Date on Master's Thesis/Doctoral Dissertation

12-2016

Document Type

Master's Thesis

Degree Name

M.S.

Department

Pharmacology and Toxicology

Degree Program

Pharmacology and Toxicology, MS

Committee Chair

Lukashevich, Igor

Committee Co-Chair (if applicable)

Chung, Donghoon

Committee Member

Chung, Donghoon

Committee Member

Cave, Matthew

Author's Keywords

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

Abstract

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.

Download

Share

COinS