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11 pages, 1287 KiB

Open AccessArticle

Analysis of Powassan Virus Genome Sequences from Human Cases Reveals Substantial Genetic Diversity with Implications for Molecular Assay Development

by Erik H. Klontz, Navid Chowdhury, Nolan Holbrook, Isaac H. Solomon, Sam R. Telford 3rd, Matthew T. Aliota, Chantal B. F. Vogels, Nathan D. Grubaugh, Jeffrey Helgager, Holly R. Hughes, Jason Velez, Anne Piantadosi, Charles Y. Chiu, Jacob Lemieux and John A. Branda

Viruses 2024, 16(11), 1653; https://doi.org/10.3390/v16111653 - 23 Oct 2024

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Abstract

Powassan virus (POWV) is an emerging tick-borne virus that causes severe meningoencephalitis in the United States, Canada, and Russia. Serology is generally the preferred diagnostic modality, but PCR on cerebrospinal fluid, blood, or urine has an important role, particularly in immunocompromised patients who [...] Read more.

Powassan virus (POWV) is an emerging tick-borne virus that causes severe meningoencephalitis in the United States, Canada, and Russia. Serology is generally the preferred diagnostic modality, but PCR on cerebrospinal fluid, blood, or urine has an important role, particularly in immunocompromised patients who are unable to mount a serologic response. Although the perceived poor sensitivity of PCR in the general population may be due to the biology of infection and health-seeking behavior (with short viremic periods that end before hospital presentation), limitations in assay design may also contribute. Genome sequences from clinical POWV cases are extremely scarce; PCR assay design has been informed by those available, but the numbers are limited. Larger numbers of genome sequences from tick-derived POWV are available, but it is not known if POWV genomes from human infections broadly mirror genomes from tick hosts, or if human infections are caused by a subset of more virulent strains. We obtained viral genomic data from 10 previously unpublished POWV human infections and showed that they broadly mirror the diversity of genome sequences seen in ticks, including all three major clades (lineage I, lineage II Northeast, and lineage II Midwest). These newly published clinical POWV genome sequences include the first confirmed lineage I infection in the United States, highlighting the relevance of all clades in human disease. An in silico analysis of published POWV PCR assays shows that many assays were optimized against a single clade and have mismatches that may affect their sensitivity when applied across clades. This analysis serves as a launching point for improved PCR design for clinical diagnostics and environmental surveillance. Full article

(This article belongs to the Special Issue Tick-Borne Viruses: Transmission and Surveillance)

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9 pages, 397 KiB

Open AccessArticle

Clinical Evaluation of the VirClia IgM/IgG Chemiluminescence Tests for the Diagnosis of Tick-Borne Encephalitis in an Endemic Part of Norway

by Åshild Marvik and Susanne Gjeruldsen Dudman

Viruses 2024, 16(9), 1505; https://doi.org/10.3390/v16091505 - 23 Sep 2024

Viewed by 802

Abstract

The aim of this study was to evaluate the clinical usefulness of VirClia IgM/IgG single-assay chemiluminescence tests for the diagnosis of tick-borne encephalitis (TBE) in an endemic part of Norway. Patients hospitalized at Vestfold or Telemark Hospitals with suspected infection in the central [...] Read more.

The aim of this study was to evaluate the clinical usefulness of VirClia IgM/IgG single-assay chemiluminescence tests for the diagnosis of tick-borne encephalitis (TBE) in an endemic part of Norway. Patients hospitalized at Vestfold or Telemark Hospitals with suspected infection in the central nervous system (CNS) in the period between May 2021 and December 2023 were included, with 85 TBE cases identified. The VirClia IgM assay was positive in the initial serum sample in 75/85 cases, giving a sensitivity of 88.2% (95% CI, 79.4–94.2). The ReaScan TBE IgM rapid test was positive in 80/85 cases, with an estimated sensitivity of 94.1% (95% CI, 86.8–98.1). Vaccine breakthrough infections were the predominant cause of non-reactive IgM cases. The calculated specificity for the VirClia IgM was 95.8% (95% CI, 92.5–98.0). In conclusion, the sensitivity of the VirClia IgM was non-inferior to the ReaScan TBE IgM rapid test. However, isolated IgM reactive results must be interpreted with caution, since false-reactive results occur. Full article

(This article belongs to the Special Issue Tick-Borne Viruses: Transmission and Surveillance)

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10 pages, 795 KiB

Open AccessArticle

First Broad-Range Serological Survey of Crimean–Congo Hemorrhagic Fever among Hungarian Livestock

by Nóra Deézsi-Magyar, Béla Dénes, Bereniké Novák, Gyula Zsidei, Dániel Déri, Judit Henczkó, Bernadett Pályi and Zoltán Kis

Viruses 2024, 16(6), 875; https://doi.org/10.3390/v16060875 - 29 May 2024

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Abstract

(1) Background: Crimean–Congo hemorrhagic fever (CCHF) is an emerging tick-borne disease endemic in Africa, Asia, the Middle East, and the Balkan and Mediterranean regions of Europe. Although no human CCHF cases have been reported, based on vector presence, serological evidence among small vertebrates, [...] Read more.

