title: Human Metapneumovirus Impairs Apoptosis of Nasal Epithelial Cells in Asthma via HSP70.
abstract: Asthmatics are highly susceptible to respiratory viral infections, possibly due to impaired innate immunity. However, the exact mechanisms of susceptibility are likely to differ amongst viruses. Therefore, we infected primary nasal epithelial cells (NECs) from adults with mild-to-moderate asthma, with respiratory syncytial virus (RSV) or human metapneumovirus (hMPV) in vitro and investigated the antiviral response. NECs from these asthmatics supported elevated hMPV but not RSV infection, compared to non-asthmatic controls. This correlated with reduced apoptosis and reduced activation of caspase-9 and caspase-3/7 in response to hMPV, but not RSV. The expression of heat shock protein 70 (HSP70), a known inhibitor of caspase activation and subsequent apoptosis, was amplified in response to hMPV infection. Chemical inhibition of HSP70 function restored caspase activation and reduced hMPV infection in NECs from asthmatic subjects. There was no impairment in the production of IFN by NECs from asthmatics in response to either hMPV or RSV, demonstrating that increased infection of asthmatic airway cells by hMPV is IFN-independent. This study demonstrates, for the first time, a mechanism for elevated hMPV infection in airway epithelial cells from adult asthmatics and identifies HSP70 as a potential target for antiviral and asthma therapies.
authors.affiliation: School of Medicine, The University of Queensland, Brisbane, Qld., Australia.
authors.forename: Engin
authors.initials: E
authors.lastname: Baturcam
authors.forename: Natale
authors.initials: N
authors.lastname: Snape
authors.forename: Tiong Han
authors.initials: TH
authors.lastname: Yeo
authors.forename: Johanna
authors.initials: J
authors.lastname: Schagen
authors.forename: Emma
authors.initials: E
authors.lastname: Thomas
authors.forename: Jayden
authors.initials: J
authors.lastname: Logan
authors.forename: Sally
authors.initials: S
authors.lastname: Galbraith
authors.forename: Natasha
authors.initials: N
authors.lastname: Collinson
authors.forename: Simon
authors.initials: S
authors.lastname: Phipps
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Fantino
authors.forename: Peter D
authors.initials: PD
authors.lastname: Sly
authors.forename: Kirsten M
authors.initials: KM
authors.lastname: Spann
mesh_terms: D000328:Adult; D017209:Apoptosis; D001249:Asthma / Q000150:complications / Q000276:immunology*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007372:Interferons / Q000378:metabolism; D008297:Male; D029121:Metapneumovirus / Q000276:immunology*; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009297:Nasal Mucosa / Q000502:physiology* / Q000821:virology; D018184:Paramyxoviridae Infections / Q000150:complications / Q000276:immunology*; D011684:Purine Nucleosides / Q000494:pharmacology; D018357:Respiratory Syncytial Virus Infections / Q000150:complications / Q000276:immunology; D012136:Respiratory Syncytial Viruses / Q000276:immunology; D055815:Young Adult
chemical_list: D018840:HSP70 Heat-Shock Proteins; D011684:Purine Nucleosides; C550733:VER 155008; D007372:Interferons; D053148:Caspase 3; D053453:Caspase 9