1. Immunology and Inflammation
  2. Medicine
Download icon

Cytokine ranking via mutual information algorithm correlates cytokine profiles with presenting disease severity in patients infected with SARS-CoV-2

  1. Kelsey E Huntington
  2. Anna D Louie
  3. Chun Geun Lee
  4. Jack A Elias
  5. Eric A Ross
  6. Wafik S El-Deiry  Is a corresponding author
  1. Brown University, United States
  2. Fox Chase Cancer Center, United States
Short Report
  • Cited 1
  • Views 1,272
  • Annotations
Cite this article as: eLife 2021;10:e64958 doi: 10.7554/eLife.64958

Abstract

Although the range of immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is variable, cytokine storm is observed in a subset of symptomatic individuals. To further understand the disease pathogenesis and, consequently, to develop an additional tool for clinicians to evaluate patients for presumptive intervention we sought to compare plasma cytokine levels between a range of donor and patient samples grouped by a COVID-19 Severity Score (CSS) based on need for hospitalization and oxygen requirement. Here we utilize a mutual information algorithm that classifies the information gain for CSS prediction provided by cytokine expression levels and clinical variables. Using this methodology, we found that a small number of clinical and cytokine expression variables are predictive of presenting COVID-19 disease severity, raising questions about the mechanism by which COVID-19 creates severe illness. The variables that were the most predictive of CSS included clinical variables such as age and abnormal chest x-ray as well as cytokines such as macrophage colony-stimulating factor (M-CSF), interferon-inducible protein 10 (IP-10) and Interleukin-1 Receptor Antagonist (IL-1RA). Our results suggest that SARS-CoV-2 infection causes a plethora of changes in cytokine profiles and that particularly in severely ill patients, these changes are consistent with the presence of Macrophage Activation Syndrome and could furthermore be used as a biomarker to predict disease severity.

Data availability

Source data and source code files have been provided.

Article and author information

Author details

  1. Kelsey E Huntington

    Pathobiology Program, Brown University, Providence, United States
    Competing interests
    No competing interests declared.
  2. Anna D Louie

    Department of Surgery, Brown University, Providence, United States
    Competing interests
    No competing interests declared.
  3. Chun Geun Lee

    Department of Molecular Microbiology and Immunology, Brown University, Providence, United States
    Competing interests
    No competing interests declared.
  4. Jack A Elias

    Department of Molecular Microbiology and Immunology, Brown University, Providence, United States
    Competing interests
    No competing interests declared.
  5. Eric A Ross

    Biostatistics and Bioinformatics, Fox Chase Cancer Center, Philadelphia, United States
    Competing interests
    No competing interests declared.
  6. Wafik S El-Deiry

    Department of Pathology and Laboratory Medicine, Brown University, Providence, United States
    For correspondence
    wafik_el-deiry@brown.edu
    Competing interests
    Wafik S El-Deiry, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9577-8266

Funding

Brown University

  • Wafik S El-Deiry

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

Reviewing Editor

  1. Jameel Iqbal, James J. Peters Veterans Affairs Medical Center, United States

Publication history

  1. Received: November 17, 2020
  2. Accepted: January 13, 2021
  3. Accepted Manuscript published: January 14, 2021 (version 1)
  4. Version of Record published: February 9, 2021 (version 2)

Copyright

© 2021, Huntington 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

  • 1,272
    Page views
  • 159
    Downloads
  • 1
    Citations

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

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

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

  1. Further reading

Further reading

    1. Epidemiology and Global Health
    2. Immunology and Inflammation
    Corbin SC Johnson et al.
    Research Article

    Dietary changes associated with industrialization substantially increase the prevalence of chronic diseases, such as obesity, type II diabetes, and cardiovascular disease, major contributors to the public health burden. The high prevalence of these chronic diseases is often attributed to an 'evolutionary mismatch' between human physiology and modern nutritional environments. Western diets enriched with foods that were scarce throughout human evolutionary history (e.g., simple sugars and saturated fats) promote inflammation and disease relative to diets more akin to ancestral human hunter-gatherer diets, such as a Mediterranean diet. Peripheral blood monocytes, precursors to macrophages and important mediators of innate immunity and inflammation, are sensitive to the environment and may represent a critical intermediate in the pathway linking diet to disease. We evaluated the effects of 15 months of whole diet manipulations mimicking human Western or Mediterranean diet patterns on monocyte polarization using a well-established model of human health, the cynomolgus macaque (Macaca fascicularis). Monocyte transcriptional profiles differed markedly between the two diets, with 40% of transcripts showing differential expression (FDR < 0.05). Monocytes from Western diet consumers were polarized toward a more proinflammatory phenotype. Compared to the Mediterranean diet, the Western diet shifted the co-expression of 445 gene pairs, including small RNAs and transcription factors associated with metabolism and adiposity in humans, and dramatically altered behavior. For example, Western-fed individuals were more anxious and less socially integrated compared to the Mediterranean-fed subjects. These behavioral changes were also associated with some of the effects of diet on gene expression, suggesting an interaction between diet, central nervous system activity, and monocyte gene expression. The results of this study provide new insights into evolutionary mismatch at the molecular level and uncover new pathways through which Western diets alter monocyte polarization toward a proinflammatory phenotype.

    1. Immunology and Inflammation
    2. Medicine
    Daniela Fraccarollo et al.
    Research Article Updated

    Immature neutrophils and HLA-DRneg/low monocytes expand in cancer, autoimmune diseases and viral infections, but their appearance and immunoregulatory effects on T-cells after acute myocardial infarction (AMI) remain underexplored. We found an expansion of circulating immature CD16+CD66b+CD10neg neutrophils and CD14+HLA-DRneg/low monocytes in AMI patients, correlating with cardiac damage, function and levels of immune-inflammation markers. Immature CD10neg neutrophils expressed high amounts of MMP-9 and S100A9, and displayed resistance to apoptosis. Moreover, we found that increased frequency of CD10neg neutrophils and elevated circulating IFN-γ levels were linked, mainly in patients with expanded CD4+CD28null T-cells. Notably, the expansion of circulating CD4+CD28null T-cells was associated with cytomegalovirus (CMV) seropositivity. Using bioinformatic tools, we identified a tight relationship among the peripheral expansion of immature CD10neg neutrophils, CMV IgG titers, and circulating levels of IFN-γ and IL-12 in patients with AMI. At a mechanistic level, CD10neg neutrophils enhanced IFN-γ production by CD4+ T-cells through a contact-independent mechanism involving IL-12. In vitro experiments also highlighted that HLA-DRneg/low monocytes do not suppress T-cell proliferation but secrete high levels of pro-inflammatory cytokines after differentiation to macrophages and IFN-γ stimulation. Lastly, using a mouse model of AMI, we showed that immature neutrophils (CD11bposLy6GposCD101neg cells) are recruited to the injured myocardium and migrate to mediastinal lymph nodes shortly after reperfusion. In conclusion, immunoregulatory functions of CD10neg neutrophils play a dynamic role in mechanisms linking myeloid cell compartment dysregulation, Th1-type immune responses and inflammation after AMI.