Pro-inflammatory cytokines promote viral replication and cell cycle mediators in arenavirus-induced hepatitis.

TNF alpha;IL-6;LCMV;lymphocytic choriomeningitis virus;hepatocytes;AML-12;RAW 264.7

Gretchen E. Holz

University:University of Louisville

Department:Pharmacology and Toxicology

关键词: TNF alpha;    IL-6;    LCMV;    lymphocytic choriomeningitis virus;    hepatocytes;    AML-12;    RAW 264.7;   

Others  :  https://ir.library.louisville.edu/cgi/viewcontent.cgi?article=3652&context=etd

美国|英语

来源: The Universite of Louisville's Institutional Repository

【 摘 要 】

Lassa virus (LASV) is an arenavirus and causative agent of Lassa fever (LF), a viral hemorrhagic fever in West Africa for which there is no vaccine. Lymphocytic choriomeningitis virus (LCMV), is used as a surrogate to mimic LASV-induced liver pathology. LCMV-WE, not LCMV-ARM, causes disease in primates and mice characterized by hepatitis, high viral load, hepatocyte proliferation, and upregulated proliferative triggers (e.g. TNF-α, IL-6 ). We hypothesize LCMV-WE induces pathological hepatocyte proliferation via pro-inflammatory triggers (TNF-α, IL-6) from macrophages, leading to: increased viral replication, modulated cell cycle, and arrested cell cycle. RAW 264.7 macrophages and AML-12 hepatocytes, were used as models for liver cells and infected with LCMV. High LCMV-WE titers in RAW 264.7 resulted in upregulated TNF-α. LCMV-WE infection with TNF-α enhanced viral replication and modulated cell cycle, leading to arrest. Livers of fatal LASV-infected marmosets also displayed high viral load, IL-6, and upregulated p21, validating cell cycle arrest as key hepatic event. Altogether, these results validate AML-12 hepatocytes to study mechanisms of arenavirus-induced hepatitis.