title: Quantitative Trait Locus Based Virulence Determinant Mapping of the HSV-1 Genome in Murine Ocular Infection: Genes Involved in Viral Regulatory and Innate Immune Networks Contribute to Virulence.
abstract: Herpes simplex virus type 1 causes mucocutaneous lesions, and is the leading cause of infectious blindness in the United States. Animal studies have shown that the severity of HSV-1 ocular disease is influenced by three main factors; innate immunity, host immune response and viral strain. We previously showed that mixed infection with two avirulent HSV-1 strains (OD4 and CJ994) resulted in recombinants that exhibit a range of disease phenotypes from severe to avirulent, suggesting epistatic interactions were involved. The goal of this study was to develop a quantitative trait locus (QTL) analysis of HSV-1 ocular virulence determinants and to identify virulence associated SNPs. Blepharitis and stromal keratitis quantitative scores were characterized for 40 OD4:CJ994 recombinants. Viral titers in the eye were also measured. Virulence quantitative trait locus mapping (vQTLmap) was performed using the Lasso, Random Forest, and Ridge regression methods to identify significant phenotypically meaningful regions for each ocular disease parameter. The most predictive Ridge regression model identified several phenotypically meaningful SNPs for blepharitis and stromal keratitis. Notably, phenotypically meaningful nonsynonymous variations were detected in the UL24, UL29 (ICP8), UL41 (VHS), UL53 (gK), UL54 (ICP27), UL56, ICP4, US1 (ICP22), US3 and gG genes. Network analysis revealed that many of these variations were in HSV-1 regulatory networks and viral genes that affect innate immunity. Several genes previously implicated in virulence were identified, validating this approach, while other genes were novel. Several novel polymorphisms were also identified in these genes. This approach provides a framework that will be useful for identifying virulence genes in other pathogenic viruses, as well as epistatic effects that affect HSV-1 ocular virulence.
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Aaron W
authors.initials: AW
authors.lastname: Kolb
authors.affiliation: Department of Computer Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.|Department of Biostatistics and Medical Informatics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Kyubin
authors.initials: K
authors.lastname: Lee
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Inna
authors.initials: I
authors.lastname: Larsen
authors.affiliation: Department of Biostatistics and Medical Informatics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.|Department of Computer Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Mark
authors.initials: M
authors.lastname: Craven
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.|Department of Medical Microbiology and Immunology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.|McPherson Eye Research Institute, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Curtis R
authors.initials: CR
authors.lastname: Brandt
mesh_terms: D000818:Animals; D001483:Base Sequence; D002522:Chlorocebus aethiops; D004279:DNA, Viral / Q000235:genetics; D015817:Eye Infections / Q000276:immunology* / Q000821:virology; D056726:Genetic Association Studies; D018259:Herpesvirus 1, Human / Q000235:genetics* / Q000276:immunology / Q000472:pathogenicity; D016014:Linear Models; D051379:Mice; D008969:Molecular Sequence Data; D040641:Quantitative Trait Loci / Q000235:genetics*; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D014709:Vero Cells; D014774:Virulence; D037521:Virulence Factors; D014779:Virus Replication
chemical_list: D004279:DNA, Viral; D037521:Virulence Factors