Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans

TLDR

COVID‑19 is a global crisis, yet key gaps remain in understanding human immunity to SARS‑CoV‑2. The study profiled immune responses in 76 COVID‑19 patients and 69 healthy controls from Hong Kong and Atlanta. Patients with severe COVID‑19 show reduced HLA‑DR expression and impaired mTOR/IFN‑α signaling in myeloid and plasmacytoid dendritic cells, elevated plasma inflammatory mediators that correlate with severity, and transient type I IFN responses, highlighting potential therapeutic targets.

Abstract

Coronavirus disease 2019 (COVID-19) represents a global crisis, yet major knowledge gaps remain about human immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We analyzed immune responses in 76 COVID-19 patients and 69 healthy individuals from Hong Kong and Atlanta, Georgia, United States. In the peripheral blood mononuclear cells (PBMCs) of COVID-19 patients, we observed reduced expression of human leukocyte antigen class DR (HLA-DR) and proinflammatory cytokines by myeloid cells as well as impaired mammalian target of rapamycin (mTOR) signaling and interferon-α (IFN-α) production by plasmacytoid dendritic cells. By contrast, we detected enhanced plasma levels of inflammatory mediators-including EN-RAGE, TNFSF14, and oncostatin M-which correlated with disease severity and increased bacterial products in plasma. Single-cell transcriptomics revealed a lack of type I IFNs, reduced HLA-DR in the myeloid cells of patients with severe COVID-19, and transient expression of IFN-stimulated genes. This was consistent with bulk PBMC transcriptomics and transient, low IFN-α levels in plasma during infection. These results reveal mechanisms and potential therapeutic targets for COVID-19.