The itaconate shunt hypothesis

Re female predominance
Monocytes are the main source of STING-mediated IFN-a production, 2022

Summary
Background
Type I interferon (IFN-I) production by plasmacytoid dendritic cells (pDCs) occurs during viral infec- tion, in response to Toll-like receptor 7 (TLR7) stimulation and is more vigorous in females than in males. Whether this sex bias persists in ageing people is currently unknown. In this study, we investigated the effect of sex and aging on IFN-a production induced by PRR agonist ligands.

Methods
In a large cohort of individuals from 19 to 97 years old, we measured the production of IFN-a and inflam- matory cytokines in whole-blood upon stimulation with either R-848, ODN M362 CpG-C, or cGAMP, which activate the TLR7/8, TLR9 or STING pathways, respectively. We further characterized the cellular sources of IFN-a.

Findings
We observed a female predominance in IFN-a production by pDCs in response to TLR7 or TLR9 ligands. The higher TLR7-driven IFN-a production in females was robustly maintained across ages, including the elderly. The sex-bias in TLR9-driven interferon production was lost after age 60, which correlated with the decline in circu- lating pDCs. By contrast, STING-driven IFN-a production was similar in both sexes, preserved with aging, and cor- related with circulating monocyte numbers. Indeed, monocytes were the primary cellular source of IFN-a in response to cGAMP.

Interpretation
We show that the sex bias in the TLR7-induced IFN-I production is strongly maintained through ages, and identify monocytes as the main source of IFN-I production via STING pathway.


"This is particularly clear for Toll Like Receptor (TLR)-7, a single-stranded RNA (ssRNA) receptor encoded by an X- linked gene. The response of innate immune cells and B cells initiated by the TLR7-mediated sensing of ssRNA is an essential line of defense against exogenous RNA viruses1114 and endogenous retroviruses."

 

This recent paper is very readable, giving background on IFN; there's quite a few interesting points for our purposes:
Importance of Type I and III Interferons at Respiratory and Intestinal Barrier Surfaces

From what I can see, Type III IFNs can be produced by many cells, but the receptors to Type III IFNs are found on epithelial cells and some immune cells. Type III IFNs do trigger the ISG - the interferon stimulated genes - so can cause uninfected epithelial cells to produce more interferon on that positive feedback loop.

It seems that among a whole lot of the same sort cells in a person, only some will produce IFNs - so perhaps there are particular conditions that increase the proportion of cells that secrete IFN. I guess also, there might be differences in the number of IFN receptors, so there might be differences in the sensitivity to a given level of IFN.

Interferonpathies! Of course the molecules that act as brakes on interferon signalling like SOCS are not necessarily straightforward - they may not work in all parts of the body or on all relelvant IFNs.

 

More from that Type I and Type III paper linked in the last post:

There are lots of issues important to be aware of when studying the cells. How close together cells and whether they are polarised are might influence whether the ISG's, the interferon stimulated genes, get turned on by interferon, and so whether they go on to secrete more interferon. The history of the cells might also influence whether they produce interferon. It seems as though there is a lot to learn, and studying the cells in vitro or in mouse models may not give us the right answers.

The intensity of the infection, and possibly even how it enters the body (through the nose or otherwise) might influence which interferons are employed to deal with an infection. The type III's seem to be consistent with a lower level grumbling immune response. I wonder if Robert's team measured type III interferons in the blood. I wonder if they could usefully be measured in the gut.

That review is really information-rich. I recommend it as a way to understand how complex all this is, and how many opportunities there are for something to go wrong, both in the body and in the research.

I do think this 'Itaconate shunt interferon-signalling' hypothesis is worth exploring; thanks to Robert and his collaborators and funders for continuing to do so.

 

Perhaps, if a subset of cells are impaired but are themselves able to compensate just enough to maintain degraded function, then there might be a balancing of energy needs or other functions across the system. If demands increase (eg standing, moving, thinking) maybe the usual compensation mechanism can be out-stripped. This could be detrimental to the affected cell subset, leading to more symptoms relating to functions of those cells; but might also affect the normal cells that are doing the compensating - perhaps they're driven just a little too hard and/or have to use more and less favourable emergency backup mechanisms. In so doing they may develop temporary impairments to their usual functions that takes time to return to baseline?

It could even be that "too much PEM" can lead to a deterioration in disease severity, as the previously normal compensating cells became damaged from doing too much or using unfavourable biochemical mechanisms. That might also be an itaconate shunt or some different biochemical pathway or just generic "mitochondrial damage" from say reactive oxygen species.

Signals showing favouring of eg fatty acids, or other metabolic shifts, might be occurring in the otherwise normal cells, that are contributing to the compensation. I'm thinking of ideas like the paper that described lactate as a universal fuel that allowed the balance of energy needs across the whole system.

 

From the thread we have on the Pariente study of interferon treatment for people with Hepatitis C, some excerpts posted by chrisb from a 1988 study:

It suggests that the people were experiencing a range symptoms that were like influenza, and that the fatigue was exacerbated by physical exercise. So, it could just possibly be the same thing as ME/CFS. It would be interesting to talk with people who have experienced interferon treatment.

On the question of PEM -
There's the suggestion that cells in the anti-viral state are "burning dirty", producing ammonia as a waste product which is toxic. Maybe when cells are having to work hard, there's a lot of toxic waste products? And maybe cells that run out of energy or are overwhelmed by toxins send out distress signals and/or die an unregulated cell death that might contribute to a systemic 'sickness response'?

I haven't had time to think through that well, it's just a guess.

 

There are probably better review articles to be found, but Google highlighted this slideshow PDF from Washington University at St Louis with a simple summary —