A single mutation in Crimean-Congo hemorrhagic fever virus discovered in ticks impairs infectivity in human cells

  1. Brian L Hua
  2. Florine EM Scholte
  3. Valerie Ohlendorf
  4. Anne Kopp
  5. Marco Marklewitz
  6. Christian Drosten
  7. Stuart T Nichol
  8. Christina Spiropoulou
  9. Sandra Junglen  Is a corresponding author
  10. Éric Bergeron  Is a corresponding author
  1. Centers for Disease Control and Prevention, United States
  2. Charité-Universitätsmedizin Berlin, Germany
  3. Charité - Universitätsmedizin Berlin, Germany
  4. Charité Universitätsmedizin, Germany

Abstract

Crimean-Congo Hemorrhagic Fever (CCHF) is the most widely distributed tick-borne viral infection in the world. Strikingly, reported mortality rates for CCHF are extremely variable, ranging from 5 to 80% (1). CCHF virus (CCHFV, Nairoviridae) exhibits extensive genomic sequence diversity across strains (2, 3). It is currently unknown if genomic diversity is a factor contributing to variation in its pathogenicity. We obtained complete genome sequences of CCHFV directly from the tick reservoir. These new strains belong to a solitary lineage named Europe 2 that is circumstantially reputed to be less pathogenic than the epidemic strains from Europe 1 lineage. We identified a single tick-specific amino acid variant in the viral glycoprotein region that dramatically reduces its fusion activity in human cells, providing evidence that a GPC variant, present in ticks, have severely impaired function in human cells.

Data availability

All sequencing data have been deposited in GB under accession codes MK299338, MK299339, MK299340, MK299341, MK299342, MK299343, MK299344, MK299345 and MK299346

Article and author information

Author details

  1. Brian L Hua

    Viral Special Pathogens Branch, Centers for Disease Control and Prevention, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7580-3399
  2. Florine EM Scholte

    Viral Special Pathogens Branch, Centers for Disease Control and Prevention, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Valerie Ohlendorf

    Institute of Virology, Charité-Universitätsmedizin Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Anne Kopp

    Institute of Virology, Charité-Universitätsmedizin Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Marco Marklewitz

    Institute of Virology, Charité - Universitätsmedizin Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1828-8770
  6. Christian Drosten

    Institute of Virology, Charité Universitätsmedizin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Stuart T Nichol

    Viral Special Pathogens Branch, Centers for Disease Control and Prevention, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Christina Spiropoulou

    Viral Special Pathogens Branch, Centers for Disease Control and Prevention, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8406-3161
  9. Sandra Junglen

    Institute of Virology, Charité-Universitätsmedizin Berlin, Berlin, Germany
    For correspondence
    sandra.junglen@charite.de
    Competing interests
    The authors declare that no competing interests exist.
  10. Éric Bergeron

    Viral Special Pathogens Branch, Centers for Disease Control and Prevention, Atlanta, United States
    For correspondence
    ebergeron@cdc.gov
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3398-8628

Funding

American Society for Microbiology

  • Brian L Hua

Centers for Disease Control and Prevention

  • Stuart T Nichol
  • Christina Spiropoulou
  • Éric Bergeron

Federal Ministry of Education and Research (01KI1716)

  • Sandra Junglen

German Center for Infection Research (TTU 01.801)

  • Christian Drosten

National Institutes of Health (R01AI109008)

  • Éric Bergeron

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Sara L Sawyer, University of Colorado Boulder, United States

Version history

  1. Received: August 9, 2019
  2. Accepted: October 8, 2020
  3. Accepted Manuscript published: October 21, 2020 (version 1)
  4. Version of Record published: November 9, 2020 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Metrics

  • 1,910
    Page views
  • 258
    Downloads
  • 11
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Brian L Hua
  2. Florine EM Scholte
  3. Valerie Ohlendorf
  4. Anne Kopp
  5. Marco Marklewitz
  6. Christian Drosten
  7. Stuart T Nichol
  8. Christina Spiropoulou
  9. Sandra Junglen
  10. Éric Bergeron
(2020)
A single mutation in Crimean-Congo hemorrhagic fever virus discovered in ticks impairs infectivity in human cells
eLife 9:e50999.
https://doi.org/10.7554/eLife.50999

Share this article

https://doi.org/10.7554/eLife.50999

Further reading

    1. Microbiology and Infectious Disease
    2. Physics of Living Systems
    Ray Chang, Ari Davydov ... Manu Prakash
    Research Article

    Microsporidia are eukaryotic, obligate intracellular parasites that infect a wide range of hosts, leading to health and economic burdens worldwide. Microsporidia use an unusual invasion organelle called the polar tube (PT), which is ejected from a dormant spore at ultra-fast speeds, to infect host cells. The mechanics of PT ejection are impressive. Anncaliia algerae microsporidia spores (3–4 μm in size) shoot out a 100-nm-wide PT at a speed of 300 μm/s, creating a shear rate of 3000 s-1. The infectious cargo, which contains two nuclei, is shot through this narrow tube for a distance of ∼60–140 μm (Jaroenlak et al, 2020) and into the host cell. Considering the large hydraulic resistance in an extremely thin tube and the low-Reynolds-number nature of the process, it is not known how microsporidia can achieve this ultrafast event. In this study, we use Serial Block-Face Scanning Electron Microscopy to capture 3-dimensional snapshots of A. algerae spores in different states of the PT ejection process. Grounded in these data, we propose a theoretical framework starting with a systematic exploration of possible topological connectivity amongst organelles, and assess the energy requirements of the resulting models. We perform PT firing experiments in media of varying viscosity, and use the results to rank our proposed hypotheses based on their predicted energy requirement. We also present a possible mechanism for cargo translocation, and quantitatively compare our predictions to experimental observations. Our study provides a comprehensive biophysical analysis of the energy dissipation of microsporidian infection process and demonstrates the extreme limits of cellular hydraulics.

    1. Microbiology and Infectious Disease
    Hui Han, Rong-Hua Luo ... Cheng-Gang Zou
    Research Article

    Angiotensin-converting enzyme 2 (ACE2) is a major cell entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The induction of ACE2 expression may serve as a strategy by SARS-CoV-2 to facilitate its propagation. However, the regulatory mechanisms of ACE2 expression after viral infection remain largely unknown. Using 45 different luciferase reporters, the transcription factors SP1 and HNF4α were found to positively and negatively regulate ACE2 expression, respectively, at the transcriptional level in human lung epithelial cells (HPAEpiCs). SARS-CoV-2 infection increased the transcriptional activity of SP1 while inhibiting that of HNF4α. The PI3K/AKT signaling pathway, activated by SARS-CoV-2 infection, served as a crucial regulatory node, inducing ACE2 expression by enhancing SP1 phosphorylation—a marker of its activity—and reducing the nuclear localization of HNF4α. However, colchicine treatment inhibited the PI3K/AKT signaling pathway, thereby suppressing ACE2 expression. In Syrian hamsters (Mesocricetus auratus) infected with SARS-CoV-2, inhibition of SP1 by either mithramycin A or colchicine resulted in reduced viral replication and tissue injury. In summary, our study uncovers a novel function of SP1 in the regulation of ACE2 expression and identifies SP1 as a potential target to reduce SARS-CoV-2 infection.