Expression of elevated levels of pro-inflammatory cytokines in SARS-CoV-infected ACE2+ cells in SARS patients: relation to the acute lung injury and pathogenesis of SARS

J Pathol. 2006 Nov;210(3):288-97. doi: 10.1002/path.2067.

Abstract

The authors have previously shown that acute lung injury (ALI) produces a wide spectrum of pathological processes in patients who die of severe acute respiratory syndrome (SARS) and that the SARS coronavirus (SARS-CoV) nucleoprotein is detectable in the lungs, and other organs and tissues, in these patients. In the present study, immunohistochemistry (IHC) and in situ hybridization (ISH) assays were used to analyse the expression of angiotensin-converting enzyme 2 (ACE2), SARS-CoV spike (S) protein, and some pro-inflammatory cytokines (PICs) including MCP-1, TGF-beta1, TNF-alpha, IL-1beta, and IL-6 in autopsy tissues from four patients who died of SARS. SARS-CoV S protein and its RNA were only detected in ACE2+ cells in the lungs and other organs, indicating that ACE2-expressing cells are the primary targets for SARS-CoV infection in vivo in humans. High levels of PICs were expressed in the SARS-CoV-infected ACE2+ cells, but not in the uninfected cells. These results suggest that cells infected by SARS-CoV produce elevated levels of PICs which may cause immuno-mediated damage to the lungs and other organs, resulting in ALI and, subsequently, multi-organ dysfunction. Therefore application of PIC antagonists may reduce the severity and mortality of SARS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Chemokine CCL2 / analysis
  • Cytokines / analysis*
  • Humans
  • Immunohistochemistry / methods
  • In Situ Hybridization / methods
  • Interleukin-1beta / analysis
  • Interleukin-6 / analysis
  • Lung / chemistry*
  • Lung / pathology
  • Male
  • Models, Biological
  • Peptidyl-Dipeptidase A / analysis*
  • Severe Acute Respiratory Syndrome / immunology
  • Severe Acute Respiratory Syndrome / metabolism*
  • Severe Acute Respiratory Syndrome / pathology
  • Transforming Growth Factor beta1 / analysis
  • Tumor Necrosis Factor-alpha / analysis
  • Viral Proteins / analysis

Substances

  • CCL2 protein, human
  • Chemokine CCL2
  • Cytokines
  • Interleukin-1beta
  • Interleukin-6
  • Transforming Growth Factor beta1
  • Tumor Necrosis Factor-alpha
  • Viral Proteins
  • Peptidyl-Dipeptidase A
  • angiotensin converting enzyme 2