Molecular Insights into Crimean-Congo Hemorrhagic Fever Virus

Zivcec, Marko; Scholte, Florine E. M.; Spiropoulou, Christina F.; Spengler, Jessica R.; Bergeron, Éric

doi:10.3390/v8040106

Cited by 99 publications

(112 citation statements)

References 124 publications

(211 reference statements)

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“…Previous reviews have focused on epidemiology, molecular characterization, seroepidemiological studies, and the role of wild and domestic vertebrate animals in CCHFV maintenance and amplification of the infection (Bente et al, 2013; Spengler et al, 2016a, b; Zivcec et al, 2016). …”

Section: Scope Of This Reviewmentioning

confidence: 99%

The role of ticks in the maintenance and transmission of Crimean-Congo hemorrhagic fever virus: A review of published field and laboratory studies

et al. 2017

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This manuscript is part of a series of reviews that aim to cover published research on Crimean-Congo hemorrhagic fever (CCHF) and its etiological agent, CCHF virus (CCHFV). The virus is maintained and transmitted in a vertical and horizontal transmission cycle involving a variety of wild and domestic vertebrate species that act as amplification hosts, without showing signs of illness. These vertebrates have traditionally been considered reservoirs of CCHFV, but in fact they develop only a transient viremia, while the virus can persist in ticks for their entire lifespan, and can also be transmitted vertically to the next generation. As a result, ticks are now considered to be both the vector and the reservoir for the virus. CCHFV has been detected in a wide range of tick species, but only a few have been proven to be vectors and reservoirs, mainly because most published studies have been performed under a broad variety of conditions, precluding definitive characterization. This article reviews the published literature, summarizes current knowledge of the role of ticks in CCHFV maintenance and transmission and provides guidance for how to fill the knowledge gaps. Special focus is given to existing data on tick species in which vertical passage has been demonstrated under natural or experimental conditions. At the same time, we identify earlier reports that used unreliable methods and perceptions to ascribe a vector role to some species of ticks, and have contributed to confusion regarding viral transmission. We also examine epidemiological pathways of CCHFV circulation and discuss priority areas for future research.

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Section: Scope Of This Reviewmentioning

confidence: 99%

The role of ticks in the maintenance and transmission of Crimean-Congo hemorrhagic fever virus: A review of published field and laboratory studies

et al. 2017

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“…Additional articles in this series will review the role of ticks in the maintenance of CCHFV and its transmission to vertebrates including humans, and the attempts to replicate important features of CCHF through experimental infection of laboratory animals. Readers are also referred to a general review of the epidemiology, viral genetic diversity, and other features of CCHF; a review of the public health implications of CCHF; and a recent review of experimental molecular studies of the virus (3–5). …”

Section: Scope Of This Reviewmentioning

confidence: 99%

A chronological review of experimental infection studies of the role of wild animals and livestock in the maintenance and transmission of Crimean-Congo hemorrhagic fever virus

Spengler¹,

et al. 2016

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This article provides a definitive review of experimental studies of the role of wild animals and livestock in the maintenance and transmission of Crimean-Congo hemorrhagic fever virus (CCHFV), the etiologic agent of Crimean-Congo hemorrhagic fever (CCHF), beginning with the first recognized outbreak of the human disease in Crimea in 1944. Published reports by researchers in the former Soviet Union, Bulgaria, South Africa, and other countries where CCHF has been observed show that CCHFV is maintained in nature in a tick-vertebrate-tick enzootic cycle. Human disease most commonly results from the bite of an infected tick, but may also follow crushing of infected ticks or exposure to the blood and tissues of infected animals during slaughter. Wild and domestic animals are susceptible to infection with CCHFV, but do not develop clinical illness. Vertebrates are important in CCHF epidemiology, as they provide blood meals to support tick populations, transport ticks across wide geographic areas, and transmit CCHFV to ticks and humans during the period of viremia. Many aspects of vertebrate involvement in the maintenance and spread of CCHFV are still poorly understood. Experimental investigations in wild animals and livestock provide important data to aid our understanding of CCHFV ecology. This article is the second in a series of reviews of more than 70 years of research on CCHF, summarizing important findings, identifying gaps in knowledge, and suggesting directions for future research.

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“…The structural glycoproteins Gn (GPC residues 520-842; residue numbering throughout this article is based on CCHFV IbAr 10200) and Gc (GPC residues 1041-1684) form spikes on the viral surface and mediate virus entry into target cells, but the role of the secreted glycoproteins remains poorly understood. Nairoviruses are the only bunyaviruses that are known to encode secreted glycoproteins, such as the 38 kDa glycoprotein (GP38) that is produced by CCHFV (9). GP38 (GPC residues 248-519) does not share substantial sequence homology with other viral or cellular proteins.…”

Section: Introductionmentioning

confidence: 99%

Structure and Characterization of Crimean-Congo Hemorrhagic Fever Virus GP38

Mishra

Moyer

Abelson

et al. 2020

J Virol

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Crimean-Congo hemorrhagic fever virus (CCHFV) is the causative agent of the most widespread tick-borne viral infection in humans. CCHFV encodes a secreted glycoprotein (GP38) of unknown function that is the target of a protective antibody. Here, we present the crystal structure of GP38 at a resolution of 2.5 Å, which revealed a novel fold primarily consisting of a 3-helix bundle and a β-sandwich. Sequence alignment and homology modeling showed distant homology between GP38 and the ectodomain of Gn (a structural glycoprotein in CCHFV), suggestive of a gene duplication event. Analysis of convalescent-phase sera showed high titers of GP38 antibodies indicating immunogenicity in humans during natural CCHFV infection. The only protective antibody for CCHFV in an adult mouse model reported to date, 13G8, bound GP38 with subnanomolar affinity and protected against heterologous CCHFV challenge in a STAT1-knockout mouse model. Our data strongly suggest that GP38 should be evaluated as a vaccine antigen and that its structure provides a foundation to investigate functions of this protein in the viral life cycle. IMPORTANCE Crimean-Congo hemorrhagic fever virus (CCHFV) is a priority pathogen that poses a high risk to public health. Due to the high morbidity and mortality rates associated with CCHFV infection, there is an urgent need to develop medical countermeasures for disease prevention and treatment. CCHFV GP38, a secreted glycoprotein of unknown function unique to the Nairoviridae family, was recently shown to be the target of a protective antibody against CCHFV. Here, we present the crystal structure of GP38, which revealed a novel fold with distant homology to another CCHFV glycoprotein that is suggestive of a gene duplication event. We also demonstrate that antibody 13G8 protects STAT1-knockout mice against heterologous CCHFV challenge using a clinical isolate from regions where CCHFV is endemic. Collectively, these data advance our understanding of GP38 structure and antigenicity and should facilitate future studies investigating its function.

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Molecular Insights into Crimean-Congo Hemorrhagic Fever Virus

Cited by 99 publications

References 124 publications

The role of ticks in the maintenance and transmission of Crimean-Congo hemorrhagic fever virus: A review of published field and laboratory studies

The role of ticks in the maintenance and transmission of Crimean-Congo hemorrhagic fever virus: A review of published field and laboratory studies

A chronological review of experimental infection studies of the role of wild animals and livestock in the maintenance and transmission of Crimean-Congo hemorrhagic fever virus

Structure and Characterization of Crimean-Congo Hemorrhagic Fever Virus GP38

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