(1) Background: Crimean–Congo hemorrhagic fever (CCHF) is an emerging tick-borne disease endemic in Africa, Asia, the Middle East, and the Balkan and Mediterranean regions of Europe. Although no human CCHF cases have been reported, based on vector presence, serological evidence among small vertebrates, and the general human population, Hungary lies within high evidence consensus for potential CCHF introduction and future human infection. Thus, the aim of our pilot serosurvey was to assess CCHF seropositivity among cattle and sheep as indicator animals for virus circulation in the country. (2) Methods: In total, 1905 serum samples taken from free-range cattle and sheep in 2017 were tested for the presence of anti-CCHF virus IgG antibodies using commercial ELISA and commercial and in-house immunofluorescent assays. (3) Results: We found a total of eleven reactive samples (0.58%) from five administrative districts of Hungary comprising 8 cattle and 3 sheep. The most affected regions were the south–central and northwestern parts of the country. (4) Conclusions: Based on these results, more extended surveillance is advised, especially in the affected areas, and there should be greater awareness among clinicians and other high-risk populations of the emerging threat of CCHF in Hungary and Central Europe. Full article

(This article belongs to the Special Issue Tick-Borne Viruses: Transmission and Surveillance)

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18 pages, 2507 KiB

Open AccessArticle

Clinical Factors Associated with SFTS Diagnosis and Severity in Cats

by Hiromu Osako, Qiang Xu, Takeshi Nabeshima, Jean Claude Balingit, Khine Mya Nwe, Fuxun Yu, Shingo Inoue, Daisuke Hayasaka, Mya Myat Ngwe Tun, Kouichi Morita and Yuki Takamatsu

Viruses 2024, 16(6), 874; https://doi.org/10.3390/v16060874 - 29 May 2024

Cited by 1 | Viewed by 1369

Abstract

Severe fever with thrombocytopenia syndrome (SFTS) is a potentially fatal tick-borne zoonosis caused by SFTS virus (SFTSV). In addition to tick bites, animal-to-human transmission of SFTSV has been reported, but little is known about feline SFTSV infection. In this study, we analyzed data [...] Read more.

Severe fever with thrombocytopenia syndrome (SFTS) is a potentially fatal tick-borne zoonosis caused by SFTS virus (SFTSV). In addition to tick bites, animal-to-human transmission of SFTSV has been reported, but little is known about feline SFTSV infection. In this study, we analyzed data on 187 cats with suspected SFTS to identify biomarkers for SFTS diagnosis and clinical outcome. Body weight, red and white blood cell and platelet counts, and serum aspartate aminotransferase and total bilirubin levels were useful for SFTS diagnosis, whereas alanine aminotransferase, aspartate aminotransferase and serum SFTSV RNA levels were associated with clinical outcome. We developed a scoring model to predict SFTSV infection. In addition, we performed a phylogenetic analysis to reveal the relationship between disease severity and viral strain. This study provides comprehensive information on feline SFTS and could contribute to the protection of cat owners, community members, and veterinarians from the risk of cat-transmitted SFTSV infection. Full article

(This article belongs to the Special Issue Tick-Borne Viruses: Transmission and Surveillance)

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12 pages, 2259 KiB

Open AccessArticle

Strain-Dependent Assessment of Powassan Virus Transmission to Ixodes scapularis Ticks

by Rebekah J. McMinn, Emily N. Gallichotte, Samantha Courtney, Sam R. Telford and Gregory D. Ebel

Viruses 2024, 16(6), 830; https://doi.org/10.3390/v16060830 - 23 May 2024

Viewed by 1163

Abstract

Powassan virus (POWV) is an emerging tick-borne encephalitic virus in Lyme disease-endemic sites in North America. Due to range expansion and local intensification of blacklegged tick vector (Ixodes scapularis) populations in the northeastern and upper midwestern U.S., human encephalitis cases are [...] Read more.

