Anti-spike IgG Causes Severe Acute Lung Injury by Skewing Macrophage Responses During Acute SARS-CoV Infection

JCI Insight. 2019 Feb 21;4(4):e123158. doi: 10.1172/jci.insight.123158.

Abstract

Newly emerging viruses, such as severe acute respiratory syndrome coronavirus (SARS-CoV), Middle Eastern respiratory syndrome CoVs (MERS-CoV), and H7N9, cause fatal acute lung injury (ALI) by driving hypercytokinemia and aggressive inflammation through mechanisms that remain elusive. In SARS-CoV/macaque models, we determined that anti-spike IgG (S-IgG), in productively infected lungs, causes severe ALI by skewing inflammation-resolving response. Alveolar macrophages underwent functional polarization in acutely infected macaques, demonstrating simultaneously both proinflammatory and wound-healing characteristics. The presence of S-IgG prior to viral clearance, however, abrogated wound-healing responses and promoted MCP1 and IL-8 production and proinflammatory monocyte/macrophage recruitment and accumulation. Critically, patients who eventually died of SARS (hereafter referred to as deceased patients) displayed similarly accumulated pulmonary proinflammatory, absence of wound-healing macrophages, and faster neutralizing antibody responses. Their sera enhanced SARS-CoV-induced MCP1 and IL-8 production by human monocyte-derived wound-healing macrophages, whereas blockade of FcγR reduced such effects. Our findings reveal a mechanism responsible for virus-mediated ALI, define a pathological consequence of viral specific antibody response, and provide a potential target for treatment of SARS-CoV or other virus-mediated lung injury.

Keywords: Cytokines; Immunoglobulins; Infectious disease; Macrophages; Pulmonology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Lung Injury / blood
  • Acute Lung Injury / immunology*
  • Acute Lung Injury / virology
  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Antibodies, Neutralizing / administration & dosage
  • Antibodies, Neutralizing / blood
  • Antibodies, Neutralizing / immunology
  • Antibodies, Viral / administration & dosage
  • Antibodies, Viral / blood
  • Antibodies, Viral / immunology*
  • Cell Line
  • Disease Models, Animal
  • Female
  • Humans
  • Immunization, Passive / methods
  • Immunoglobulin G / administration & dosage
  • Immunoglobulin G / blood
  • Immunoglobulin G / immunology*
  • Lung / immunology
  • Lung / pathology
  • Lung / virology
  • Macaca mulatta
  • Macrophages, Alveolar / immunology
  • Macrophages, Alveolar / metabolism
  • Male
  • Middle Aged
  • SARS Virus / immunology*
  • SARS Virus / pathogenicity
  • Severe Acute Respiratory Syndrome / blood
  • Severe Acute Respiratory Syndrome / immunology*
  • Severe Acute Respiratory Syndrome / virology
  • Spike Glycoprotein, Coronavirus / genetics
  • Spike Glycoprotein, Coronavirus / immunology*
  • Vaccinia virus / genetics
  • Vaccinia virus / immunology
  • Viral Vaccines / administration & dosage
  • Viral Vaccines / immunology
  • Young Adult

Substances

  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Immunoglobulin G
  • Spike Glycoprotein, Coronavirus
  • Viral Vaccines