title: Respiratory syncytial virus infection is associated with an altered innate immunity and a heightened pro-inflammatory response in the lungs of preterm lambs.
abstract: BACKGROUND
  Factors explaining the greater susceptibility of preterm infants to severe lower respiratory infections with respiratory syncytial virus (RSV) remain poorly understood. Fetal/newborn lambs are increasingly appreciated as a model to study key elements of RSV infection in newborn infants due to similarities in lung alveolar development, immune response, and susceptibility to RSV. Previously, our laboratory demonstrated that preterm lambs had elevated viral antigen and developed more severe lesions compared to full-term lambs at seven days post-infection. Here, we compared the pathogenesis and immunological response to RSV infection in lungs of preterm and full-term lambs.
  
  
  METHODS
  Lambs were delivered preterm by Caesarian section or full-term by natural birth, then inoculated with bovine RSV (bRSV) via the intratracheal route. Seven days post-infection, lungs were collected for evaluation of cytokine production, histopathology and cellular infiltration.
  
  
  RESULTS
  Compared to full-term lambs, lungs of preterm lambs had a heightened pro-inflammatory response after infection, with significantly increased MCP-1, MIP-1α, IFN-γ, TNF-α and PD-L1 mRNA. RSV infection in the preterm lung was characterized by increased epithelial thickening and periodic acid-Schiff staining, indicative of glycogen retention. Nitric oxide levels were decreased in lungs of infected preterm lambs compared to full-term lambs, indicating alternative macrophage activation. Although infection induced significant neutrophil recruitment into the lungs of preterm lambs, neutrophils produced less myeloperoxidase than those of full-term lambs, suggesting decreased functional activation.
  
  
  CONCLUSIONS
  Taken together, our data suggest that increased RSV load and inadequate immune response may contribute to the enhanced disease severity observed in the lungs of preterm lambs.
authors.affiliation: Department of Veterinary Pathology, College of Veterinary Medicine, Iowa State University, Ames, IA 50011, USA. fsow@yahoo.com
authors.forename: Fatoumata B
authors.initials: FB
authors.lastname: Sow
authors.forename: Jack M
authors.initials: JM
authors.lastname: Gallup
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Krishnan
authors.forename: Andriani C
authors.initials: AC
authors.lastname: Patera
authors.forename: Joann
authors.initials: J
authors.lastname: Suzich
authors.forename: Mark R
authors.initials: MR
authors.lastname: Ackermann
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D053148:Caspase 3 / Q000378:metabolism; D002585:Cesarean Section; D018932:Chemokine CCL2 / Q000235:genetics; D054405:Chemokine CCL3 / Q000235:genetics; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D005865:Gestational Age; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism*; D007371:Interferon-gamma / Q000235:genetics; D008168:Lung / Q000276:immunology* / Q000473:pathology / Q000821:virology; D008262:Macrophage Activation; D018375:Neutrophil Activation; D009569:Nitric Oxide / Q000378:metabolism; D011024:Pneumonia, Viral / Q000276:immunology* / Q000473:pathology / Q000821:virology; D047928:Premature Birth; D012333:RNA, Messenger / Q000378:metabolism; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology* / Q000473:pathology / Q000821:virology; D012136:Respiratory Syncytial Viruses / Q000276:immunology* / Q000472:pathogenicity; D012756:Sheep; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D015703:Antigens, CD; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D016207:Cytokines; D018836:Inflammation Mediators; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007371:Interferon-gamma; D053148:Caspase 3