Type 2 immune responses are associated with less severe COVID-19 in a hospitalized cohort

Abstract

Background: The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread rapidly after its identification in December 2019 to cause a global pandemic. The respiratory tract is the primary site of infection, and there is a large range in the severity of respiratory illnesses caused by the virus. Defining molecular and cellular factors for protection from severe disease and death has been a goal to better understand and to predict and mitigate the effects of SARS-CoV-2 and future coronaviruses.

Objective: Despite well-known susceptibilities to respiratory viral infections, respiratory allergy and allergic asthma have not been identified as risk factors for severe coronavirus disease 2019 (COVID-19) in most epidemiologic studies and may be protective. We sought to investigate associations between markers of type 2 (T2) immune responses with SARS-CoV-2 clinical outcomes and virus loads in a cohort of 1164 individuals hospitalized for COVID-19 from May 2020 to March 2021 as part of the IMPACC study.

Methods: We characterized the clinical outcomes, as defined by severity trajectory groups reflecting the degree of respiratory support required, virus loads, and antibody titers of COVID-19 infections in IMPACC participants in relation to molecular and cellular markers of T2 immune responses through multiple assays, including, (1) IL-4, IL-5, and IL-13 levels in serum Olink data, (2) T2 cellular signatures in blood cytometry by time of flight data, (3) relative quantification of T2 signaling gene pathways in airway RNA sequencing data, and/or (4) T2 pathways in peripheral blood mononuclear cell RNA sequencing data. We also investigated the outcomes of individuals with self-reported asthma and evidence of T2 immune responses.

Results: The diagnosis of asthma (odd ratio = 1.27), elevated serum T2 cytokine levels (median fold change = 1.06), and a higher frequency of T_H2 cells (difference = +2%) were associated with less severe clinical disease during hospitalization. Distinct T2-related transcriptomic changes in nasal and blood samples were associated with reduced virus loads. This included the expression of T2-regulated genes implicated in T-/B-cell activation and apoptosis in nasal samples and the expression of T2-regulated genes implicated in myeloid differentiation and reactive oxygen species signaling in blood. Among these, several canonical T2-regulated genes that were increased in less severe disease were identified to have antiviral properties in large high-throughput screens.

Conclusion: T2 immune responses were associated with lower virus loads and more favorable clinical outcomes, suggesting that T2 inflammation related to asthma and allergic diseases may have a direct protective effect against SARS-CoV-2.

Keywords: Asthma; IMPACC; SARS-CoV-2.

Fig 1

Asthma association with COVID-19 disease severity. Top, Bar plot showing proportion of participants with reported asthma as comorbidity (opaque) separated by TGs. Bottom, Heat map showing difference in observed number of participants with asthma to number of participants expected to have asthma (based on prevalence of asthmatic participants in IMPACC cohort), separated by TG. Blue–white–red gradient depicts number lower, similar, or greater than expected by chance alone.

Fig 2

T_H2 cytokine levels by clinical TGs (A) IL-4, IL-5, and IL-13 NPX levels in serum at visit 1 in 5 TGs: TG1, n = 252; TG2, n = 297; TG3, n = 259; TG4, n = 199; TG5, n = 104. (B) IL-4 (n = 755), IL-5 (n = 755), and IL-13 (n = 755) NPX levels in serum at visit 1 as function of nasal virus load (C_t); lower C_t values indicate higher virus load. C_t, Cycle threshold; NPX, normalized protein expression.

Fig 3

Elevated frequency of differentiated T helper cell subsets is associated with milder disease course. (A) Box plots of frequency of CD4⁺ T cells, CD8⁺ T cells, and eosinophils out of total CD45⁺ blood cells in each TG at visit 1 (TG1, n = 171; TG2, n = 212; TG3, n = 190; TG4, n = 133; TG5, n = 58). (B) Jitter plot of frequencies of Th1, T_H2, and T_H17 subsets relative to parent CD4⁺ T helper cell subset (CD4⁺CD45RO⁺CD45RA⁻) as function of TGs at visit 1. (A and B) For statistical testing, Kruskal-Wallis test was used to test differences between TGs.

Fig 4

Transcriptional profile of T2 gene signatures. (A) Scaled expression of T2-related genes identified in MSigDB database and measured by PBMC RNA-Seq. Genes were separated into 6 clusters based on enrichment analysis. Nasal virus load is presented as column annotation. Samples (columns) are ordered by increasing levels of T2 gene signatures. (B) Scaled expression of T2-related genes identified in MSigDB database and measured by nasal RNA-Seq.