Abstract
Experimental data indicate that during persistent infection, lymphocytic choriomeningitis virus (LCMV) may both directly or indirectly modulate regulatory cellular processes and alter cellular functions that are not critical for survival, but are essential for cell homeostasis. In order to shed more light on these processes, two-dimensional differential in-gel electrophoresis (2D-DIGE) and MALDI-TOF tandem mass spectrometry were used to determine the proteome response of the HeLa cell line to persistent LCMV infection. Quantitative analysis revealed 24 differentially abundant proteins. Functional analysis showed that LCMV-responsive proteins were primarily involved in metabolism, stress, and the defense response. Among identified proteins, we discovered significant changes for peroxiredoxins, a family of antioxidant enzymes. Decreased amount of these antioxidant proteins correlated with elevation of reactive oxygen species (ROS) in infected cells. Increased levels of ROS were accompanied by changes in the pattern of telomere restriction fragments (TRFs) in infected cells and mediated activation of hypoxia-inducible transcription factor-1 (HIF-1) and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways. Moreover, treatment with antioxidants resulted in reduced levels of viral nucleoprotein, indicating a connection between ROS-dependent signaling and viral replication.
Highlights
Persistent viral infections are currently one of the most important global health problems in the world
To investigate global protein changes in Human cervical carcinoma cells (HeLa) cells during persistent infection with the MX strain of lymphocytic choriomeningitis virus (LCMV), equal amounts of total proteins prepared from mock-infected and LCMV-infected HeLa cells were subjected to 2D-DIGE analysis
Another antioxidant enzyme, thioredoxin reductase 1 (TrxR1), was more abundant in infected cells (Table 1), yet this seems to be insufficient to counterbalance the decrease in the levels of peroxiredoxins
Summary
Persistent viral infections are currently one of the most important global health problems in the world. LCMV is a neglected human pathogen of clinical significance that may lead to severe disease and consequences after prenatal infection (Barton and Mets, 1999; Mets et al, 2000; Barton et al, 2002), and life-threatening conditions in immunosuppressed individuals (Fischer et al, 2006; Palacios et al, 2008; Macneil et al, 2011). Several mammarenaviruses, such as the Lassa, Junin, and Machupo viruses, are associated with severe hemorrhagic fever disease with significant morbidity and mortality in humans, representing serious public health concerns in their endemic regions (Geisbert and Jahrling, 2004; Buchmeier et al, 2007). Understanding how viruses and the hosts interact and how their interactions change over time would help in the rational design of targeting compounds
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