Abstract
Viruses interact intimately with the host cell at nearly every stage of replication, and the cell model that is chosen to study virus infection is critically important. Although primary cells reflect the phenotype of healthy cells in vivo better than cell lines, their limited lifespan makes experimental manipulation challenging. However, many tumor-derived and artificially immortalized cell lines have defects in induction of interferon-stimulated genes and other antiviral defenses. These defects can affect virus replication, especially when cells are infected at lower, more physiologically relevant, multiplicities of infection. Understanding the selective pressures and mechanisms underlying the loss of innate signaling pathways is helpful to choose immortalized cell lines without impaired antiviral defense. We describe the trials and tribulations we encountered while searching for an immortalized cell line with intact innate signaling, and how directed immortalization of primary cells avoids many of the pitfalls of spontaneous immortalization.
Highlights
As an obligate intracellular parasite, a virus’s success depends on strategies evolved to exploit host cells and the suitability of these strategies to overcome cellular antiviral defenses
(dsRNA) analog polyinosinic-polycytidylic acid, most do not mount an IFN-independent response to low-level infection
While in vitro studies will never be able to recapitulate the totality and complexity of the host antiviral response to infection, understanding specific virus–host interactions at the molecular level requires the use of model systems that best reflect the status of the host organism
Summary
As an obligate intracellular parasite, a virus’s success depends on strategies evolved to exploit host cells and the suitability of these strategies to overcome cellular antiviral defenses. Since the IFN-independent response is tuned to low-level infection, only cells with intact antiviral defense pathways are able to respond properly. While tumor-derived cell lines may retain the ability to respond to IFN-I and potent IFN-I inducers, like replicating Sendai virus (SeV) and the synthetic double stranded RNA (dsRNA) analog polyinosinic-polycytidylic acid (poly I:C), most do not mount an IFN-independent response to low-level infection. Basal IFN-β signaling regulates a number of ISGs involved in antiviral defense, virus recognition and induction of IFN-α This basal activity allows signaling components upregulated by IFN-β to amplify the response to virus infection. Cells lacking such signaling lack basal expression of important genes that regulate the induction of IFN-β
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