title: Functional genomics reveals an essential and specific role for Stat1 in protection of the central nervous system following herpes simplex virus corneal infection.
abstract: Innate immune deficiencies result in a spectrum of severe clinical outcomes following infection. In particular, there is a strong association between loss of the signal transducer and activator of transcription (Stat) pathway, breach of the blood-brain barrier (BBB), and virus-induced neuropathology. The gene signatures that characterize resistance, disease, and mortality in the virus-infected nervous system have not been defined. Herpes simplex virus type 1 (HSV-1) is commonly associated with encephalitis in humans, and humans and mice lacking Stat1 display increased susceptibility to HSV central nervous system (CNS) infections. In this study, two HSV-1 strains were used, KOS (wild type [WT]), and Δvhs, an avirulent recombinant lacking the virion host shutoff (vhs) function. In addition, two mouse strains were used: strain 129 (control) and a Stat1-deficient (Stat1(-/-)) strain. Using combinations of these virus and mouse strains, we established a model of infection resulting in three different outcomes: viral clearance without neurological disease (Δvhs infection of control mice), neurological disease followed by viral clearance (Δvhs infection of Stat1(-/-) mice and WT infection of control mice), or neurological disease followed by death (WT infection of Stat1(-/-) mice). Through the use of functional genomics on the infected brain stems, we determined gene signatures that were representative of the three infection outcomes. We demonstrated a pathological signature in the brain stem of Stat1-deficient mice characterized by upregulation of transcripts encoding chemokine receptors, inflammatory markers, neutrophil chemoattractants, leukocyte adhesion proteins, and matrix metalloproteases. Additionally, there was a greater than 100-fold increase in the inflammatory markers interleukin 1β (IL-1β) and IL-6. Consistent with this gene signature, we demonstrated profound CNS inflammation with a concomitant lethal breach of the BBB. Taken together, our results indicated an essential role for normal Stat1-dependent signaling in mediating a nonpathological immune response to viral CNS infection.
authors: Dartmouth Medical School, Department of Microbiology and Immunology, 630E Borwell Building, One Medical Center Drive HB 7556, Lebanon, NH 03756, USA.
authors: Tracy Jo
authors: TJ
authors: Pasieka
authors: Cristian
authors: C
authors: Cilloniz
authors: Victoria S
authors: VS
authors: Carter
authors: Pamela
authors: P
authors: Rosato
authors: Michael G
authors: MG
authors: Katze
authors: David A
authors: DA
authors: Leib
mesh_terms: D000818:Animals; D001933:Brain Stem / Q000473:pathology / Q000821:virology; D016207:Cytokines / Q000096:biosynthesis; D020803:Encephalitis, Herpes Simplex / Q000276:immunology* / Q000517:prevention & control*; D020869:Gene Expression Profiling; D018259:Herpesvirus 1, Human / Q000276:immunology* / Q000472:pathogenicity*; D006651:Histocytochemistry; D016849:Keratitis, Herpetic / Q000150:complications / Q000276:immunology* / Q000821:virology*; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000276:immunology*; D016019:Survival Analysis
chemical_list: D016207:Cytokines; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse