congo haemorrhagic fever viruses continue to emerge in new geographical locations. In this short review we focus on newly identified viruses associated with severe haemorrhagic disease in humans in China and the US.
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... Phleboviruses differ from other bunyaviruses in that they have an ambisense S segment that encodes the nucleoprotein in the negative sense and the non-structural proteins NSs and NSm in the positive sense via an overlapping open reading frame or by encoding a protein via an open reading frame (ORF).(Hobson-Peters et al., 2016;Elliott and Brennan, 2014).Nonetheless, both proteins are translated from subgenomic mRNAs that are transcribed from the antigenomic or genomic RNA(Elliott and Brennan, 2014) Phleboviruses are taxonomically separated into dipteran-and tick-borne viruses transmitted mainly by eponymous Phlebotomus sandflies except RVFV associated Aedes and Culex mosquitoes and ticks respectively(Wuerth and Weber, 2016).Mosquitoes and ticks have been linked to the spread of some of the phleboviruses that pose a serious public health risk, such as Rift Valley fever virus (RVFV) and Uukuniemi virus (UUKV) (Hobson-Peters et al., 2016). Phleboviruses are among the new viruses that have emerged in a variety of locations around the world. . ...
... Phleboviruses differ from other bunyaviruses in that they have an ambisense S segment that encodes the nucleoprotein in the negative sense and the non-structural proteins NSs and NSm in the positive sense via an overlapping open reading frame or by encoding a protein via an open reading frame (ORF).(Hobson-Peters et al., 2016;Elliott and Brennan, 2014).Nonetheless, both proteins are translated from subgenomic mRNAs that are transcribed from the antigenomic or genomic RNA(Elliott and Brennan, 2014) Phleboviruses are taxonomically separated into dipteran-and tick-borne viruses transmitted mainly by eponymous Phlebotomus sandflies except RVFV associated Aedes and Culex mosquitoes and ticks respectively(Wuerth and Weber, 2016).Mosquitoes and ticks have been linked to the spread of some of the phleboviruses that pose a serious public health risk, such as Rift Valley fever virus (RVFV) and Uukuniemi virus (UUKV) (Hobson-Peters et al., 2016). Phleboviruses are among the new viruses that have emerged in a variety of locations around the world. . ...
... As a result of the viruses' tripartite genomes, the genome organization promotes genetic shift due to possible reassortment in the case of co-infection of two viruses in the same host, resulting in the development of a unique chimeric virus with a different virulence capacity (Alkan et al., 2013).Several phleboviruses have been found in vectors such as sand flies, ticks, and mosquitoes.However, detection in human samples is difficult due to the overall genetic complexity and diversity of clinically important strains, as well as their predominantly nondescript clinical manifestations and a lack of awareness among some clinicians and scientists(Lambert and Hughes, 2021).The advancement in viral detection and sequencing technologies has contributed greatly in the detection and classification of phleboviruses and other viruses(Hobson-Peters et al., 2016). The phlebovirus genus comprises of 11 specific species(Lambert and Hughes, 2021) and 33 tentative named species accounting for about 70 viruses and further classified into the sand fly fever virus group and the Uukuniemi-like virus group(Elliott and Brennan, 2014) ...
... Sand flies are involved in the transmission of viruses (e.g., Phleboviruses: Naples, Sicilian and Toscana viruses; [95]) bacteria (e.g., Bartonella bacilliformis; [96]), and most importantly, of protozoa of the genus Leishmania to humans and animals [97]. The latter is transmitted by sand flies of the genus Phlebotomus spp. ...
Volatile organic compounds (VOCs) are chemicals emitted as products of cell metabolism, which reflects the physiological and pathological conditions of any living organisms. These compounds play a key role as olfactory cues for arthropod vectors such as mosquitoes, sand flies, and ticks, which act in the transmission of pathogens to many animal species, including humans. Some VOCs may influence arthropod behaviour, e.g., host preference and oviposition site selection for gravid females. Furthermore, deadly vector-borne pathogens such as Plasmodium falciparum and Leishmania infantum are suggested to manipulate the VOCs profile of the host to make them more attractive to mosquitoes and sand fly vectors, respectively. Under the above circumstances, studies on these compounds have demonstrated their potential usefulness for investigating the behavioural response of mosquitoes, sand flies, and ticks toward their vertebrate hosts, as well as potential tools for diagnosis of vector-borne diseases (VBDs). Herein, we provide an account for scientific data available on VOCs to study the host seeking behaviour of arthropod vectors, and their usefulness as attractants, repellents, or tools for an early diagnosis of VBDs.
