Mitochondrial DNA stress primes the antiviral innate immune response

[melihtas]

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.

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.

 

[Bob]

Yep, superficially (without having read the full paper) it could almost (potentially) be an investigation specifically of ME/SEID. Thanks for finding and posting this paper @melihtas.

 

[Bob]

All of the figures and tables from the paper are available to view in full:
http://www.nature.com/nature/journal/vaop/ncurrent/fig_tab/nature14156_ft.html

 

[Bob]

"Alpha- and gammaherpesviruses induce mtDNA stress, but influenza, LCMV, and vaccinia do not."

 

[Bob]

I think the mitochondria should be a central research focus for ME/CFS. I don't know why there's not more of it.

These are abstracts from a couple of other papers... This first abstract is by the lead author of the paper in the opening post in this thread...

Mitochondrial DNA Stress Primes the Antiviral Innate Immune Response
Phillip West
2015
Biophysical Journal 108, p3a, 27
http://www.cell.com/biophysj/fulltext/S0006-3495(14)01214-4

Mitochondria are central participants in a variety of cellular processes including ATP generation, programmed cell death, signal transduction, and innate immunity. Consequently, mitochondrial dysfunction is implicated in many human diseases through a wide array of pathogenic mechanisms. Mounting evidence suggests mitochondrial dysfunction engages stress-signaling cascades that can induce either beneficial or deleterious adaptive responses. Despite the biological importance of these responses, the signaling pathways involved and the mechanisms governing their activation remain poorly characterized. Here we describe an antiviral innate immune signaling pathway that is elicited by mitochondrial DNA (mtDNA) stress. Mechanistically, we have found that aberrant mtDNA packaging causes hyper-fusion of the mitochondrial network, which engages cGAS-STING-IRF3-dependent signaling to elevate interferon-stimulated gene (ISG) expression, potentiate type I interferon responses, and confer broad viral resistance. Furthermore, we demonstrate that Herpes viruses disrupt mtDNA packaging and organization, provoking mtDNA stress-dependent antiviral priming. Therefore, our results identify mtDNA stress as a trigger of innate immune signaling and suggest that viral disruption of mtDNA homeostasis may serve as a cell-intrinsic indicator of infection to enhance antiviral innate immunity.

Mitochondria: master regulators of danger signalling
Lorenzo Galluzzi, Oliver Kepp & Guido Kroemer
December 2012
Nature Reviews Molecular Cell Biology 13, 780-788
http://www.nature.com/nrm/journal/v13/n12/full/nrm3479.html

Throughout more than 1.5 billion years of obligate endosymbiotic co-evolution, mitochondria have developed not only the capacity to control distinct molecular cascades leading to cell death but also the ability to sense (and react to) multiple situations of cellular stress, including viral infection. In addition, mitochondria can emit danger signals that alert the cell or the whole organism of perturbations in homeostasis, hence promoting the induction of cell-intrinsic or systemic adaptive responses, respectively. As such, mitochondria can be considered as master regulators of danger signalling.

 

[melihtas]

I think the mitochondria should be a central research focus for ME/CFS. I don't know why there's not more of it.

I agree. Researchers searched for a virus for a long time without a success. After rituximab trial autommunity has become the center of focus but what causes autoimmunity has been a mystery. This study proves that autoimmunity can occur with or without a viral infection.

If autoimmunity in me/seid patients is caused by mithochondria, instead of killing immune cells with rituximab or cyclophosphamide and hoping not to relapse, we can target the root cause of the disease.

Figure 8: Model illustrating mtDNA stress-dependent antiviral priming.
http://www.nature.com/nature/journal/vaop/ncurrent/fig_tab/nature14156_SF8.html

TFAM depletion, induced genetically or during herpesvirus infection, triggers mtDNA stress, characterized by nucleoid loss and enlargement. This results in the release of fragmented mtDNA that recruits and activates peri-mitochondrial cGAS to generate the second messenger cyclic GMP-AMP (cGAMP) and activate endoplasmic-reticulum-resident STING. STING then activates TBK1, which phosphorylates IRF3 to induce dimerization and nuclear translocation. Active IRF3 elevates basal gene expression of ISGs with antiviral signalling and effector functions. Signalling molecules encoded by ISGs, such as IRF7, ISG15, STAT1 and STAT2, cooperate with IRF3 to potentiate the RIG-I-like receptor (RLR), interferon-stimulatory DNA (ISD) and type I interferon (IFN-I) responses, while effector molecules encoded by ISGs, such as IFI44, IFIT1, IFIT3 and OASL2, augment viral resistance. Both outcomes collectively and robustly boost innate antiviral defences to dampen viral replication.

