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ATM supports gammaherpesvirus replication by attenuating type I interferon pathway

Eric J Darrah1, Kyle P Stoltz1, Mitchell Ledwith1

  • 1Department of Microbiology and Immunology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, United States.

Virology
|July 22, 2017
PubMed

Insights

Ataxia-Telangiectasia mutated (ATM) kinase supports gammaherpesvirus replication by suppressing type I interferon (IFN) responses. Attenuating these IFN responses is the primary mechanism behind ATM's proviral function.

Area of Science:

  • Virology
  • Immunology
  • Molecular Biology

Background:

  • Ataxia-Telangiectasia mutated (ATM) kinase is crucial for DNA damage response, oxidative stress, and mitophagy.
  • ATM supports the replication of various DNA and RNA viruses, including gammaherpesviruses, which are linked to cancer.
  • The proviral role of ATM was previously attributed solely to its DNA damage response signaling.

Purpose of the Study:

  • To investigate the non-DNA damage response functions of ATM in gammaherpesvirus replication.
  • To elucidate the mechanism by which ATM influences type I interferon (IFN) responses during viral infection.
  • To determine the primary role of ATM in supporting gammaherpesvirus replication.

Main Methods:

  • Utilized a mouse model with combined ATM and type I IFN receptor deficiencies.
  • Analyzed type I IFN responses in ATM-deficient and wild-type gammaherpesvirus-infected macrophages.
  • Assessed the susceptibility of ATM-deficient macrophages to type II IFN antiviral effects.

Main Results:

  • ATM deficiency led to increased type I IFN responses in gammaherpesvirus-infected macrophages.
  • The heightened type I IFN response in ATM-deficient mice fully explained the proviral role of ATM.
  • ATM deficiency and increased type I IFN responses enhanced macrophage susceptibility to type II IFN.

Conclusions:

  • Attenuation of type I IFN responses is the primary mechanism underlying the proviral function of ATM during gammaherpesvirus infection.
  • ATM kinase plays a significant role in modulating the host's antiviral immune response.
  • Targeting ATM-mediated IFN suppression could offer novel therapeutic strategies against gammaherpesvirus infections.
Keywords:
ATMGammaherpesvirusType I interferonViral replication

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