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 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.
Recommended Citation
Holz, Gretchen E., "Pro-inflammatory cytokines promote viral replication and cell cycle mediators in arenavirus-induced hepatitis." (2016). Electronic Theses and Dissertations. Paper 2616.
https://doi.org/10.18297/etd/2616
