Exposure to ozone modulates human airway protease/antiprotease balance contributing to increased influenza A infection

PLoS One. 2012;7(4):e35108. doi: 10.1371/journal.pone.0035108. Epub 2012 Apr 9.

Abstract

Exposure to oxidant air pollution is associated with increased respiratory morbidities and susceptibility to infections. Ozone is a commonly encountered oxidant air pollutant, yet its effects on influenza infections in humans are not known. The greater Mexico City area was the primary site for the spring 2009 influenza A H1N1 pandemic, which also coincided with high levels of environmental ozone. Proteolytic cleavage of the viral membrane protein hemagglutinin (HA) is essential for influenza virus infectivity. Recent studies suggest that HA cleavage might be cell-associated and facilitated by the type II transmembrane serine proteases (TTSPs) human airway trypsin-like protease (HAT) and transmembrane protease, serine 2 (TMPRSS2), whose activities are regulated by antiproteases, such as secretory leukocyte protease inhibitor (SLPI). Based on these observations, we sought to determine how acute exposure to ozone may modulate cellular protease/antiprotease expression and function, and to define their roles in a viral infection. We utilized our in vitro model of differentiated human nasal epithelial cells (NECs) to determine the effects of ozone on influenza cleavage, entry, and replication. We show that ozone exposure disrupts the protease/antiprotease balance within the airway liquid. We also determined that functional forms of HAT, TMPRSS2, and SLPI are secreted from human airway epithelium, and acute exposure to ozone inversely alters their expression levels. We also show that addition of antioxidants significantly reduces virus replication through the induction of SLPI. In addition, we determined that ozone-induced cleavage of the viral HA protein is not cell-associated and that secreted endogenous proteases are sufficient to activate HA leading to a significant increase in viral replication. Our data indicate that pre-exposure to ozone disrupts the protease/antiprotease balance found in the human airway, leading to increased influenza susceptibility.

Publication types

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

MeSH terms

  • Adult
  • Air Pollutants / adverse effects
  • Antioxidants / pharmacology
  • Cells, Cultured
  • Humans
  • Influenza A virus / pathogenicity
  • Influenza, Human / chemically induced*
  • Nasal Mucosa / drug effects*
  • Nasal Mucosa / enzymology*
  • Nasal Mucosa / metabolism
  • Ozone / adverse effects*
  • Peptide Hydrolases / biosynthesis*
  • Peptide Hydrolases / metabolism
  • Protease Inhibitors / metabolism*
  • Secretory Leukocyte Peptidase Inhibitor / analysis
  • Secretory Leukocyte Peptidase Inhibitor / antagonists & inhibitors
  • Virus Internalization
  • Virus Replication

Substances

  • Air Pollutants
  • Antioxidants
  • Protease Inhibitors
  • SLPI protein, human
  • Secretory Leukocyte Peptidase Inhibitor
  • Ozone
  • Peptide Hydrolases