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Exposure to ozone modulates human airway protease/antiprotease balance contributing to increased influenza A infection
Kesic, M., M. Meyer, R. Bauer, AND I. Jaspers. Exposure to ozone modulates human airway protease/antiprotease balance contributing to increased influenza A infection. PLoS ONE . Public Library of Science, San Francisco, CA, 7(4):e35108, 1-12, (2012).
Despite large-scale efforts in vaccination and antiviral therapies, the morbidity and mortality rates associated with influenza infections have not significandy changed in recent years [4,5]. In the context of potentially pandemic respiratory viral infections, it is important to identify molecular targets/pathways for therapeutic intervention to protect susceptible sub-populations. Epidemiologic studies show that exposure to inhaled oxidants such as cigarette smoke, diesel exhaust, and ozone ran modulate immune function and increase susceptibility to respiratory viral infections [6,7,8,9,10,11].
Exposure to oxidant air pollution is associated with Increased respiratory morbiditses 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 Hi Ni pandemic which also coincided with high levels of environmental ozone. Proteolytic cleavage of the viral membrane protein hemagglutinin (HA) is essential foi influenza virus infectivity Recent studies suggest that HA cleavage might be cell-associated and facilitated by the type Ii transmembrane serine proteases (lISPs) human airway trypsin like protease (HAl) and transmembrane protease serlne 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 arid fi.irictlon. 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 in5luenza cleavage entry, and replication We show that ozone exposure disrupts the proteaselantsprotease balance within the airway liquid We also determined that functional forms of HAT TMPRSS2 and SLPl are secreted from human airway epithellum and acute exposure to ozone inversely alters their expression levels We also show that addition of aptpoxidaiits significantly reduces virus replication through the induction of SLPI In addition, we determined that ozone-induced deavage 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 proteasefantrotease balance found in the human airway leading to increased influenza susceptibility.