title: Murine Norovirus Infection Variably Alters Atherosclerosis in Mice Lacking Apolipoprotein E.
abstract: Macrophages play a key role in the development of atherosclerosis. Murine noroviruses (MNV) are highly prevalent in research mouse colonies and infect macrophages and dendritic cells. Our laboratory found that MNV4 infection in mice lacking the LDL receptor alters the development of atherosclerosis, potentially confounding research outcomes. Therefore, we investigated whether MNV4 likewise altered atherosclerosis in ApoE(-/-) mice. In the presence of oxidized LDL, MNV4 infection of ApoE(-/-) bone marrow-derived macrophages increased the gene expression of the inflammatory markers inducible nitric oxide synthase, monocyte chemoattractant protein 1, and IL6. In addition, proteins involved in cholesterol transport were altered in MNV4-infected ApoE -/- bone marrow-derived macrophages and consisted of increased CD36 and decreased ATP-binding cassette transporter A1. MNV4 infection of ApoE(-/-) mice at 12 wk of age (during the development of atherosclerosis) had a variable effect on atherosclerotic lesion size. In one study, MNV4 significantly increased atherosclerotic plaque area whereas in a second study, no effect was observed. Compared with controls, MNV4-infected mice had higher circulating Ly6C-positive monocytes, and viral RNA was detected in the aortas of some mice, suggesting potential mechanisms by which MNV4 alters disease progression. Plaque size did not differ when ApoE -/- mice were infected at 4 wk of age (early during disease development) or in ApoE -/- mice maintained on a high-fat, high-cholesterol diet. Therefore, these data show that MNV4 has the potential to exert a variable and unpredictable effect on atherosclerosis in ApoE(-/-) mice. We therefore propose that performing experiments in MNV-free mouse colonies is warranted.
authors.affiliation: Department of Comparative Medicine, Department of Medicine, University of Washington, Seattle, Washington, USA. chuckhsu@uw.edu.
authors.forename: Charlie C
authors.initials: CC
authors.lastname: Hsu
authors.affiliation: Department of Comparative Medicine, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Jisun
authors.initials: J
authors.lastname: Paik
authors.affiliation: Department of Comparative Medicine, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Thea L
authors.initials: TL
authors.lastname: Brabb
authors.affiliation: Department of Division of Cardiology, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: O'Brien
authors.affiliation: Department of Division of Cardiology, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Jinkyu
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Division of Cardiology, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Brittany G
authors.initials: BG
authors.lastname: Sullivan
authors.affiliation: Department of Pathology, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Hudkins
authors.affiliation: Department of Comparative Medicine, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Audrey
authors.initials: A
authors.lastname: Seamons
authors.affiliation: Department of Comparative Medicine, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Finley
authors.affiliation: Department of Comparative Medicine, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Stacey M
authors.initials: SM
authors.lastname: Meeker
authors.affiliation: Department of Comparative Medicine, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Lillian
authors.initials: L
authors.lastname: Maggio-Price
mesh_terms: D000367:Age Factors; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D017250:Caliciviridae Infections / Q000821:virology*; D002791:Cholesterol, Dietary / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D018450:Disease Progression; D020022:Genetic Predisposition to Disease; D018836:Inflammation Mediators / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D029322:Norovirus / Q000472:pathogenicity*; D010641:Phenotype; D058226:Plaque, Atherosclerotic; D000067996:RAW 264.7 Cells
chemical_list: D001057:Apolipoproteins E; D002791:Cholesterol, Dietary; D016207:Cytokines; D018836:Inflammation Mediators; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein