Live attenuated influenza vaccine strains elicit a greater innate immune response than antigenically-matched seasonal influenza viruses during infection of human nasal epithelial cell cultures.
Influenza viruses are global pathogens that infect approximately 10-20% of the world's population each year. Vaccines, including the live attenuated influenza vaccine (LAIV), are the best defense against influenza infections. The LAIV is a novel vaccine that actively replicates in the human nasal epithelium and elicits both mucosal and systemic protective immune responses. The differences in replication and innate immune responses following infection of human nasal epithelium with influenza seasonal wild type (WT) and LAIV viruses remain unknown. Using a model of primary differentiated human nasal epithelial cell (hNECs) cultures, we compared influenza WT and antigenically-matched cold adapted (CA) LAIV virus replication and the subsequent innate immune response including host cellular pattern recognition protein expression, host innate immune gene expression, secreted pro-inflammatory cytokine production, and intracellular viral RNA levels. Growth curves comparing virus replication between WT and LAIV strains revealed significantly less infectious virus production during LAIV compared with WT infection. Despite this disparity in infectious virus production the LAIV strains elicited a more robust innate immune response with increased expression of RIG-I, TLR-3, IFNβ, STAT-1, IRF-7, MxA, and IP-10. There were no differences in cytotoxicity between hNEC cultures infected with WT and LAIV strains as measured by basolateral levels of LDH. Elevated levels of intracellular viral RNA during LAIV as compared with WT virus infection of hNEC cultures at 33°C may explain the augmented innate immune response via the up-regulation of pattern recognition receptors and down-stream type I IFN expression. Taken together our results suggest that the decreased replication of LAIV strains in human nasal epithelial cells is associated with a robust innate immune response that differs from infection with seasonal influenza viruses, limits LAIV shedding and plays a role in the silent clinical phenotype seen in human LAIV inoculation.
Division of Pulmonary and Critical Care Medicine, Department of Medicine, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA; The Center for Environmental Medicine, Asthma and Lung Biology, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. Electronic address: William_Fischer@med.unc.edu.
William A
WA
Fischer
Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of North Carolina at Chapel Hill, 8033 Burnett-Womack, Chapel Hill, NC 27599-7219, USA.
Kelly D
KD
Chason
The Center for Environmental Medicine, Asthma and Lung Biology, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
Missy
M
Brighton
The Center for Environmental Medicine, Asthma and Lung Biology, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA; Department of Pediatrics, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
Ilona
I
Jaspers
D002478:Cells, Cultured; D018925:Chemokines / Q000276:immunology; D004847:Epithelial Cells / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D007252:Influenza Vaccines / Q000276:immunology*; D007251:Influenza, Human / Q000517:prevention & control*; D009666:Nose / Q000166:cytology; D009975:Orthomyxoviridae / Q000502:physiology; D012367:RNA, Viral / Q000302:isolation & purification; D014613:Vaccines, Attenuated / Q000276:immunology; D014779:Virus Replication
D018925:Chemokines; D007252:Influenza Vaccines; D012367:RNA, Viral; D014613:Vaccines, Attenuated
Human nasal epithelial cells; Influenza; Innate immune response; Live attenuated influenza vaccine (LAIV)