Graphical Abstract
... The past decade has seen many discoveries of new sandfly-borne viruses, some of which have been linked to disease and deaths in different countries, including Turkey, India, and the Balkan region (6)(7)(8)(9). Additionally, in recent years, novel viral species have been isolated from sandfly specimens collected all over the world (10). ...
Background
Until recently, arbovirus surveillance is mainly focused on mosquito and tick vectors, resulting in the discovery of several mosquito- and tick-borne arboviruses. However, the role of sandflies in arbovirus transmission and disease has remained largely unexplored. This study sought to isolate and characterize arboviruses from phlebotomine sandflies from selected pastoral ecozones in the North Rift region of Kenya.
Methods
Sandflies were collected from selected sites in North Rift Kenya between 2015 and 2018. They were sorted and pooled by sex, site, and collection date. The pools were homogenized and inoculated onto Vero cells for virus isolation. The positive pools were analyzed by polymerase chain reaction targeting different arboviruses. The isolates were further characterized by high-throughput sequencing using Illumina Miseq platform.
Results
Approximately 28,226 sandflies translating to 824 pools were sampled from the selected regions. A total of 11 showed reproducible cytopathic effects on Vero cells. We identified five arboviruses: sindbis ( n = 4) from Kacheliba and Baringo, Chandipura ( n = 4) from Turkana and Baringo, Koutango ( n = 1) and Ntepes ( n = 1) from Baringo, and Bogoria ( n = 1) from Kacheliba. The percent identities of the identified viruses were approximately 80% to 98% compared to known viruses in GenBank, suggesting that some of them could be novel viruses.
Conclusion
This study successfully isolated and characterized five arboviruses from sandflies. The findings suggest that sandflies are potential hosts of a wide range of arboviruses and are therefore important vectors to consider in arbovirus surveillance and evaluated for their ability to transmit them. Further studies are needed to determine the public health importance and extent of exposure of these viruses to humans and livestock populations.
... GERV is a bunyavirus of the family Peribunyaviridae and is thus related to phenuiviruses [8]. Similar to phenuiviruses and other bunyaviruses, peribunyaviruses bud and assemble in the Golgi network [39][40][41]. As expected, EBOVLP binding was not affected by soluble C6-GlcCer (Fig. 9G). ...
Hexosylceramides (HexCer) are implicated in the infection process of various pathogens. However, the molecular and cellular functions of HexCer in infectious cycles are poorly understood. Investigating the enveloped virus Uukuniemi (UUKV), a bunyavirus of the Phenuiviridae family, we performed a lipidomic analysis with mass spectrometry and determined the lipidome of both infected cells and derived virions. We found that UUKV alters the processing of HexCer to glycosphingolipids (GSL) in infected cells. The infection resulted in the overexpression of glucosylceramide (GlcCer) synthase (UGCG) and the specific accumulation of GlcCer and its subsequent incorporation into viral progeny. UUKV and several pathogenic bunyaviruses relied on GlcCer in the viral envelope for binding to various host cell types. Overall, our results indicate that GlcCer is a structural determinant of virions crucial for bunyavirus infectivity. This study also highlights the importance of glycolipids on virions in facilitating interactions with host cell receptors and infectious entry of enveloped viruses.
... Members of the genera Coguvirus, Mechlorovirus, Rubodvirus and Tenuivirus are transmitted by either arthropods or grafting, and infect plants associated with diseases of agricultural importance. Members of the genera Entovirus, Laulavirus and Lentinuvirus have been found in fungi[4][5][6]. ...
The family Phenuiviridae comprises viruses with 2–8 segments of negative-sense or ambisense RNA, comprising 8.1–25.1 kb in total. Virions are typically enveloped with spherical or pleomorphic morphology but can also be non-enveloped filaments. Phenuivirids infect animals including livestock and humans, birds, plants or fungi, as well as arthropods that serve as single hosts or act as biological vectors for transmission to animals or plants. Phenuivirids include important pathogens of humans, livestock, seafood and agricultural crops. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family Phenuiviridae , which is available at ictv.global/report/phenuiviridae .
... According to the report of the International Committee on Taxonomy of Viruses (ICTV), the genus Phlebovirus contains numerous viruses, including Rift Valley fever virus and sandfly fever Naples virus (Kuhn et al. 2020). In recent years, new viral species with genomic characteristics of phleboviruses have been isolated from sandfly specimens collected around the world (Elliott and Brennan 2014). ...
