1. Computational and Systems Biology
  2. Immunology and Inflammation
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Dynamically linking influenza virus infection kinetics, lung injury, inflammation, and disease severity

  1. Margaret A Myers
  2. Amanda P Smith
  3. Lindey C Lane
  4. David J Moquin
  5. Rosemary Aogo
  6. Stacie Woolard
  7. Paul Thomas
  8. Peter Vogel
  9. Amber M Smith  Is a corresponding author
  1. University of Tennessee Health Science Center, United States
  2. University of Tennessee Health Science C, United States
  3. Washington University School of Medicine, United States
  4. St Jude Children's Research Hospital, United States
Research Article
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Cite this article as: eLife 2021;10:e68864 doi: 10.7554/eLife.68864

Abstract

Influenza viruses cause a significant amount of morbidity and mortality. Understanding host immune control efficacy and how different factors influence lung injury and disease severity are critical. We established and validated dynamical connections between viral loads, infected cells, CD8+ T cells, lung injury, inflammation, and disease severity using an integrative mathematical model-experiment exchange. Our results showed that the dynamics of inflammation and virus-inflicted lung injury are distinct and nonlinearly related to disease severity, and that these two pathologic measurements can be independently predicted using the model-derived infected cell dynamics. Our findings further indicated that the relative CD8+ T cell dynamics paralleled the percent of the lung that had resolved with the rate of CD8+ T cell-mediated clearance rapidly accelerating by over 48,000 times in 2 days. This complimented our analyses showing a negative correlation between the efficacy of innate and adaptive immune-mediated infected cell clearance, and that infection duration was driven by CD8+ T cell magnitude rather than efficacy and could be significantly prolonged if the ratio of CD8+ T cells to infected cells was sufficiently low. These links between important pathogen kinetics and host pathology enhance our ability to forecast disease progression, potential complications, and therapeutic efficacy.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been provided.

Article and author information

Author details

  1. Margaret A Myers

    Pediatrics, University of Tennessee Health Science Center, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Amanda P Smith

    Pediatrics, University of Tennessee Health Science C, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Lindey C Lane

    Pediatrics, University of Tennessee Health Science C, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. David J Moquin

    Anesthesiology, Washington University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Rosemary Aogo

    Pediatrics, University of Tennessee Health Science Center, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Stacie Woolard

    Flow Cytometry Core, St Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Paul Thomas

    Flow Cytometry Core, St Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Peter Vogel

    Veterinary Pathology Core, St Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Amber M Smith

    Pediatrics, University of Tennessee Health Science Center, Memphis, United States
    For correspondence
    amber.smith@uthsc.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7092-6904

Funding

National Institute of Allergy and Infectious Diseases (AI139088)

  • Margaret A Myers
  • Amanda P Smith
  • Lindey C Lane
  • Rosemary Aogo

National Institute of Allergy and Infectious Diseases (AI125324)

  • Margaret A Myers
  • Amanda P Smith
  • Lindey C Lane
  • David J Moquin
  • Amber M Smith

National Institute of Allergy and Infectious Diseases (AI100946)

  • Amber M Smith

American Lebanese Syrian Associated Charities (Internal Funding)

  • Margaret A Myers
  • Amanda P Smith
  • Lindey C Lane
  • David J Moquin
  • Stacie Woolard
  • Paul Thomas
  • Peter Vogel
  • Amber M Smith

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

Ethics

Animal experimentation: All experimental procedures were performed under protocols O2A-020 or 17-096 approved by the Animal Care and Use Committees at St. Jude Children's Research Hospital (SJCRH) or the University of Tennessee Health Science Center (UTHSC), respectively, under relevant institutional and American Veterinary Medical Association (AVMA) guidelines. All experimental procedures were performed in a biosafety level 2 facility that is accredited by the American Association for Laboratory Animal Science (AALAS).

Reviewing Editor

  1. Joshua T Schiffer, Fred Hutchinson Cancer Research Center, United States

Publication history

  1. Received: March 28, 2021
  2. Accepted: July 14, 2021
  3. Accepted Manuscript published: July 20, 2021 (version 1)

Copyright

© 2021, Myers et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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