Dynamically linking influenza virus infection kinetics, lung injury, inflammation, and disease severity
- University of Tennessee Health Science Center, United States
- University of Tennessee Health Science C, United States
- Washington University School of Medicine, United States
- St Jude Children's Research Hospital, United States
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
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).
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.
Metrics
-
- 3,322
- views
-
- 467
- downloads
-
- 41
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
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)
Dynamically linking influenza virus infection kinetics, lung injury, inflammation, and disease severity
eLife 10:e68864.
https://doi.org/10.7554/eLife.68864
Further reading
-
- Computational and Systems Biology
- Physics of Living Systems
Planar cell polarity (PCP) – tissue-scale alignment of the direction of asymmetric localization of proteins at the cell-cell interface – is essential for embryonic development and physiological functions. Abnormalities in PCP can result in developmental imperfections, including neural tube closure defects and misaligned hair follicles. Decoding the mechanisms responsible for PCP establishment and maintenance remains a fundamental open question. While the roles of various molecules – broadly classified into ‘global’ and ‘local’ modules – have been well-studied, their necessity and sufficiency in explaining PCP and connecting their perturbations to experimentally observed patterns have not been examined. Here, we develop a minimal model that captures the proposed features of PCP establishment – a global tissue-level gradient and local asymmetric distribution of protein complexes. The proposed model suggests that while polarity can emerge without a gradient, the gradient not only acts as a global cue but also increases the robustness of PCP against stochastic perturbations. We also recapitulated and quantified the experimentally observed features of swirling patterns and domineering non-autonomy, using only three free model parameters - rate of protein binding to membrane, the concentration of PCP proteins, and the gradient steepness. We explain how self-stabilizing asymmetric protein localizations in the presence of tissue-level gradient can lead to robust PCP patterns and reveal minimal design principles for a polarized system.
-
- Computational and Systems Biology
- Neuroscience
The basolateral amygdala (BLA) is a key site where fear learning takes place through synaptic plasticity. Rodent research shows prominent low theta (~3–6 Hz), high theta (~6–12 Hz), and gamma (>30 Hz) rhythms in the BLA local field potential recordings. However, it is not understood what role these rhythms play in supporting the plasticity. Here, we create a biophysically detailed model of the BLA circuit to show that several classes of interneurons (PV, SOM, and VIP) in the BLA can be critically involved in producing the rhythms; these rhythms promote the formation of a dedicated fear circuit shaped through spike-timing-dependent plasticity. Each class of interneurons is necessary for the plasticity. We find that the low theta rhythm is a biomarker of successful fear conditioning. The model makes use of interneurons commonly found in the cortex and, hence, may apply to a wide variety of associative learning situations.
