title: Signal transducer and activator of transcription 3 (Stat3) regulates host defense and protects mice against herpes simplex virus-1 (HSV-1) infection.
abstract: Signal transducer and activator of transcription 3 (STAT3) mediates cellular responses to multiple cytokines, governs gene expression, and regulates the development and activation of immune cells. STAT3 also modulates reactivation of latent herpes simplex virus-1 (HSV-1) in ganglia. However, it is unclear how STAT3 regulates the innate immune response during the early phase of HSV-1 lytic infection. Many cell types critical for the innate immunity are derived from the myeloid lineage. Therefore, in this study, we used myeloid-specificStat3knockout mice to investigate the role of STAT3 in the innate immune response against HSV-1. Our results demonstrate thatStat3knockout bone marrow-derived macrophages (BMMs) expressed decreased levels of interferon-α (IFN-α) and interferon-stimulated genes (ISGs) upon HSV-1 infection. In vivo, knockout mice were more susceptible to HSV-1, as marked by higher viral loads and more significant weight loss. Splenic expression of IFN-α and ISGs was reduced in the absence of STAT3, indicating that STAT3 is required for optimal type I interferon response to HSV-1. Expression of TNF-α and IL-12, cytokines that have been shown to limit HSV-1 replication and pathogenesis, was also significantly lower in knockout mice. Interestingly,Stat3knockout mice failed to expand the CD8+conventional DC (cDC) population upon HSV-1 infection, and this was accompanied by impaired NK and CD8 T cell activation. Collectively, our data demonstrate that myeloid-specificStat3deletion causes defects in multiple aspects of the immune system and that STAT3 has a protective role at the early stage of systemic HSV-1 infection.
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, North Carolina, USA.|Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA; and.
authors.forename: Hung-Ching
authors.initials: HC
authors.lastname: Hsia
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA; and.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Stopford
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA; and.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA; and.|Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Blossom
authors.initials: B
authors.lastname: Damania
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, North Carolina, USA; albert_baldwin@med.unc.edu.|Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA; and.
authors.forename: Albert S
authors.initials: AS
authors.lastname: Baldwin
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D001921:Brain / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004198:Disease Susceptibility; D006561:Herpes Simplex / Q000276:immunology / Q000517:prevention & control* / Q000821:virology*; D018259:Herpesvirus 1, Human / Q000502:physiology*; D054884:Host-Pathogen Interactions / Q000276:immunology*; D019426:Integrases / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D013154:Spleen / Q000473:pathology
chemical_list: D016207:Cytokines; D050796:STAT3 Transcription Factor; C045073:Cre recombinase; D019426:Integrases
keywords: dendritic cells; innate immunity; natural killer cells; type I interferons; viral infection