 

[Snowdrop]

If autoimmunity in me/seid patients is caused by mithochondria, instead of killing immune cells with rituximab or cyclophosphamide and hoping not to relapse, we can target the root cause of disease.

For those of us who have difficulty following this but are curious/intrigued, what would the treatment look like/consist of if targeting the mitochondria? Any idea? Thanks.

 

[melihtas]

For those of us who have difficulty following this but are curious/intrigued, what would the treatment look like/consist of if targeting the mitochondria? Any idea? Thanks.

I don't know, it is beyond my knowledge. There is a lot of research on mithocondria but nothing specific to me/seid so far as far as I know.

 

[TeresaBCN]

I don't know, it is beyond my knowledge. There is a lot of research on mithocondria but nothing specific to me/seid so far as far as I know.

Action for ME are due to start a research project soon on mitochondrial DNA:

http://www.actionforme.org.uk/get-i...-related-activity/mitochondrial-dna-variation

 

[melihtas]

Action for ME are due to start a research project soon on mitochondrial DNA:

http://www.actionforme.org.uk/get-i...-related-activity/mitochondrial-dna-variation

I did not know about this project. Thank you for posting. This project looks very promising.

 

[Dr.Patient]

Action for ME are due to start a research project soon on mitochondrial DNA:

http://www.actionforme.org.uk/get-i...-related-activity/mitochondrial-dna-variation

Great project! We are heading in the right direction!

 

[Dr.Patient]

TFAM depletion, induced genetically or during herpesvirus infection, triggers mtDNA stress...

This is great! Induced genetically (explains the heritable aspect) and herpes virus infection (both oral and genital herpes, also EBV, which is human herpes virus 4), once acquired, will never leave the body, damages the mitochondria. This explains the fatigue associated with mono, and the fatigue associated with genital herpes relapses.

Having these 2 kinds of viruses probably makes the cfs me worse than it would have been with just a genetic component. Hence the improvement seen with antivirals.

Both diagnostic tests and treatments will come only from studies on the mitochondria. No doubt!

 

[melihtas]

I think this study explains both sudden onset and slow onset. Sudden onset ME/SEID is most likely caused by viral infection while slow onset caused by mtDNA mutations.

I have always wondered why it took more than ten years for my SEID to develop while it took just days for a lot of people although we have the same disease.

This mechanism can also explain PEM. Exercise puts stress on mitochondria, stressed mitochondria causes antiviral signaling and interferon response. This takes 24 to 48 hours to start flu like symptoms and lasts a week. Viral infection symptoms without a virus.

Or I am just filling in the blanks with my limited medical knowledge and jumping to the wrong conclusions.

 

[Dr.Patient]

I think this study explains both sudden onset and slow onset. Sudden onset ME/SEID is most likely caused by viral infection while slow onset caused by mtDNA mutations.

I have always wondered why it took more than ten years for my SEID to develop while it took just days for a lot of people although we have the same disease.

This mechanism can also explain PEM. Exercise put stress on mitochondria, stressed mitochondria causes antiviral signaling and interferon response. This takes 24 to 48 hours to start flu like symptoms and lasts a week. Viral infection symptoms without a virus.

Or I am just filling in the blanks with my limited medical knowledge and jumping to the wrong conclusions.

@Jonathan Edwards, I would like to hear your opinion on this study.

Great explanation on the PEM viral symptoms! Also, remember that we all have the genetic predisposition. A lot of people acquire mono, herpes, and flu infections, but they don't turn out like us.

 

[Bob]

This mechanism can also explain PEM. Exercise put stress on mitochondria, stressed mitochondria causes antiviral signaling and interferon response. This takes 24 to 48 hours to start flu like symptoms and lasts a week. Viral infection symptoms without a virus.

Yes, that's a hypothesis that I'd really like to see investigated.