Keywords: sandfly, Phlebovirus In this study, we isolated a group of viruses that can cause a cytopathic effect in BHK-21 cells from sandfly specimens collected in Yangquan County, Shanxi Province, central China. The representative virus strain is SXYQ1860 and, with increased viral injection, the suckling mice became ill and died, with viral titers continually increasing. The results of molecular genetic evolution analysis of the three gene segments of the virus, L, M, and S, indicate that the newly isolated viruses from Yangquan County are the same as the Wuxiang virus (WUXV) previously isolated from sandflies collected in Wuxiang county, China. This is the first time that the WUXV was also isolated outside Wuxiang County. Therefore, strengthening the surveillance of neglected sandflies and the viruses they transmit to help prevent and control arboviruses and the associated diseases is essential for public health.
... Several research groups have attempted to develop vaccines and antiviral therapeutics against SFTS [7,8]; however, there are no licensed vaccines against SFTS. The viral genome of SFTSV comprises three negative-stranded RNA segments, large (L), medium (M), and small (S) [9]. The L segment encodes the RNA-dependent RNA polymerase (RdRp); the M segment encodes the envelope Gn/Gc glycoproteins; and the S segment encodes two proteins, the nonstructural protein (NS) and the nucleocapsid protein (NP) [10]. ...
Currently, there are no commercial vaccines or therapeutics against severe fever with throm-bocytopenia syndrome (SFTS) virus. This study explored an engineered Salmonella as a vaccine carrier to deliver a eukaryotic self-mRNA replicating vector, pJHL204. This vector expresses multiple SFTS virus antigenic genes for the nucleocapsid protein (NP), glycoprotein precursor (Gn/Gc), and nonstructural protein (NS) to induce host immune responses. The engineered constructs were designed and validated through 3D structure modeling. Western blot and qRT-PCR analyses of transformed HEK293T cells confirmed the delivery and expression of the vaccine antigens. Significantly , mice immunized with these constructs demonstrated a cell-mediated and humoral response as balanced Th1/Th2 immunity. The JOL2424 and JOL2425 delivering NP and Gn/Gc generated strong immunoglobulin IgG and IgM antibodies and high neutralizing titers. To further examine the immunogenicity and protection, we utilized a human DC-SIGN receptor transduced mouse model for SFTS virus infection by an adeno-associated viral vector system. Among the SFTSV antigen constructs, the construct with full-length NP and Gn/Gc and the construct with NP and selected Gn/Gc epitopes induced robust cellular and humoral immune responses. These were followed by adequate protection based on viral titer reduction and reduced histopathological lesions in the spleen and liver. In conclusion, these data indicate that recombinant attenuated Salmonella JOL2424 and JOL2425 delivering NP and Gn/Gc antigens of SFTSV are promising vaccine candidates that induce strong humoral and cellular immune responses and protection against SFTSV. Moreover, the data proved that the hDC-SIGN transduced mice as a worthy tool for immunogenicity study for SFTSV.
The presence of viruses that spread to both plant and fungal populations in nature has posed intriguingly scientific question. We found a negative-strand RNA virus related to members of the family Phenuiviridae , named Valsa mali negative-strand RNA virus 1 (VmNSRV1), which induced strong hypovirulence and was prevalent in a population of the phytopathogenic fungus of apple Valsa canker ( Valsa mali ) infecting apple orchards in the Shaanxi Province of China. Intriguingly, VmNSRV1 encodes a protein with a viral cell-to-cell movement function in plant tissue. Mechanical leaf inoculation showed that VmNSRV1 could systemically infect plants. Moreover, VmNSRV1 was detected in 24 out of 139 apple trees tested in orchards in Shaanxi Province. Fungal inoculation experiments showed that VmNSRV1 could be bidirectionally transmitted between apple plants and V. mali, and VmNSRV1 infection in plants reduced the development of fungal lesions on leaves. Additionally, the nucleocapsid protein encoded by VmNSRV1 is associated with and rearranged lipid droplets in both fungal and plant cells. VmNSRV1 represents a virus that has adapted and spread to both plant and fungal hosts and shuttles between these two organisms in nature (phyto-mycovirus) and is potential to be utilized for the biocontrol method against plant fungal diseases. This finding presents further insights into the virus evolution and adaptation encompassing both plant and fungal hosts.
A new phlebovirus variant was isolated from an acute febrile patient in Chanchamayo, Peru. Genome characterization and p-distance analyses based on complete open reading frames revealed that the virus is probably a natural reassortant of the Echarate virus (large and small segments) with a yet-unidentified phlebovirus (M segment).
