Lung epithelial protein disulfide isomerase A3 (PDIA3) plays an important role in influenza infection, inflammation, and airway mechanics
Protein disulfide isomerases (PDI) are a family of redox chaperones that catalyze formation or isomerization of disulfide bonds in proteins. Previous studies have shown that one member, PDIA3, interacts with influenza A virus (IAV) hemagglutinin (HA), and this interaction is required for efficient o...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2019-04-01
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| Series: | Redox Biology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221323171831228X |
| _version_ | 1818296448745209856 |
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| author | Nicolas Chamberlain Bethany R. Korwin-Mihavics Emily M. Nakada Sierra R. Bruno David E. Heppner David G. Chapman Sidra M. Hoffman Albert van der Vliet Benjamin T. Suratt Oliver Dienz John F. Alcorn Vikas Anathy |
| author_facet | Nicolas Chamberlain Bethany R. Korwin-Mihavics Emily M. Nakada Sierra R. Bruno David E. Heppner David G. Chapman Sidra M. Hoffman Albert van der Vliet Benjamin T. Suratt Oliver Dienz John F. Alcorn Vikas Anathy |
| author_sort | Nicolas Chamberlain |
| collection | DOAJ |
| description | Protein disulfide isomerases (PDI) are a family of redox chaperones that catalyze formation or isomerization of disulfide bonds in proteins. Previous studies have shown that one member, PDIA3, interacts with influenza A virus (IAV) hemagglutinin (HA), and this interaction is required for efficient oxidative folding of HA in vitro. However, it is unknown whether these host-viral protein interactions occur during active infection and whether such interactions represent a putative target for the treatment of influenza infection. Here we show that PDIA3 is specifically upregulated in IAV-infected mouse or human lung epithelial cells and PDIA3 directly interacts with IAV-HA. Treatment with a PDI inhibitor, LOC14 inhibited PDIA3 activity in lung epithelial cells, decreased intramolecular disulfide bonds and subsequent oligomerization (maturation) of HA in both H1N1 (A/PR8/34) and H3N2 (X31, A/Aichi/68) infected lung epithelial cells. These reduced disulfide bond formation significantly decreased viral burden, and also pro-inflammatory responses from lung epithelial cells. Lung epithelial-specific deletion of PDIA3 in mice resulted in a significant decrease in viral burden and lung inflammatory-immune markers upon IAV infection, as well as significantly improved airway mechanics. Taken together, these results indicate that PDIA3 is required for effective influenza pathogenesis in vivo, and pharmacological inhibition of PDIs represents a promising new anti-influenza therapeutic strategy during pandemic and severe influenza seasons. |
| first_indexed | 2024-12-13T04:03:42Z |
| format | Article |
| id | doaj.art-282375a9e83041f5b51ed2149738bcfb |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-12-13T04:03:42Z |
| publishDate | 2019-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-282375a9e83041f5b51ed2149738bcfb2022-12-22T00:00:19ZengElsevierRedox Biology2213-23172019-04-0122Lung epithelial protein disulfide isomerase A3 (PDIA3) plays an important role in influenza infection, inflammation, and airway mechanicsNicolas Chamberlain0Bethany R. Korwin-Mihavics1Emily M. Nakada2Sierra R. Bruno3David E. Heppner4David G. Chapman5Sidra M. Hoffman6Albert van der Vliet7Benjamin T. Suratt8Oliver Dienz9John F. Alcorn10Vikas Anathy11Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, United StatesDepartment of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, United StatesDepartment of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, United StatesDepartment of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, United StatesDepartment of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, United StatesDepartment of Medicine, University of Vermont College of Medicine, Burlington, VT, United States; Woolcock Institute of Medical Research, University of Sydney, Sydney, Australia; Sydney Medical School, University of Sydney, Sydney, Australia; Translational Airways Group, School of Life Sciences, University of Technology, Sydney, AustraliaDepartment of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, United StatesDepartment of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, United StatesDepartment of Medicine, University of Vermont College of Medicine, Burlington, VT, United StatesDepartment of Surgery, University of Vermont College of Medicine, Burlington, VT, United StatesDivision of Pulmonary Medicine, Allergy, and Immunology, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, PA, United StatesDepartment of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, United States; Corresponding author.Protein disulfide isomerases (PDI) are a family of redox chaperones that catalyze formation or isomerization of disulfide bonds in proteins. Previous studies have shown that one member, PDIA3, interacts with influenza A virus (IAV) hemagglutinin (HA), and this interaction is required for efficient oxidative folding of HA in vitro. However, it is unknown whether these host-viral protein interactions occur during active infection and whether such interactions represent a putative target for the treatment of influenza infection. Here we show that PDIA3 is specifically upregulated in IAV-infected mouse or human lung epithelial cells and PDIA3 directly interacts with IAV-HA. Treatment with a PDI inhibitor, LOC14 inhibited PDIA3 activity in lung epithelial cells, decreased intramolecular disulfide bonds and subsequent oligomerization (maturation) of HA in both H1N1 (A/PR8/34) and H3N2 (X31, A/Aichi/68) infected lung epithelial cells. These reduced disulfide bond formation significantly decreased viral burden, and also pro-inflammatory responses from lung epithelial cells. Lung epithelial-specific deletion of PDIA3 in mice resulted in a significant decrease in viral burden and lung inflammatory-immune markers upon IAV infection, as well as significantly improved airway mechanics. Taken together, these results indicate that PDIA3 is required for effective influenza pathogenesis in vivo, and pharmacological inhibition of PDIs represents a promising new anti-influenza therapeutic strategy during pandemic and severe influenza seasons.http://www.sciencedirect.com/science/article/pii/S221323171831228X |
| spellingShingle | Nicolas Chamberlain Bethany R. Korwin-Mihavics Emily M. Nakada Sierra R. Bruno David E. Heppner David G. Chapman Sidra M. Hoffman Albert van der Vliet Benjamin T. Suratt Oliver Dienz John F. Alcorn Vikas Anathy Lung epithelial protein disulfide isomerase A3 (PDIA3) plays an important role in influenza infection, inflammation, and airway mechanics Redox Biology |
| title | Lung epithelial protein disulfide isomerase A3 (PDIA3) plays an important role in influenza infection, inflammation, and airway mechanics |
| title_full | Lung epithelial protein disulfide isomerase A3 (PDIA3) plays an important role in influenza infection, inflammation, and airway mechanics |
| title_fullStr | Lung epithelial protein disulfide isomerase A3 (PDIA3) plays an important role in influenza infection, inflammation, and airway mechanics |
| title_full_unstemmed | Lung epithelial protein disulfide isomerase A3 (PDIA3) plays an important role in influenza infection, inflammation, and airway mechanics |
| title_short | Lung epithelial protein disulfide isomerase A3 (PDIA3) plays an important role in influenza infection, inflammation, and airway mechanics |
| title_sort | lung epithelial protein disulfide isomerase a3 pdia3 plays an important role in influenza infection inflammation and airway mechanics |
| url | http://www.sciencedirect.com/science/article/pii/S221323171831228X |
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