title: Mixed Lineage Kinase 3 deficiency delays viral clearance in the lung and is associated with diminished influenza-induced cytopathic effect in infected cells.
abstract: Influenza virus leads to acute respiratory disease resulting in seasonal epidemics and periodic pandemics. Little is known about the signaling events that regulate host defense to influenza. One particular pathway, the c-Jun amino-terminal kinase (JNK) cascade is activated following influenza infection and blocking JNK leads to enhanced viral replication. We hypothesize that Mixed Lineage Kinase 3 (MLK3), an upstream regulator of JNK, is involved in the host response to influenza. To test this, wild-type and MLK3-/- mice were infected with pathogenic strain of influenza A virus, A/PR/8/34 (PR8). Although, cellular and humoral immune responses were similar between wild-type and MLK3-/- hosts, the viral load in the lungs was comparatively higher in MLK3-/- mice at day 8 post-infection. Consistent with this, MLK3-/- murine lung fibroblast and epithelial cells had prolonged survival and increased virion production following infection compared to wild-type. These findings support a role for MLK3 in viral production during influenza infection.
authors.affiliation: Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA. Emily_desmet@urmc.rochester.edu
authors.forename: Emily A
authors.initials: EA
authors.lastname: Desmet
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Hollenbaugh
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Sime
authors.forename: Terry W
authors.initials: TW
authors.lastname: Wright
authors.forename: David J
authors.initials: DJ
authors.lastname: Topham
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Sant
authors.forename: Toru
authors.initials: T
authors.lastname: Takimoto
authors.forename: Stephen
authors.initials: S
authors.lastname: Dewhurst
authors.forename: Sanjay B
authors.initials: SB
authors.lastname: Maggirwar
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D002470:Cell Survival; D003588:Cytopathogenic Effect, Viral; D004847:Epithelial Cells / Q000821:virology; D005347:Fibroblasts / Q000821:virology; D009980:Influenza A virus / Q000276:immunology*; D008168:Lung / Q000821:virology*; D020930:MAP Kinase Kinase Kinases / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000473:pathology* / Q000821:virology; D013601:T-Lymphocytes / Q000276:immunology; D019562:Viral Load; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
chemical_list: D000914:Antibodies, Viral; D020930:MAP Kinase Kinase Kinases; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11