Signal transducer and activator of transcription 3 (Stat3) regulates host defense and protects mice against herpes simplex virus-1 (HSV-1) infection

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

Zhang, Zhigang¹  Baldwin, Albert S.¹  Stopford, Charles M.⁵  Damania, Blossom⁵ 

[1] and;and..Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, USA;..Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA;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

关键词: innate immunity;    viral infection;    type I interferons;    dendritic cells;    natural killer cells;   

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

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-specific Stat3 knockout mice to investigate the role of STAT3 in the innate immune response against HSV-1. Our results demonstrate that Stat3 knockout 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, Stat3 knockout 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-specific Stat3 deletion 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.

【 授权许可】

CC BY