Heartland Virus-Associated Death in Tennessee

Muehlenbachs, Atis; Fata, Cynthia R.; Lambert, Amy J.; Paddock, Christopher D.; Velez, Jason O.; Blau, Dianna M.; Staples, J. Erin; Karlekar, Mohana; Bhatnagar, Julu; Nasci, Roger S.; Zaki, Sherif R.

doi:10.1093/cid/ciu434

Cited by 83 publications

(102 citation statements)

References 17 publications

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“…SFTSV and related viruses have also been isolated in ticks collected in Korea and Australia Yun et al, 2014). Furthermore, Heartland virus, another tick-borne phlebovirus sharing 60-73 % amino acid sequence homology with SFTSV, has been shown to be aetiologically associated with a severe fever with thrombocytopenia syndrome-like severe disease in the USA (McMullan et al, 2012;Muehlenbachs et al, 2014). Thus, SFTSV and closely related human pathogens are distributed widely.…”

mentioning

confidence: 99%

Suppression of type I and type III IFN signalling by NSs protein of severe fever with thrombocytopenia syndrome virus through inhibition of STAT1 phosphorylation and activation

Chaudhary

Zhang

Yuen

et al. 2015

Journal of General Virology

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Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne pathogen causing significant morbidity and mortality in Asia. NSs protein of SFTSV is known to perturb type I IFN induction and signalling, but the mechanism remains to be fully understood. Here, we showed the suppression of both type I and type III IFN signalling by SFTSV NSs protein is mediated through inhibition of STAT1 phosphorylation and activation. Infection with live SFTSV or expression of NSs potently suppressed IFN-stimulated genes but not NFkB activation. NSs was capable of counteracting the activity of IFN-a1, IFN-b, IFN-l1 and IFN-l2. Mechanistically, NSs associated with STAT1 and STAT2, mitigated IFN-b-induced phosphorylation of STAT1 at S727, and reduced the expression and activity of STAT1 protein in IFN-b-treated cells, resulting in the inhibition of STAT1 and STAT2 recruitment to IFNstimulated promoters. Taken together, SFTSV NSs protein is an IFN antagonist that suppresses phosphorylation and activation of STAT1.

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mentioning

confidence: 99%

Suppression of type I and type III IFN signalling by NSs protein of severe fever with thrombocytopenia syndrome virus through inhibition of STAT1 phosphorylation and activation

Chaudhary

Zhang

Yuen

et al. 2015

Journal of General Virology

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“…Although human cases caused by SFTS virus have only been reported in Asia, the recent emergence of another tick-borne phlebovirus, Heartland virus, a close relative of SFTS virus, responsible for serious and fatal cases in the United States (3,42), and the recognition of another tick-borne phlebovirus with zoonotic potential in Australia (43), named Hunter samples were collected at each step of the purification process for evaluation by plaque assay. The sample resulting from the immune-selection step using anti-CD63 beads is depicted in the figure as the CD63 selected, whereas those resulting from the subsequent immune-(negative) selection step are shown as the CD63/SFTSV selected.…”

Section: Discussionmentioning

confidence: 99%

“…Due to advances in genomic and virus identification approaches, novel bunyaviruses have been discovered and identified as important causes of human disease during recent years (1)(2)(3). One example is severe fever with thrombocytopenia syndrome (SFTS) virus, a new member of the family Bunyaviridae, genus Phlebovirus (1,4).…”

mentioning

confidence: 99%

Extracellular Vesicles Mediate Receptor-Independent Transmission of Novel Tick-Borne Bunyavirus

Silvas

Popov

Paulucci-Holthauzen

et al. 2016

J Virol

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Severe fever with thrombocytopenia syndrome (SFTS) virus is a newly recognized member of the genus Phlebovirus in the family Bunyaviridae. The virus was isolated from patients presenting with hemorrhagic manifestations and an initial case fatality rate of 12 to 30% was reported. Due to the recent emergence of this pathogen, there is limited knowledge on the molecular virology of SFTS virus. Recently, we reported that the SFTS virus NSs protein inhibited the activation of the beta interferon (IFN-␤) promoter. Furthermore, we also found that SFTS virus NSs relocalizes key components of the IFN response into NSs-induced cytoplasmic structures. Due to the important role these structures play during SFTS virus replication, we conducted live cell imaging studies to gain further insight into the role and trafficking of these cytoplasmic structures during virus infection. We found that some of the SFTS virus NSs-positive cytoplasmic structures were secreted to the extracellular space and endocytosed by neighboring cells. We also found that these secreted structures isolated from NSs-expressing cells and SFTS virus-infected cells were positive for the viral protein NSs and the host protein CD63, a protein associated with extracellular vesicles. Electron microscopy studies also revealed that the isolated CD63-immunoprecipitated extracellular vesicles produced during SFTS virus infection contained virions. The virions harbored within these structures were efficiently delivered to uninfected cells and were able to sustain SFTS virus replication. Altogether, these results suggest that SFTS virus exploits extracellular vesicles to mediate virus receptor-independent transmission to host cells and open the avenue for novel therapeutic strategies against SFTS virus and related pathogens. IMPORTANCESFTS virus is novel bunyavirus associated with hemorrhagic fever illness. Currently, limited information is available about SFTS virus. In the present study, we demonstrated that extracellular vesicles produced by SFTS virus-infected cells harbor infectious virions. We sought to determine whether these "infectious" extracellular vesicles can mediate transmission of the virus and confirmed that the SFTS virions were efficiently transported by these secreted structures into uninfected cells and were able to sustain efficient replication of SFTS virus. These results have significant impact on our understanding of how the novel tick-borne phleboviruses hijack cellular machineries to establish infection and point toward a novel mechanism for virus replication among arthropod-borne viruses. The Bunyaviridae family comprises five genera, including Orthobunyavirus, Phlebovirus, Nairovirus, Hantavirus, and Tospovirus. The majority of viruses within this family (with the exception of Hantaviruses) are considered arthropod-borne viruses and are important causes of morbidity and mortality around the world. These viruses are associated with a range of clinical symptoms characterized by febrile illness and in the most severe cases fatal hepa...

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“…El paciente falleció en el hospital 15 días después y muestras provenientes de la autopsia fueron probadas para diversos agentes patógenos como parte de una evaluación de una muerte inexplicable. Se detectaron antígenos HRTV post mortem en el bazo y los ganglios linfáticos por inmunohistoquímica y HRTV se detectó en la sangre pre mortem por RT-PCR y el virus se aisló en cultivo celular (6).…”

Section: O S T P a T I E N T S W I T H H Rtunclassified