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Stimulation of immature lung macrophages with intranasal interferon gamma in a novel neonatal mouse model of respiratory syncytial virus infection

Empey, KM and Orend, JG and Peebles, RS and Egaña, L and Norris, KA and Oury, TD and Kolls, JK (2012) Stimulation of immature lung macrophages with intranasal interferon gamma in a novel neonatal mouse model of respiratory syncytial virus infection. PLoS ONE, 7 (7).

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Abstract

Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and viral death in infants. Reduced CD8 T-cells and negligible interferon gamma (IFNγ) in the airway are associated with severe infant RSV disease, yet there is an abundance of alveolar macrophages (AM) and neutrophils. However, it is unclear, based on our current understanding of macrophage functional heterogeneity, if immature AM improve viral clearance or contribute to inflammation and airway obstruction in the IFNγ-deficient neonatal lung environment. The aim of the current study was to define the age-dependent AM phenotype during neonatal RSV infection and investigate their differentiation to classically activated macrophages (CAM) using i.n. IFNγ in the context of improving viral clearance. Neonatal and adult BALB/cJ mice were infected with 1×106 plaque forming units (PFU)/gram (g) RSV line 19 and their AM responses compared. Adult mice showed a rapid and robust CAM response, indicated by increases in major histocompatibility complex class II (MHC II), CD86, CCR7, and a reduction in mannose receptor (MR). Neonatal mice showed a delayed and reduced CAM response, likely due to undetectable IFNγ production. Intranasal (i.n.) treatment with recombinant mouse IFNγ (rIFNγ) increased the expression of CAM markers on neonatal AM, reduced viral lung titers, and improved weight gain compared to untreated controls with no detectable increase in CD4 or CD8 T-cell infiltration. In vitro infection of J774A.1 macrophages with RSV induced an alternatively activated macrophage (AAM) phenotype however, when macrophages were first primed with IFNγ, a CAM phenotype was induced and RSV spread to adjacent Hep-2 cells was reduced. These studies demonstrate that the neonatal AM response to RSV infection is abundant and immature, but can be exogenously stimulated to express the antimicrobial phenotype, CAM, with i.n. rIFNγ. © 2012 Empey et al.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Empey, KMkme33@pitt.eduKME33
Orend, JG
Peebles, RS
Egaña, L
Norris, KAkan1@pitt.eduKAN1
Oury, TDtdoury@pitt.eduTDOURY
Kolls, JK
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorSemple, Malcolm GracieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 6 July 2012
Date Type: Publication
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Journal or Publication Title: PLoS ONE
Volume: 7
Number: 7
DOI or Unique Handle: 10.1371/journal.pone.0040499
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Immunology
School of Medicine > Pathology
School of Pharmacy > Pharmaceutical Sciences
Refereed: Yes
Other ID: NLM PMC3391240
PubMed Central ID: PMC3391240
PubMed ID: 22792355
Date Deposited: 05 Oct 2012 19:06
Last Modified: 02 Feb 2019 16:58
URI: http://d-scholarship.pitt.edu/id/eprint/15586

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