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Cited by 1,295COVID-19 Clinical Research StudiesSARS-CoV-2 and COVID-19 ResearchInflammation biomarkers and pathways

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Pathogenic T-cells and inflammatory monocytes incite inflammatory storms in severe COVID-19 patients

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Zhou, Yonggang, Fu, Binqing, Zheng, Xiaohu, Wang, Dongsheng, Zhao, Changcheng, Qi, Yingjie, Sun, Rui, Tian, Zhigang, Xu, Xiaoling, Wei, Haiming·2020·National Science Review
DOI 10.1093/nsr/nwaa041PMC PMC7108005

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Abstract

Pathogenic human coronavirus infections, such as severe acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV), cause high morbidity and mortality [1,2]. Recently, a severe pneumonia-associated respiratory syndrome caused by a new coronavirus (SARS-CoV-2) was reported in December 2019 in the city of Wuhan, Hubei province, China [3–5], which was also named as pneumonia-associated respiratory syndrome (PARS) [6] and can cause coronavirus disease 2019 (COVID-19) to seriously endanger human health. Up to 24 February 2020, at least 77 779 cases had been reported, with 2666 fatal cases according to the report from China CDC. However, the immune mechanism that potentially orchestrates acute mortality from COVID-19 patients is still unknown. Here, we show that, after the SARS-CoV-2 infection, CD4+ T lymphocytes are rapidly activated to become pathogenic T helper (Th) 1 cells and generate GM-CSF, etc. The cytokine environment induces inflammatory CD14+CD16+ monocytes with a high expression of IL-6 and accelerates the inflammation. Given that a large number of inflammatory-cell infiltrations have been observed in lungs from severe COVID-19 patients [7,8], these aberrant pathogenic Th1 cells and inflammatory monocytes may enter the pulmonary circulation in huge numbers and play an immune-damaging role causing lung functional disability and quick mortality. Our results demonstrate that excessive non-effective host-immune responses by pathogenic T-cells and inflammatory monocytes may be associated with severe lung pathology. Thus, we suggest that monoclonal antibodies targeting GM-CSF or interleukin 6 may be effective in blocking inflammatory storms and, therefore, be a promising treatment for severe COVID-19 patients. Coronavirus, including SARS and MERS, has caused two large-scale pandemics in the last two decades [1,2]. Although viral evasion of host-immune responses and virus-induced cytopathic effects are believed to be critical in disease severity, studies from humans who died of SARS and animal models have suggested that an excessive and aberrant host-cytokine storm results in an exuberant immunopathology and lethal disease [9–11]. Inflammatory cytokine storm refers to the immune system gone awry and an excessive inflammatory response flaring out of control. Cytokine storms are associated with a wide variety of infectious and non-infectious diseases including graft-versus-host disease, autoimmune disease, severe virus infection, multiple organ dysfunction syndromes and chimeric antigen receptor (CAR) T-cell therapy [12,13]. It has been reported that, following SARS-CoV infection, dysregulated cytokine/chemokine responses and higher virus titers cause an inflammatory cytokine storm with lung immunopathological injury [12,14]. Such inflammation associated with the cytokine storm may begin at one local site but spread farther throughout the body via the systemic circulation [12,14]. Similarly, patients infected with SARS-CoV-2 who have been reported recently have had increased plasma concentrations of inflammation-related cytokines, including interleukins (IL) 2, 7 and 10, granulocyte-colony-stimulating factor (G-CSF), interferon-γ-inducible protein 10 (IP10), monocyte chemoattractant protein 1 (MCP1), macrophage inflammatory protein 1 alpha (MIP1A) and tumour necrosis factor α (TNF-α), especially in moribund patients [15]. Importantly, COVID-19 patients have developed characteristic pulmonary ground glass changes on imaging and peripheral lymphocytes decreasing [14,16,17]. More importantly, a large number of inflammatory immune-cell infiltrations were also found in a COVID-19 patient with pulmonary pathology [7,8]. These phenomena suggest that severe pulmonary inflammation and cytokine storm also exist in SARS-CoV-2 infection. At present, symptomatic treatments with organ support to moribund patients are the mainstays of clinical management [17]. It is urgent to identify the immunopathology mechanism to delay the pulmonary immune injury. In patients infected with SARS-CoV, it has been reported that the severity of pulmonary immune injury correlated with extensive infiltration of neutrophils and macrophages in the lungs [18,19], accompanied by increased numbers of neutrophils and monocytes and lower CD8+ and CD4+ T-cell counts in the peripheral blood samples [20–22]. To identify the immune characteristics of patients infected with SARS-CoV-2, peripheral blood samples from patients with severe pneumonia were collected for immune analysis. Consistently with previous clinical-characteristics reports [23], these hospitalized patients with confirmed SARS-CoV-2 infection involved in the First Affiliated Hospital of University of Science and Technology of China commonly have fever symptoms. Patients in intensive care units (ICUs) have significantly decreased concentrations of haemoglobin and albumin, but increased concentrations of C-reactive protein, alanine aminotransferase, asparta

