Severe immunosuppression and not a cytokine storm characterizes COVID-19 infections

JCI Insight. 2020 Sep 3;5(17):e140329. doi: 10.1172/jci.insight.140329.


COVID-19-associated morbidity and mortality have been attributed to a pathologic host response. Two divergent hypotheses have been proposed: hyperinflammatory cytokine storm; and failure of host protective immunity that results in unrestrained viral dissemination and organ injury. A key explanation for the inability to address this controversy has been the lack of diagnostic tools to evaluate immune function in COVID-19 infections. ELISpot, a highly sensitive, functional immunoassay, was employed in 27 patients with COVID-19, 51 patients with sepsis, 18 critically ill nonseptic (CINS) patients, and 27 healthy control volunteers to evaluate adaptive and innate immune status by quantitating T cell IFN-ɣ and monocyte TFN-α production. Circulating T cell subsets were profoundly reduced in COVID-19 patients. Additionally, stimulated blood mononuclear cells produced less than 40%-50% of the IFN-ɣ and TNF-α observed in septic and CINS patients, consistent with markedly impaired immune effector cell function. Approximately 25% of COVID-19 patients had increased IL-6 levels that were not associated with elevations in other canonical proinflammatory cytokines. Collectively, these findings support the hypothesis that COVID-19 suppresses host functional adaptive and innate immunity. Importantly, IL-7 administered ex vivo restored T cell IFN-ɣ production in COVID-19 patients. Thus, ELISpot may functionally characterize host immunity in COVID-19 and inform prospective therapies.

Keywords: Adaptive immunity; COVID-19.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptive Immunity / immunology*
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Betacoronavirus
  • COVID-19
  • Case-Control Studies
  • Coronavirus Infections / immunology*
  • Critical Illness
  • Cytokine Release Syndrome / immunology*
  • Enzyme-Linked Immunospot Assay
  • Female
  • Healthy Volunteers
  • Humans
  • Immune Tolerance / immunology*
  • Immunity, Innate / immunology*
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • Interleukin-6 / immunology
  • Male
  • Middle Aged
  • Monocytes / immunology
  • Monocytes / metabolism
  • Pandemics
  • Pneumonia, Viral / immunology*
  • SARS-CoV-2
  • Sepsis / immunology*
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Necrosis Factor-alpha / metabolism
  • Young Adult


  • IFNG protein, human
  • IL6 protein, human
  • Interleukin-6
  • TNF protein, human
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma