title: Exposure to combustion generated environmentally persistent free radicals enhances severity of influenza virus infection.
abstract: BACKGROUND
  Exposures to elevated levels of particulate matter (PM) enhance severity of influenza virus infection in infants. The biological mechanism responsible for this phenomenon is unknown. The recent identification of environmentally persistent free radicals (EPFRs) associated with PM from a variety of combustion sources suggests its role in the enhancement of influenza disease severity.
  
  
  METHODS
  Neonatal mice (< seven days of age) were exposed to DCB230 (combustion derived PM with a chemisorbed EPFR), DCB50 (non-EPFR PM sample), or air for 30 minutes/day for seven consecutive days. Four days post-exposure, neonates were infected with influenza intranasally at 1.25 TCID50/neonate. Neonates were assessed for morbidity (% weight gain, peak pulmonary viral load, and viral clearance) and percent survival. Lungs were isolated and assessed for oxidative stress (8-isoprostanes and glutathione levels), adaptive immune response to influenza, and regulatory T cells (Tregs). The role of the EPFR was also assessed by use of transgenic mice expressing human superoxide dismutase 2.
  
  
  RESULTS
  Neonates exposed to EPFRs had significantly enhanced morbidity and decreased survival following influenza infection. Increased oxidative stress was also observed in EPFR exposed neonates. This correlated with increased pulmonary Tregs and dampened protective T cell responses to influenza infection. Reduction of EPFR-induced oxidative stress attenuated these effects.
  
  
  CONCLUSIONS
  Neonatal exposure to EPFR containing PM resulted in pulmonary oxidative stress and enhanced influenza disease severity. EPFR-induced oxidative stress resulted in increased presence of Tregs in the lungs and subsequent suppression of adaptive immune response to influenza.
authors.forename: Greg I
authors.initials: GI
authors.lastname: Lee
authors.forename: Jordy
authors.initials: J
authors.lastname: Saravia
authors.forename: Dahui
authors.initials: D
authors.lastname: You
authors.forename: Bishwas
authors.initials: B
authors.lastname: Shrestha
authors.forename: Sridhar
authors.initials: S
authors.lastname: Jaligama
authors.forename: Valerie Y
authors.initials: VY
authors.lastname: Hebert
authors.forename: Tammy R
authors.initials: TR
authors.lastname: Dugas
authors.forename: Stephania A
authors.initials: SA
authors.lastname: Cormier
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects; D000818:Animals; D000831:Animals, Newborn; D015237:Dinoprost / Q000031:analogs & derivatives / Q000378:metabolism; D005609:Free Radicals / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology / Q000472:pathogenicity*; D019570:Inhalation Exposure / Q000009:adverse effects; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000503:physiopathology / Q000821:virology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009976:Orthomyxoviridae Infections / Q000139:chemically induced* / Q000276:immunology / Q000503:physiopathology / Q000821:virology*; D018384:Oxidative Stress / Q000187:drug effects; D052638:Particulate Matter / Q000633:toxicity*; D018570:Risk Assessment; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000821:virology; D013997:Time Factors; D019562:Viral Load; D000099156:Superoxide Dismutase 2
chemical_list: D015237:Dinoprost; D005609:Free Radicals; D005978:Glutathione; D052638:Particulate Matter; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C075750:8-epi-prostaglandin F2alpha