melihtas
Senior Member
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Antiviral immune activity, without the presence of a virus sounds like it might explain at least some part of cfs/me/seid mechanism.
Rest of the study is behind paywall.
Article about the study:
Rest of the study is behind paywall.
Mitochondrial DNA stress primes the antiviral innate immune response
Nature (2015) doi:10.1038/nature14156
Received 04 July 2014 Accepted 15 December 2014 Published online 02 February 2015
Mitochondrial DNA (mtDNA) is normally present at thousands of copies per cell and is packaged into several hundred higher-order structures termed nucleoids. The abundant mtDNA-binding protein TFAM (transcription factor A, mitochondrial) regulates nucleoid architecture, abundance and segregation. Complete mtDNA depletion profoundly impairs oxidative phosphorylation, triggering calcium-dependent stress signalling and adaptive metabolic responses. However, the cellular responses to mtDNA instability, a physiologically relevant stress observed in many human diseases and ageing, remain poorly defined. Here we show that moderate mtDNA stress elicited by TFAM deficiency engages cytosolic antiviral signalling to enhance the expression of a subset of interferon-stimulated genes. Mechanistically, we find that aberrant mtDNA packaging promotes escape of mtDNA into the cytosol, where it engages the DNA sensor cGAS (also known as MB21D1) and promotes STING (also known as TMEM173)–IRF3-dependent signalling to elevate interferon-stimulated gene expression, potentiate type I interferon responses and confer broad viral resistance. Furthermore, we demonstrate that herpesviruses induce mtDNA stress, which enhances antiviral signalling and type I interferon responses during infection. Our results further demonstrate that mitochondria are central participants in innate immunity, identify mtDNA stress as a cell-intrinsic trigger of antiviral signalling and suggest that cellular monitoring of mtDNA homeostasis cooperates with canonical virus sensing mechanisms to fully engage antiviral innate immunity.
Article about the study:
Research team uncovers genetic trigger for immune response
By Ziba Kashef
The thousands of mitochondrial DNA (mtDNA) molecules present in each cell are known primarily for their role converting food and oxygen into energy. But Yale researchers have identified an unexpected relationship between mtDNA and the innate immune response.
The Yale team and co-authors at the University of Alberta and Washington University School of Medicine made this discovery while examining mouse models of mtDNA "stress," or damage that normally happens during disease and aging. The specific mouse model examined was engineered to lack a gene that supports normal mtDNA stability. What the researchers observed was an antiviral response. "We were surprised that there was an interferon response, which you would see if you were being infected by a pathogen," said Gerald Shadel, professor of pathology and genetics at Yale School of Medicine. "We had cells that looked like they were infected with a virus but they were not."
This unexpected antiviral activity, without the presence of a virus, may point to new areas of research on human diseases. "It's pretty well accepted that mitochondria are involved in inflammatory pathology like that seen in autoimmune diseases," said Shadel. The study, however, suggests a new source of inflammation that could promote common diseases and aging, he added.
The researchers also tested the effect of certain viruses, such as the herpes simplex virus (HSV), on mtDNA and the antiviral response. They discovered that HSV actually attacked mtDNA during infection, making mtDNA stress or instability a normal, and necessary, part of the way that a cell senses and responds to infection.
Shadel and first author on the study, Yale postdoctoral fellow Phillip West, plan to further explore these phenomena in studies of aging and human illness. "We found a pathway that is leading to an antiviral, pro-inflammatory state. We want to know if the mtDNA instability triggers these pathways, contributing to disease and age-related pathology," Shadel explained. The first area to which Shadel and his team plan to apply this new knowledge is cancer.
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