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. 2021 Jul 16:12:706902.
doi: 10.3389/fgene.2021.706902. eCollection 2021.

Th2/Th1 Cytokine Imbalance Is Associated With Higher COVID-19 Risk Mortality

Ana B Pavel  1   2 , Jacob W Glickman  2 , James R Michels  1 , Seunghee Kim-Schulze  3 , Rachel L Miller  4 , Emma Guttman-Yassky  2
Affiliations

Th2/Th1 Cytokine Imbalance Is Associated With Higher COVID-19 Risk Mortality

Ana B Pavel et al. Front Genet. .

Abstract

A major component of COVID-19 severe respiratory syndrome is the patient's immune response to the SARS-CoV-2 virus and the consequential multi-organ inflammatory response. Several studies suggested a potential role of CD4+ T cells in COVID-19 severe respiratory syndrome. We first hypothesized that there is a type 2 helper (Th2)/type 1 helper (Th1) imbalance in older age, male, asthma, smokers, and high ACE2 expression phenotype in the airway of non-infected patients. Next, we hypothesized that a Th2/Th1 imbalance may predict higher mortality in COVID-19 infected hospitalized patients with and without patient reported current asthma. We first analyzed publicly available gene expression from the sputum of 118 moderate-to-severe asthma patients and 21 healthy controls, and from nasal epithelium of 26 healthy current smokers and 21 healthy never smokers. Secondly, we profiled 288 new serum proteomics samples measured at admission from patients hospitalized within the Mount Sinai Health System with positive SARS-CoV-2 infection. We first computed Th1 and Th2 pathway enrichment scores by gene set variation analysis and then compared the differences in Th2 and Th1 pathway scores between patients that died compared to those that survived, by linear regression. The level of Th2/Th1 imbalance, as determined by the enrichment score, was associated with age, sex, and ACE2 expression in sputum, and with active smoking status in nasal epithelium (p < 0.05). Th2/Th1 imbalance at hospital admission in sera of patients was not significantly associated with death from COVID-19 (p = 0.11), unless evaluated in the asthmatic strata (p = 0.01). Using a similar approach we also observed a higher Th17/Th1 cytokine imbalance in all deceased patients compared to those that survived (p < 0.001), as well as in the asthmatic strata only (p < 0.01). Th2/Th1 imbalance is higher in the sera of asthma patients at admission that do not survive COVID-19, suggesting that the Th2/Th1 interplay may affect patient outcomes in SARS-CoV2 infection. In addition, we report that Th17/Th1 imbalance is increased in all patients that die of COVID-19.

Keywords: COVID-19; SARS-CoV-2; T-cells; Th1; Th17; Th2; gene expression; serum proteomics.

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Conflict of interest statement

AP is an employee of the University of Mississippi and has received a research grant from Mount Sinai. EG-Y is an employee of Mount Sinai and has received research funds (grants paid to the institution) from: Abbvie, Celgene, Eli Lilly, Janssen, Medimmune/Astra Zeneca, Novartis, Pfizer, Regeneron, Vitae, Glenmark, Galderma, Asana, Innovaderm, Dermira, and UCB. EG-Y is also a consultant for Sanofi Aventis, Regeneron, Stiefel/GlaxoSmithKline, MedImmune, Celgene, Anacor, AnaptysBio, Dermira, Galderma, Glenmark, Novartis, Pfizer, Vitae, Leo Pharma, Abbvie, Eli Lilly, Kyowa, Mitsubishi Tanabe, Asana Biosciences, and Promius. JG, SK-S and RM are employees of Mount Sinai and have no other financial relationships to disclose. JM has no financial relationships to disclose. The reviewer RJ declared a past co-authorship with the authors AP, JG, and EG-Y to the handling editor.

Figures

FIGURE 1
FIGURE 1
(A) Mean difference in Th2 and Th1 enrichment scores in the sputum of healthy individuals (CTRL) and severe asthma patients stratified by age. Horizontal bars denote standard error. (B) Mean difference in Th2 and Th1 enrichment scores in sputum of healthy individuals (CTRL) and of asthma patients in both males (M) and females (F) stratified by age. Horizontal bars denote standard error. (C) Correlation scatterplot between Th2/Th1 enrichment score and ACE2 gene expression in healthy individuals. Gray shaded area denotes the 95% confidence interval. Pearson correlation coefficient and p-value are provided. (D) Mean difference in Th2 and Th1 enrichment scores in nasal epithelium of healthy smokers and healthy never smokers. Horizontal bars denote standard error. +p < 0.1, *p < 0.05, **p < 0.01.
FIGURE 2
FIGURE 2
(A) Heatmap of mean enrichment score by gene set variation analysis in all patients in the hospitalized COVID-19 cohort, stratified by subsequent mortality, with fold-change differences provided in the side table. (B) Mean difference in Th2 and Th1 enrichment scores in deceased versus survived patients. (C) Heatmap of mean enrichment scores by gene set variation analysis in asthma and non-asthma patients, stratified by mortality, with fold-changes provided in the side table. (D) Mean difference in Th2 and Th1 enrichment scores in deceased versus survived patients stratified by asthma status; means were estimated by a linear regression with age adjustment; +p < 0.1, *p < 0.05, **p < 0.01, ***p < 0.001.
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