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hTERT extends the life of human fibroblasts without compromising type I interferon signaling

Miles C Smith1, Erica T Goddard, Mirna Perusina Lanfranca

  • 1Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas, USA.

Plos One
|March 9, 2013
PubMed

Insights

Introducing human telomerase reverse transcriptase (hTERT) into primary cells extends their lifespan without compromising antiviral defenses. This creates a valuable tool for studying viral replication and host-virus interactions, unaffected by interferon signaling.

Area of Science:

  • Virology
  • Cell Biology
  • Immunology

Background:

  • Primary cells are crucial for studying viral replication but have limited lifespans.
  • Conventional immortalization methods using viral oncogenes often disrupt innate antiviral pathways, like interferon (IFN) responses.
  • Telomerase reverse transcriptase (TERT) can extend cell lifespan, but its effect on antiviral responses is unclear.

Purpose of the Study:

  • To investigate the impact of human TERT (hTERT) expression on the antiviral response in primary human embryonic lung (HEL-299) cells.
  • To determine if hTERT immortalization preserves the innate antiviral capacity against RNA and DNA viruses.
  • To evaluate the utility of hTERT-immortalized cells for viral replication and host-virus interaction studies.

Main Methods:

  • Introduced the hTERT gene into primary HEL-299 cells to create HEL-TERT cells.
  • Assessed cell lifespan, senescence, and response to type I interferon (IFN-β) by measuring IFN-stimulated genes (ISGs).
  • Evaluated viral replication of herpes simplex virus type 1 (HSV-1) and vesicular stomatitis virus (VSV) in HEL-299 and HEL-TERT cells, with and without IFN-β pretreatment.
  • Compared the effects of hTERT immortalization with simian virus 40 (SV40) large T-antigen immortalization.

Main Results:

  • HEL-TERT cells replicated beyond 100 population doublings without senescence.
  • Both HEL-299 and HEL-TERT cells upregulated ISGs upon IFN-β treatment, indicating intact type I IFN signaling.
  • IFN-β pretreatment impaired HSV-1 and VSV replication in both cell lines.
  • SV40 large T-antigen, unlike hTERT, significantly impaired the IFN-β-mediated antiviral effect.

Conclusions:

  • Expression of hTERT in HEL-299 cells generates a long-lived cell line (HEL-TERT) that retains functional type I IFN signaling.
  • hTERT immortalization does not impede the antiviral response to IFN-β or the replication of HSV-1 and VSV.
  • HEL-TERT cells are a suitable reagent for studying viral replication and host-virus interactions without the confounding effects of disrupted antiviral pathways.

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