Powassan virus (POWV) is an emerging tick-borne encephalitic virus in Lyme disease-endemic sites in North America. Due to range expansion and local intensification of blacklegged tick vector (Ixodes scapularis) populations in the northeastern and upper midwestern U.S., human encephalitis cases are increasingly being reported. A better understanding of the transmission cycle between POWV and ticks is required in order to better predict and understand their public health burden. Recent phylogeographic analyses of POWV have identified geographical structuring, with well-defined northeastern and midwestern clades of the lineage II subtype. The extent that geographic and genetically defined sublineages differ in their ability to infect and be transmitted by blacklegged ticks is unclear. Accordingly, we determined whether there are strain-dependent differences in the transmission of POWV to ticks at multiple life stages. Five recent, low-passage POWV isolates were used to measure aspects of vector competence, using viremic and artificial infection methods. Infection rates in experimental ticks remained consistent between all five isolates tested, resulting in a 12–20% infection rate and some differences in viral load. We confirm that these differences are likely not due to differences in host viremia. Our results demonstrate that blacklegged ticks are susceptible to, and capable of transmitting, all tested strains and suggest that the tick–virus association is stable across diverse viral genotypes. Full article

(This article belongs to the Special Issue Tick-Borne Viruses: Transmission and Surveillance)

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19 pages, 7467 KiB

Open AccessArticle

Comparative Pathogenesis of Two Lineages of Powassan Virus Reveals Distinct Clinical Outcome, Neuropathology, and Inflammation

by Erin S. Reynolds, Charles E. Hart, Jacob T. Nelson, Brandon J. Marzullo, Allen T. Esterly, Dakota N. Paine, Jessica Crooker, Paul T. Massa and Saravanan Thangamani

Viruses 2024, 16(6), 820; https://doi.org/10.3390/v16060820 - 22 May 2024

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Abstract

Tick-borne flaviviruses (TBFV) can cause severe neuroinvasive disease which may result in death or long-term neurological deficit in over 50% of survivors. Multiple mechanisms for invasion of the central nervous system (CNS) by flaviviruses have been proposed including axonal transport, transcytosis, endothelial infection, [...] Read more.

Tick-borne flaviviruses (TBFV) can cause severe neuroinvasive disease which may result in death or long-term neurological deficit in over 50% of survivors. Multiple mechanisms for invasion of the central nervous system (CNS) by flaviviruses have been proposed including axonal transport, transcytosis, endothelial infection, and Trojan horse routes. Flaviviruses may utilize different or multiple mechanisms of neuroinvasion depending on the specific virus, infection site, and host variability. In this work we have shown that the infection of BALB/cJ mice with either Powassan virus lineage I (Powassan virus) or lineage II (deer tick virus) results in distinct spatial tropism of infection in the CNS which correlates with unique clinical presentations for each lineage. Comparative transcriptomics of infected brains demonstrates the activation of different immune pathways and downstream host responses. Ultimately, the comparative pathology and transcriptomics are congruent with different clinical signs in a murine model. These results suggest that the different disease presentations occur in clinical cases due to the inherent differences in the two lineages of Powassan virus. Full article

(This article belongs to the Special Issue Tick-Borne Viruses: Transmission and Surveillance)

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14 pages, 1716 KiB

Open AccessArticle

The Prevalence of Tick-Borne Encephalitis Virus in Wild Rodents Captured in Tick-Borne Encephalitis Foci in Highly Endemic Lithuania

by Evelina Simkute, Arnoldas Pautienius, Juozas Grigas, Marina Sidorenko, Jana Radzijevskaja, Algimantas Paulauskas and Arunas Stankevicius

Viruses 2024, 16(3), 444; https://doi.org/10.3390/v16030444 - 13 Mar 2024

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Abstract

Wild rodents are considered to be one of the most important TBEV-amplifying reservoir hosts; therefore, they may be suitable for foci detection studies. To investigate the effectiveness of viral RNA detection in wild rodents for suspected TBEV foci confirmation, we trapped small rodents [...] Read more.

