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Respiratory viral infection in lung transplantation induces exosomes that trigger chronic rejection

Authors
  • Gunasekaran, Muthukumar1
  • Bansal, Sandhya1
  • Ravichandran, Ranjithkumar1
  • Sharma, Monal1
  • Perincheri, Sudhir2
  • Rodriguez, Francisco1
  • Hachem, Ramsey3
  • Fisher, Cynthia E.4
  • Limaye, Ajit P.4
  • Omar, Ashraf1
  • Smith, Michael A.1
  • Bremner, Ross M.1
  • Mohanakumar, Thalachallour1
  • 1 St. Joseph's Hospital and Medical Center, Norton Thoracic Institute, Phoenix, Arizona
  • 2 Department of Pathology, Yale School of Medicine, New Haven, Connecticut
  • 3 Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
  • 4 Division of Allergy and Infectious Diseases, University of Washington, Seattle, Washington
Type
Published Article
Journal
The Journal of Heart and Lung Transplantation
Publisher
International Society for Heart and Lung Transplantation.
Publication Date
Jan 21, 2020
Volume
39
Issue
4
Pages
379–388
Identifiers
DOI: 10.1016/j.healun.2019.12.009
PMID: 32033844
PMCID: PMC7102671
Source
PubMed Central
Keywords
License
Unknown

Abstract

BACKGROUND Respiratory viral infections can increase the risk of chronic lung allograft dysfunction after lung transplantation, but the mechanisms are unknown. In this study, we determined whether symptomatic respiratory viral infections after lung transplantation induce circulating exosomes that contain lung-associated self-antigens and assessed whether these exosomes activate immune responses to self-antigens. METHODS Serum samples were collected from lung transplant recipients with symptomatic lower- and upper-tract respiratory viral infections and from non-symptomatic stable recipients. Exosomes were isolated via ultracentrifugation; purity was determined using sucrose cushion; and presence of lung self-antigens, 20S proteasome, and viral antigens for rhinovirus, coronavirus, and respiratory syncytial virus were determined using immunoblot. Mice were immunized with circulating exosomes from each group and resulting differential immune responses and lung histology were analyzed. RESULTS Exosomes containing self-antigens, 20S proteasome, and viral antigens were detected at significantly higher levels ( p < 0.05) in serum of recipients with symptomatic respiratory viral infections ( n = 35) as compared with stable controls ( n = 32). Mice immunized with exosomes from recipients with respiratory viral infections developed immune responses to self-antigens, fibrosis, small airway occlusion, and significant cellular infiltration; mice immunized with exosomes from controls did not ( p < 0.05). CONCLUSIONS Circulating exosomes isolated from lung transplant recipients diagnosed with respiratory viral infections contained lung self-antigens, viral antigens, and 20S proteasome and elicited immune responses to lung self-antigens that resulted in development of chronic lung allograft dysfunction in immunized mice.

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