title: IL-12 p80-dependent macrophage recruitment primes the host for increased survival following a lethal respiratory viral infection.
abstract: A protective immune response to a respiratory viral infection requires a series of coordinated cellular and molecular responses. We have previously demonstrated that increased expression of airway epithelial cell interleukin (IL)-12 p80, a macrophage chemoattractant, is associated with human respiratory viral infection and mediates post-viral mortality in the mouse. To better understand the role of IL-12 p80-dependent macrophage chemotaxis in mediating viral immunity, we generated a transgenic mouse strain utilizing a promoter to drive IL-12 p40 gene expression in the airway epithelium. This transgenic strain secreted biologically active IL-12 p80 in a lung-specific manner, and demonstrated a selective increase in the number of resident, unactivated airway macrophages at baseline. Following infection with a sublethal dose of mouse parainfluenza virus type 1 (Sendai virus), the transgenic mice demonstrated an earlier peak and decline in the number of airway inflammatory cells. The transgenic mice were resistant to a lethal dose of virus and this viral resistance was dependent on the increased number of airway macrophages at baseline as partial depletion prior to infection abrogated this phenotype. The survival advantage in the transgenic mice was independent of viral load but was associated with a more rapid decline in the number of airway inflammatory cells and concentrations of multiple chemokines including the CC chemokine ligand 2 (CCL2)/JE, CCL3/macrophage inflammatory protein (MIP)-1alpha, CCL4/MIP-1beta, and CCL5/RANTES. Collectively, these results suggest that IL-12 p80-driven increases in the number of resident airway macrophages prime the host for a protective immune response that can confer increased survival following a lethal respiratory viral infection.
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Gunsten
authors.forename: Cassandra L
authors.initials: CL
authors.lastname: Mikols
authors.forename: Mitchell H
authors.initials: MH
authors.lastname: Grayson
authors.forename: Reto A
authors.initials: RA
authors.lastname: Schwendener
authors.forename: Eugene
authors.initials: E
authors.lastname: Agapov
authors.forename: Rose M
authors.initials: RM
authors.lastname: Tidwell
authors.forename: Carolyn L
authors.initials: CL
authors.lastname: Cannon
authors.forename: Steven L
authors.initials: SL
authors.lastname: Brody
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Walter
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D018925:Chemokines / Q000378:metabolism; D002633:Chemotaxis / Q000276:immunology; D005260:Female; D018664:Interleukin-12 / Q000276:immunology*; D008168:Lung / Q000473:pathology; D008262:Macrophage Activation / Q000276:immunology; D016676:Macrophages, Alveolar / Q000276:immunology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D012141:Respiratory Tract Infections / Q000276:immunology* / Q000473:pathology / Q000821:virology; D010253:Respirovirus Infections / Q000276:immunology* / Q000473:pathology / Q000821:virology; D029082:Sendai virus / Q000302:isolation & purification; D019562:Viral Load
chemical_list: D018925:Chemokines; C513581:IL-12 p80, mouse; D018664:Interleukin-12
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