MiPsummer Programme pdf - Mitochondrial Physiology Society

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Abstract # 42
CVB3-induced oxidative stress regulates cell metabolism and innate immune response to infection
via mitochondrial antiviral signaling protein (MAVS)
Andreas Koenig 1 , Iwona A.Buskiewicz 2 , Sally A. Huber 2 and Ralph C. Budd 1
Department of Medicine – Immunobiology 1 , Department of Pathology 2 and Vermont Center for
Immunology and Infectious Diseases, University of Vermont, Burlington, VT 05405, USA
The RNA virus Coxsackie B3 (CVB3) is an important human pathogen, which is one of the leading
causes of severe alimentary tract infection and viral myocarditis. In addition to activating “classical”
innate and adaptive immune responses, CVB 3 infection stimulates other cellular activities such as
production of reactive oxygen species (ROS). There is little knowledge on the cross-talk between ROS
and the innate antiviral response. Our data suggest that CVB3 infection leads to the production of ROS
in T cells, and that ROS plays a critical role in activation of mitochondria associated innate immune
RIG-I pathway. In this pathway the cytosolic RIG-I like helicases recognize the viral RNA and upon
interaction with the mitochondrial antiviral signaling protein (MAVS), recruit signaling molecules that
activate the transcription factors NF-B and IRF-3/7 to promote secretion of type I interferon (IFN). The
exact mechanism and regulation downstream of MAVS-sequestered complex remains unclear but our
preliminary and published data suggest that pro-apoptotic caspase-3 and -9 may regulate signaling of the
RIG-I pathway in MAVS dependent fashion via ROS stimulated glutathionylation, which promotes
redox-sensitive signaling. Furthermore, our data suggest that CVB3 affects cellular metabolism by
depleting MAVS from the mitochondrial membrane, which in turn influences T cell proliferation and
expansion. Our data supports the idea that the innate immune system not only detects specific viral
molecules but also senses the cellular oxidative stress level, and integrates this into the innate immune
response to infections.