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Crossref · 10.1093/nsr/nwaa041

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Figures

Figure 1. Pathogenic Th1 cells with high expression of GM-CSF in COVID-19 patients. (A) Representative density plots showing an analysis of GM-CSF and IL-6 expressions in gated CD45+CD3+CD4+ T-cells (gating strategy shown in Supplementary Fig. 2a) isolated from peripheral blood in healthy controls, ICU and non-ICU patients of COVID-19. (B) Representative density plots showing an analysis of co-expression of GM-CSF and IFN-γ in gated CD45+CD3+CD4+ T-cells isolated from peripheral blood in healthy controls, ICU and non-ICU patients of COVID-19. (C) Statistics calculated by the percentage of GM-CSF+ or IL-6+ cells from CD4+ T-cells. (D) Statistics calculated by the percentage of GM-CSF+ and IFN-γ+ co-expressing CD4+ T-cells. Data represent the mean ± SEM. One-way ANOVA. P < 0.05 was considered statistically significant.
Figure 1. Pathogenic Th1 cells with high expression of GM-CSF in COVID-19 patients. (A) Representative density plots showing an analysis of GM-CSF and IL-6 expressions in gated CD45+CD3+CD4+ T-cells (gating strategy shown in Supplementary Fig. 2a) isolated from peripheral blood in healthy controls, ICU and non-ICU patients of COVID-19. (B) Representative density plots showing an analysis of co-expression of GM-CSF and IFN-γ in gated CD45+CD3+CD4+ T-cells isolated from peripheral blood in healthy controls, ICU and non-ICU patients of COVID-19. (C) Statistics calculated by the percentage of GM-CSF+ or IL-6+ cells from CD4+ T-cells. (D) Statistics calculated by the percentage of GM-CSF+ and IFN-γ+ co-expressing CD4+ T-cells. Data represent the mean ± SEM. One-way ANOVA. P < 0.05 was considered statistically significant.CC BY · PubMed Central
Figure 2. Inflammatory monocytes with high expression of IL-6 in COVID-19 patients. (A) Representative density plots showing an analysis of CD14 and CD16 expressions in gated CD45+ monocytes (gating strategy shown in Supplementary Fig. 2a) isolated from peripheral blood in healthy controls, ICU and non-ICU patients of COVID-19. (B) Representative density plots showing an analysis of GM-CSF and IL-6 expressions in gated CD45+CD14+ monocyte cells isolated from peripheral blood in healthy controls, ICU and non-ICU patients of COVID-19. (C) Statistics calculated by the percentage of CD14+CD16+ subsets from monocytes. (D) Statistics calculated by the percentage of GM-CSF+ or IL-6+ cells from CD14+ monocytes. (E) Statistics calculated by the cell number of GM-CSF+ CD14+ or IL-6+CD14+ monocytes. Data represent the mean ± SEM. One-way ANOVA. P < 0.05 was considered statistically significant.
Figure 2. Inflammatory monocytes with high expression of IL-6 in COVID-19 patients. (A) Representative density plots showing an analysis of CD14 and CD16 expressions in gated CD45+ monocytes (gating strategy shown in Supplementary Fig. 2a) isolated from peripheral blood in healthy controls, ICU and non-ICU patients of COVID-19. (B) Representative density plots showing an analysis of GM-CSF and IL-6 expressions in gated CD45+CD14+ monocyte cells isolated from peripheral blood in healthy controls, ICU and non-ICU patients of COVID-19. (C) Statistics calculated by the percentage of CD14+CD16+ subsets from monocytes. (D) Statistics calculated by the percentage of GM-CSF+ or IL-6+ cells from CD14+ monocytes. (E) Statistics calculated by the cell number of GM-CSF+ CD14+ or IL-6+CD14+ monocytes. Data represent the mean ± SEM. One-way ANOVA. P < 0.05 was considered statistically significant.CC BY · PubMed Central
Figure 3. Pathogenic Th1 cells and inflammatory monocytes in severe COVID-19. Pathogenic CD4+ Th1 (GM-CSF+IFN-γ+) cells were rapidly activated to produce GM-CSF and other inflammatory cytokines to form a cascade signature of inflammatory monocytes (CD14+CD16+ with high expression of IL-6) and their progeny. These activated immune cells may enter the pulmonary circulation in large numbers and played an immune-damaging role in severe-pulmonary-syndrome patients. The monoclonal antibodies that target the GM-CSF or interleukin-6 receptor may potentially prevent or curb immunopathology caused by COVID-19.
Figure 3. Pathogenic Th1 cells and inflammatory monocytes in severe COVID-19. Pathogenic CD4+ Th1 (GM-CSF+IFN-γ+) cells were rapidly activated to produce GM-CSF and other inflammatory cytokines to form a cascade signature of inflammatory monocytes (CD14+CD16+ with high expression of IL-6) and their progeny. These activated immune cells may enter the pulmonary circulation in large numbers and played an immune-damaging role in severe-pulmonary-syndrome patients. The monoclonal antibodies that target the GM-CSF or interleukin-6 receptor may potentially prevent or curb immunopathology caused by COVID-19.CC BY · PubMed Central

