Immunocompetent mouse model for Crimean-Congo hemorrhagic fever virus

  1. David W Hawman  Is a corresponding author
  2. Kimberly Meade-White
  3. Shanna Leventhal
  4. Friederike Feldmann
  5. Atsushi Okumura
  6. Brian Smith
  7. Dana Scott
  8. Heinz Feldmann  Is a corresponding author
  1. NIAID/NIH, United States
  2. Texas Veterinary Pathology, United States

Abstract

Crimean-Congo hemorrhagic fever (CCHF) is a severe tick-borne febrile illness with wide geographic distribution. CCHF is caused by infection with the Crimean-Congo hemorrhagic fever virus (CCHFV) and case fatality rates can be as high as 30%. Despite causing severe disease in humans, our understanding of the host and viral determinants of CCHFV pathogenesis are limited. A major limitation in the investigation of CCHF has been the lack of suitable small animal models. Wild-type mice are resistant to clinical isolates of CCHFV and consequently, mice must be deficient in type I interferon responses to study the more severe aspects of CCHFV. We report here a mouse-adapted variant of CCHFV that recapitulates in adult, immunocompetent mice the severe CCHF observed in humans. This mouse-adapted variant of CCHFV significantly improves our ability to study host and viral determinants of CCHFV-induced disease in a highly tractable mouse model.

Data availability

Relevant source data for figures is provided and the consensus sequence of MA-CCHFV has been deposited to Genbank (Accession #s MW058028 - MW058030)

Article and author information

Author details

  1. David W Hawman

    Laboratory of Virology, NIAID/NIH, Hamilton, United States
    For correspondence
    david.hawman@nih.gov
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8233-8176
  2. Kimberly Meade-White

    Laboratory of Virology, NIAID/NIH, Hamilton, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Shanna Leventhal

    Laboratory of Virology, NIAID/NIH, Hamilton, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Friederike Feldmann

    Laboratory of Virology, NIAID/NIH, Hamilton, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Atsushi Okumura

    Laboratory of Virology, NIAID/NIH, Hamilton, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Brian Smith

    Texas Veterinary Pathology, Texas Veterinary Pathology, Spring Branch, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Dana Scott

    Rocky Mountain Veterinary Branch, NIAID/NIH, Hamilton, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Heinz Feldmann

    Rocky Mountain Veterinary Branch, NIAID/NIH, Hamilton, United States
    For correspondence
    feldmannh@niaid.nih.gov
    Competing interests
    The authors declare that no competing interests exist.

Funding

Department of Intramural Research, NIH

  • David W Hawman

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

Ethics

Animal experimentation: Animal experiments were approved by the institutional animal care and use committee, protocol #s 2017-68 and 2019-63. Studies performed by experienced personnel under veterinary oversight. Mice were group-housed in HEPA-filtered cage systems and acclimatized to BSL4 conditions prior to start of the experiment. They were provided with nesting material and food and water ad libitum.

Reviewing Editor

  1. Amy Hartman, University of Pittsburgh

Publication history

  1. Received: October 10, 2020
  2. Accepted: January 7, 2021
  3. Accepted Manuscript published: January 8, 2021 (version 1)
  4. Version of Record published: January 15, 2021 (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

  • 1,228
    Page views
  • 181
    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. David W Hawman
  2. Kimberly Meade-White
  3. Shanna Leventhal
  4. Friederike Feldmann
  5. Atsushi Okumura
  6. Brian Smith
  7. Dana Scott
  8. Heinz Feldmann
(2021)
Immunocompetent mouse model for Crimean-Congo hemorrhagic fever virus
eLife 10:e63906.
https://doi.org/10.7554/eLife.63906

Further reading

    1. Epidemiology and Global Health
    2. Immunology and Inflammation
    James A Hay, Stephen M Kissler ... Yonatan H Grad
    Research Article Updated

    Background:

    The combined impact of immunity and SARS-CoV-2 variants on viral kinetics during infections has been unclear.

    Methods:

    We characterized 1,280 infections from the National Basketball Association occupational health cohort identified between June 2020 and January 2022 using serial RT-qPCR testing. Logistic regression and semi-mechanistic viral RNA kinetics models were used to quantify the effect of age, variant, symptom status, infection history, vaccination status and antibody titer to the founder SARS-CoV-2 strain on the duration of potential infectiousness and overall viral kinetics. The frequency of viral rebounds was quantified under multiple cycle threshold (Ct) value-based definitions.

    Results:

    Among individuals detected partway through their infection, 51.0% (95% credible interval [CrI]: 48.3–53.6%) remained potentially infectious (Ct <30) 5 days post detection, with small differences across variants and vaccination status. Only seven viral rebounds (0.7%; N=999) were observed, with rebound defined as 3+days with Ct <30 following an initial clearance of 3+days with Ct ≥30. High antibody titers against the founder SARS-CoV-2 strain predicted lower peak viral loads and shorter durations of infection. Among Omicron BA.1 infections, boosted individuals had lower pre-booster antibody titers and longer clearance times than non-boosted individuals.

    Conclusions:

    SARS-CoV-2 viral kinetics are partly determined by immunity and variant but dominated by individual-level variation. Since booster vaccination protects against infection, longer clearance times for BA.1-infected, boosted individuals may reflect a less effective immune response, more common in older individuals, that increases infection risk and reduces viral RNA clearance rate. The shifting landscape of viral kinetics underscores the need for continued monitoring to optimize isolation policies and to contextualize the health impacts of therapeutics and vaccines.

    Funding:

    Supported in part by CDC contract #200-2016-91779, a sponsored research agreement to Yale University from the National Basketball Association contract #21-003529, and the National Basketball Players Association.

    1. Immunology and Inflammation
    Sara E Vazquez, Sabrina A Mann ... Joseph L DeRisi
    Research Advance Updated

    Phage immunoprecipitation sequencing (PhIP-seq) allows for unbiased, proteome-wide autoantibody discovery across a variety of disease settings, with identification of disease-specific autoantigens providing new insight into previously poorly understood forms of immune dysregulation. Despite several successful implementations of PhIP-seq for autoantigen discovery, including our previous work (Vazquez et al., 2020), current protocols are inherently difficult to scale to accommodate large cohorts of cases and importantly, healthy controls. Here, we develop and validate a high throughput extension of PhIP-seq in various etiologies of autoimmune and inflammatory diseases, including APS1, IPEX, RAG1/2 deficiency, Kawasaki disease (KD), multisystem inflammatory syndrome in children (MIS-C), and finally, mild and severe forms of COVID-19. We demonstrate that these scaled datasets enable machine-learning approaches that result in robust prediction of disease status, as well as the ability to detect both known and novel autoantigens, such as prodynorphin (PDYN) in APS1 patients, and intestinally expressed proteins BEST4 and BTNL8 in IPEX patients. Remarkably, BEST4 antibodies were also found in two patients with RAG1/2 deficiency, one of whom had very early onset IBD. Scaled PhIP-seq examination of both MIS-C and KD demonstrated rare, overlapping antigens, including CGNL1, as well as several strongly enriched putative pneumonia-associated antigens in severe COVID-19, including the endosomal protein EEA1. Together, scaled PhIP-seq provides a valuable tool for broadly assessing both rare and common autoantigen overlap between autoimmune diseases of varying origins and etiologies.