Wild rodents are considered to be one of the most important TBEV-amplifying reservoir hosts; therefore, they may be suitable for foci detection studies. To investigate the effectiveness of viral RNA detection in wild rodents for suspected TBEV foci confirmation, we trapped small rodents (n = 139) in various locations in Lithuania where TBEV was previously detected in questing ticks. Murine neuroblastoma Neuro-2a cells were inoculated with each rodent sample to maximize the chances of detecting viral RNA in rodent samples. TBEV RNA was detected in 74.8% (CI 95% 66.7–81.1) of the brain and/or internal organ mix suspensions, and the prevalence rate increased significantly following sample cultivation in Neuro-2a cells. Moreover, a strong correlation (r = 0.88; p < 0.05) was found between the average monthly air temperature of rodent trapping and the TBEV RNA prevalence rate in cell culture isolates of rodent suspensions, which were PCR-negative before cultivation in cell culture. This study shows that wild rodents are suitable sentinel animals to confirm TBEV foci. In addition, the study results demonstrate that sample cultivation in cell culture is a highly efficient method for increasing TBEV viral load to detectable quantities. Full article

(This article belongs to the Special Issue Tick-Borne Viruses: Transmission and Surveillance)

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15 pages, 4972 KiB

Open AccessArticle

Difference in Intraspecies Transmissibility of Severe Fever with Thrombocytopenia Syndrome Virus Depending on Abrogating Type 1 Interferon Signaling in Mice

by Byungkwan Oh, Seok-Chan Park, Myeon-Sik Yang, Daram Yang, Gaeul Ham, Dongseob Tark, Myung Jo You, Sang-Ik Oh and Bumseok Kim

Viruses 2024, 16(3), 401; https://doi.org/10.3390/v16030401 - 5 Mar 2024

Viewed by 1651

Abstract

Severe fever with thrombocytopenia syndrome (SFTS), a tick-borne zoonotic disease, is caused by infection with SFTS virus (SFTSV). A previous study reported that human-to-human direct transmission of SFTSV can occur. However, potential animal-to-animal transmission of SFTSV without ticks has not been fully clarified. [...] Read more.

Severe fever with thrombocytopenia syndrome (SFTS), a tick-borne zoonotic disease, is caused by infection with SFTS virus (SFTSV). A previous study reported that human-to-human direct transmission of SFTSV can occur. However, potential animal-to-animal transmission of SFTSV without ticks has not been fully clarified. Thus, the objective of this study was to investigate potential mice-to-mice transmission of SFTSV by co-housing three groups of mice [i.e., wild-type mice (WT), mice injected with an anti-type I interferon-α receptor-blocking antibody (IFNAR Ab), and mice with knockout of type I interferon-α receptor (IFNAR KO)] as spreaders or recipients with different immune competence. As a result, co-housed IFNAR Ab and IFNAR KO mice showed body weight loss with SFTS viral antigens detected in their sera, extracorporeal secretions, and various organs. Based on histopathology, white pulp atrophy in the spleen was observed in all co-housed mice except WT mice. These results obviously show that IFNAR Ab and IFNAR KO mice, as spreaders, exhibited higher transmissibility to co-housed mice than WT mice. Moreover, IFNAR KO mice, as recipients, were more susceptible to SFTSV infection than WT mice. These findings suggest that type I interferon signaling is a pivotal factor in mice intraspecies transmissibility of SFTSV in the absence of vectors such as ticks. Full article

(This article belongs to the Special Issue Tick-Borne Viruses: Transmission and Surveillance)

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18 pages, 2652 KiB

Open AccessArticle

Multiplex Serology for Sensitive and Specific Flavivirus IgG Detection: Addition of Envelope Protein Domain III to NS1 Increases Sensitivity for Tick-Borne Encephalitis Virus IgG Detection

by Coralie Valle, Sandhya Shrestha, Gert-Jan Godeke, Marieke N. Hoogerwerf, Johan Reimerink, Dirk Eggink and Chantal Reusken

Viruses 2024, 16(2), 286; https://doi.org/10.3390/v16020286 - 13 Feb 2024

Viewed by 2113

Abstract

Tick-borne encephalitis is a vaccine-preventable disease of concern for public health in large parts of Europe, with EU notification rates increasing since 2018. It is caused by the orthoflavivirus tick-borne encephalitis virus (TBEV) and a diagnosis of infection is mainly based on serology [...] Read more.