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Research works printed but not linked: 3

  1. Tian, 2020, J Thorac Oncol
  2. Li, 2020, J Med Virol, 92
  3. Wang, 2020, JAMA, 323

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Metadata

Authors
Zhou, Y., Fu, B., Zheng, X., Wang, D., Zhao, C., Qi, Y., Sun, R., Tian, Z., Xu, X., & Wei, H.
Affiliations
University of Science and Technology of China (CN)
Corresponding author
  • Xu, Xiaoling
  • Wei, Haiming
ORCID
Venue
National Science Review
Publisher
Oxford University Press (OUP)
Published
2020-03-13
Volume
7
Issue
6
Pages
998-1002
ISSN
  • 2053-714X (ISSN-L)
  • 2095-5138
DOI
10.1093/nsr/nwaa041
PMC
PMC7108005
OpenAlex
W3011230498
Cited by
1,295
References
36
Citations by year
2026: 14 · 2025: 48 · 2024: 78 · 2023: 131 · 2022: 201 · 2021: 392 · 2020: 431
FWCI
37.89
Type
journal article
Language
en
Open access
Licence
Locations
  • National Science Review (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • China National Center for Biotechnology Development (2020YFC0843800)
  • Natural Science Foundation of China (81788101, 81922028)
  • Youth Innovation Promotion Association of Chinese Academy of Sciences (2019442)
Topics
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
Keywords
COVID-19 pandemic, SARS-CoV-2, CD4+ T cells, inflammatory monocytes, CD14+CD16+ monocytes, interleukin-6, GM-CSF, cytokine storm, lung inflammation, immunopathology, monoclonal antibodies, IL-6 inhibition, severe pneumonia

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