A newly discovered tick-borne virus called the severe fever with thrombocytopenia syndrome virus (SFTSV) can cause the severe fever with thrombocytopenia syndrome (SFTS). The mortality and incidence rate of SFTS patients remain extremely high due to the fast global dissemination of its arthropod vectors, and the mechanism of viral pathogenesis remains largely unknown. In this study, high-throughput RNA sequencing (RNA-Seq) was used to sequence HEK 293 cells treated with SFTSV at four time points. 115, 191, 259, and 660 differentially expressed genes (DEGs) were identified at 6, 12, 24, and 48 h post-infection, respectively. We found that SFTSV infection induced the expression of genes responsible for numerous cytokine-related pathways, including TNF, CXCL1, CXCL2, CXCL3, CXCL8, CXCL10, and CCL20. With the extension of infection time, the expression of most genes involved in these pathways increased significantly, indicating the host's inflammatory response to SFTSV. Moreover, the expression levels of GNA13, ARHGEF12, RHOA, ROCK1, and MYL12A, elements of the platelet activation signaling pathway, were downregulated during SFTSV infection, suggesting that the SFTSV infection may cause thrombocytopenia by inhibiting platelet activation. Our results contribute to further understanding the interaction between SFTSV and the host.
The discovery of an emerging viral disease, severe fever with thrombocytopenia syndrome (SFTS), caused by SFTS virus (SFTSV), has prompted the need to understand pathogenesis of SFTSV. We are unique in establishing an infectious model of SFTS in C57/BL6 mice, resulting in hallmark symptoms of thrombocytopenia and leukocytopenia. Viral RNA and histopathological changes were identified in the spleen, liver, and kidney. However, viral replication was only found in the spleen, which suggested the spleen to be the principle target organ of SFTSV. Moreover, the number of macrophages and platelets were largely increased in the spleen, and SFTSV colocalized with platelets in cytoplasm of macrophages in the red pulp of the spleen. In vitro cellular assays further revealed that SFTSV adhered to mouse platelets and facilitated the phagocytosis of platelets by mouse primary macrophages, which in combination with in vivo findings, suggests that SFTSV-induced thrombocytopenia is caused by clearance of circulating virus-bound platelets by splenic macrophages. Thus, this study has elucidated the pathogenic mechanisms of thrombocytopenia in a mouse model resembling human SFTS disease.
Background. Severe fever with thrombocytopenia syndrome (SFTS) is caused by SFTS virus (SFTSV), a novel bunyavirus reported to be endemic in central and northeastern China. This article describes the first identified patient with SFTS and a retrospective study on SFTS in Japan.Methods. Virologic and pathologic examinations were performed on the patient's samples. Laboratory diagnosis of SFTS was made by isolation/genome amplification and/or the detection of anti-SFTSV immunoglobulin G antibody in sera. Physicians were alerted to the initial diagnosis and asked whether they had previously treated patients with symptoms similar to those of SFTS.Results. A female patient who died in 2012 received a diagnosis of SFTS. Ten additional patients with SFTS were then retrospectively identified. All patients were aged ≥50 years and lived in western Japan. Six cases were fatal. The ratio of males to females was 8:3. SFTSV was isolated from 8 patients. Phylogenetic analyses indicated that all of the Japanese SFTSV isolates formed a genotype independent to those from China. Most patients showed symptoms due to hemorrhage, possibly because of disseminated intravascular coagulation and/or hemophagocytosis.Conclusions. SFTS has been endemic to Japan, and SFTSV has been circulating naturally within the country. © 2013 The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: [email protected]
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We report a retrospectively identified fatal case of severe fever with thrombocytopenia syndrome (SFTS) in South Korea from 2012. SFTS virus was isolated from the stored blood of the patient. Phylogenetic analysis revealed this isolate was closely related to SFTS virus strains from China and Japan.
Heartland virus (HRTV), the first pathogenic Phlebovirus (Family: Bunyaviridae) discovered in the United States, was recently described from two Missouri farmers. In 2012, we collected 56,428 ticks representing three species at 12 sites including both patients' farms. Amblyomma americanum and Dermacentor variabilis accounted for nearly all ticks collected. Ten pools composed of deplete nymphs of A. americanum collected at a patient farm and a nearby conservation area were reverse transcription-polymerase chain reaction positive, and eight pools yielded viable viruses. Sequence data from the nonstructural protein of the Small segment indicates that tick strains and human strains are very similar, ≥ 97.6% sequence identity. This is the first study to isolate HRTV from field-collected arthropods and to implicate ticks as potential vectors. Amblyomma americanum likely becomes infected by feeding on viremic hosts during the larval stage, and transmission to humans occurs during the spring and early summer when nymphs are abundant and actively host seeking.