Tick-borne encephalitis is a vaccine-preventable disease of concern for public health in large parts of Europe, with EU notification rates increasing since 2018. It is caused by the orthoflavivirus tick-borne encephalitis virus (TBEV) and a diagnosis of infection is mainly based on serology due to its short viremic phase, often before symptom onset. The interpretation of TBEV serology is hampered by a history of orthoflavivirus vaccination and by previous infections with related orthoflaviviruses. Here, we sought to improve TBEV sero-diagnostics using an antigen combination of in-house expressed NS1 and EDIII in a multiplex, low-specimen-volume set-up for the detection of immune responses to TBEV and other clinically important orthoflaviviruses (i.e., West Nile virus, dengue virus, Japanese encephalitis virus, Usutu virus and Zika virus). We show that the combined use of NS1 and EDIII results in both a specific and sensitive test for the detection of TBEV IgG for patient diagnostics, vaccination responses and in seroprevalence studies. This novel approach potentially allows for a low volume-based, simultaneous analysis of IgG responses to a range of orthoflaviviruses with overlapping geographic circulations and clinical manifestations. Full article

(This article belongs to the Special Issue Tick-Borne Viruses: Transmission and Surveillance)

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9 pages, 632 KiB

Open AccessArticle

Active Surveillance of Powassan Virus in Massachusetts Ixodes scapularis Ticks, Comparing Detection Using a New Triplex Real-Time PCR Assay with a Luminex Vector-Borne Panel

by Guang Xu, Eric Siegel, Nolan Fernandez, Emily Bechtold, Timothy Daly, Alan P. Dupuis II, Alexander Ciota and Stephen M. Rich

Viruses 2024, 16(2), 250; https://doi.org/10.3390/v16020250 - 4 Feb 2024

Cited by 1 | Viewed by 3749

Abstract

Powassan virus is an emerging tick-borne pathogen capable of causing severe neuroinvasive disease. As the incidence of human Powassan virus grows both in magnitude and geographical range, the development of sensitive detection methods for diagnostics and surveillance is critical. In this study, a [...] Read more.

Powassan virus is an emerging tick-borne pathogen capable of causing severe neuroinvasive disease. As the incidence of human Powassan virus grows both in magnitude and geographical range, the development of sensitive detection methods for diagnostics and surveillance is critical. In this study, a Taqman-based triplex real-time PCR assay was developed for the simultaneous and quantitative detection of Powassan virus and Powassan virus lineage II (deer tick virus) in Ixodes scapularis ticks. An exon–exon junction internal control was built-in to allow for accurate detection of RNA quality and the failure of RNA extraction. The newly developed assay was also applied to survey deer tick virus in tick populations at 13 sites on Cape Cod and Martha’s Vineyard Island in Massachusetts. The assay’s performance was compared with the Luminex xMAP MultiFLEX Vector-borne Panel 2. The results suggested that the real-time PCR method was more sensitive. Powassan virus infection rates among ticks collected from these highly endemic tick areas ranged from 0.0 to 10.4%, highlighting the fine-scale geographic variations in deer tick virus presence in this region. Looking forward, our PCR assay could be adopted in other Powassan virus surveillance systems. Full article

(This article belongs to the Special Issue Tick-Borne Viruses: Transmission and Surveillance)

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7 pages, 497 KiB

Open AccessBrief Report

Direct Evidence of Powassan Virus Vertical Transmission in Ixodes scapularis in Nature

by Rachel E. Lange, Melissa A. Prusinski, Alan P. Dupuis II and Alexander T. Ciota

Viruses 2024, 16(3), 456; https://doi.org/10.3390/v16030456 - 16 Mar 2024

Cited by 2 | Viewed by 1643

Abstract

Powassan virus (POWV) is a tick-borne flavivirus endemic in North America and Russia. Experimental infections with POWV have confirmed horizontal, transstadial, vertical, and cofeeding transmission routes for potential virus maintenance. In the field, vertical transmission has never been observed. During New York State [...] Read more.

Powassan virus (POWV) is a tick-borne flavivirus endemic in North America and Russia. Experimental infections with POWV have confirmed horizontal, transstadial, vertical, and cofeeding transmission routes for potential virus maintenance. In the field, vertical transmission has never been observed. During New York State tick-borne pathogen surveillance, POWV RNA and/or infectious POWV was detected in five pools of questing Ixodes scapularis larvae. Additionally, engorged female I. scapularis adults were collected from hunter-harvested white-tailed deer (Odocoileus virginianus) in a region with relatively high tick infection rates of POWV and allowed to oviposit under laboratory conditions. POWV RNA was detected in three female adult husks and one pool of larvae from a positive female. Infectious virus was isolated from all three RNA-positive females and the single positive larval pool. The detection of RNA and infectious virus in unfed questing larvae from the field and larvae from replete females collected from the primary tick host implicates vertical transmission as a potential mechanism for the maintenance of POWV in I. scapularis in nature, and elucidates the potential epidemiological significance of larval ticks in the transmission of POWV to humans. Full article

(This article belongs to the Special Issue Tick-Borne Viruses: Transmission and Surveillance)

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