Prior immunization with severe acute respiratory syndrome (SARS)-associated coronavirus (SARS-CoV) nucleocapsid protein causes severe pneumonia in mice infected with SARS-CoV

J Immunol. 2008 Nov 1;181(9):6337-48. doi: 10.4049/jimmunol.181.9.6337.

Abstract

The details of the mechanism by which severe acute respiratory syndrome-associated coronavirus (SARS-CoV) causes severe pneumonia are unclear. We investigated the immune responses and pathologies of SARS-CoV-infected BALB/c mice that were immunized intradermally with recombinant vaccinia virus (VV) that expressed either the SARS-CoV spike (S) protein (LC16m8rVV-S) or simultaneously all the structural proteins, including the nucleocapsid (N), membrane (M), envelope (E), and S proteins (LC16m8rVV-NMES) 7-8 wk before intranasal SARS-CoV infection. The LC16m8rVV-NMES-immunized group exhibited as severe pneumonia as the control groups, although LC16m8rVV-NMES significantly decreased the pulmonary SARS-CoV titer to the same extent as LC16m8rVV-S. To identify the cause of the exacerbated pneumonia, BALB/c mice were immunized with recombinant VV that expressed the individual structural proteins of SARS-CoV (LC16mOrVV-N, -M, -E, -S) with or without LC16mOrVV-S (i.e., LC16mOrVV-N, LC16mOrVV-M, LC16mOrVV-E, or LC16mOrVV-S alone or LC16mOrVV-N + LC16mOrVV-S, LC16mOrVV-M + LC16mOrVV-S, or LC16mOrVV-E + LC16mOrVV-S), and infected with SARS-CoV more than 4 wk later. Both LC16mOrVV-N-immunized mice and LC16mOrVV-N + LC16mOrVV-S-immunized mice exhibited severe pneumonia. Furthermore, LC16mOrVV-N-immunized mice upon infection exhibited significant up-regulation of both Th1 (IFN-gamma, IL-2) and Th2 (IL-4, IL-5) cytokines and down-regulation of anti-inflammatory cytokines (IL-10, TGF-beta), resulting in robust infiltration of neutrophils, eosinophils, and lymphocytes into the lung, as well as thickening of the alveolar epithelium. These results suggest that an excessive host immune response against the nucleocapsid protein of SARS-CoV is involved in severe pneumonia caused by SARS-CoV infection. These findings increase our understanding of the pathogenesis of SARS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Viral / biosynthesis
  • Cell Line
  • Chlorocebus aethiops
  • Cytokines / biosynthesis
  • Female
  • Humans
  • Lung / immunology
  • Lung / pathology
  • Lung / virology
  • Mice
  • Mice, Inbred BALB C
  • Nucleocapsid Proteins / administration & dosage
  • Nucleocapsid Proteins / immunology*
  • Pneumonia, Viral / immunology*
  • Pneumonia, Viral / pathology
  • Pneumonia, Viral / virology
  • RNA, Messenger / biosynthesis
  • Rabbits
  • SARS Virus / immunology*
  • Severe Acute Respiratory Syndrome / pathology
  • Severe Acute Respiratory Syndrome / prevention & control*
  • Severe Acute Respiratory Syndrome / virology
  • Severity of Illness Index
  • Vero Cells
  • Viral Vaccines / administration & dosage
  • Viral Vaccines / immunology*

Substances

  • Antibodies, Viral
  • Cytokines
  • Nucleocapsid Proteins
  • RNA, Messenger
  • Viral Vaccines
  • nucleocapsid protein, Coronavirus