Multi-omics Examination of Q Fever Fatigue Syndrome Identifies Similarities with Chronic Fatigue Syndrome (Preprint, 2020) Raijmakers et al.

ME/CFS Skeptic

ME/CFS Skeptic

Senior Member (Voting Rights)
Abstract:
Background:

Q fever fatigue syndrome (QFS) is characterised by a state of prolonged fatigue that is seen in 20% of acute Q fever infections and has major health-related consequences. The molecular mechanisms underlying QFS are largely unclear. In order to better understand its pathogenesis, we applied a multi-omics approach to study the patterns of the gut microbiome, blood metabolome, and inflammatory proteome of QFS patients, and compared these with those of chronic fatigue syndrome (CFS) patients and healthy controls (HC).

Methods:

The study population consisted of 31 QFS patients, 50 CFS patients, and 72 HC. All subjects were matched for age, gender, and general geographical region (South-East part of the Netherlands). The gut microbiome composition was assessed by Metagenomic sequencing using the Illumina HiSeq platform. A total of 92 circulating inflammatory markers were measured using Proximity Extension Essay and 1607 metabolic features were assessed with a high-throughput non-targeted metabolomics approach.

Results:

Inflammatory markers, including 4E-BP1 (P = 9.60-16 and 1.41-7) and MMP-1 (P = 7.09-9 and 3.51-9), are significantly more expressed in both QFS and CFS patients compared to HC, and QFS patients show more of an inflammatory profile than CFS patients and HC. Blood metabolite profiles show significant differences when comparing QFS (319 metabolites) and CFS (441 metabolites) patients to HC, and are significantly enriched in pathways like sphingolipid (P = 0.0256 and 0.0033) metabolism. When comparing QFS to CFS patients, almost no significant differences in metabolome were found. Comparison of microbiome taxonomy of QFS and CFS patients with that of HC, shows both in- and decreases in abundancies in Bacteroidetes (with emphasis on Bacteroides and Alistiples spp.), and Firmicutes and Actinobateria (with emphasis on Ruminococcus and Bifidobacterium spp.). When we compare QFS patients to CFS patients, there is a striking resemblance and hardly any significant differences in microbiome taxonomy are found.

Conclusions:

We show that QFS and CFS patients are similar across three different omics layers and 4E-BP1 and MMP-1 have the potential to distinguish QFS and CFS patients from HC.
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Full preprint available at: https://www.researchsquare.com/article/rs-54097/v1
 
This is an interesting comment in the Discussion section:
These findings are important, as they indicate that QFS patients and CFS patients show a common denominator in the long term, i.e., alterations in inflammatory and metabolomic profiles, together with gut microbiome taxonomy, regardless of the precipitating event that started the complaints. It also corroborates our previous findings that QFS patients exhibit more of an inflammatory profile than CFS patients (and healthy controls) (12). The profile of important characteristics such as microbiome and metabolome is very similar in QFS and CFS, but differences are seen in their inflammatory profiles (5, 12).

One could speculate that the microbial origin of QFS plays a role in this low-grade persistent inflammation. Together with previous findings on differences in fatigue-perpetuating factors and response to cognitive behavioural therapy (CBT) (42-44), one could advocate that QFS should be seen as a separate, more inflammatory, fatigue syndrome entity that requires a different diagnostic (27, 28) and therapeutic (44, 45) approach. These findings argue for a ‘splitting’ rather than a ‘lumping’ approach to chronic fatigue
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If I recall rightly,

the pathogen coxilla burnettii survives - strangely - in the phagosome. Its SOD is, in contrast to other cells, not manganese dependent. A sequestering from Mn, done by the host (Kehl-Fie and Skaar 2009), therefore hasn´t effects on the pathogen´s defence against H2O2 coming from the host (a comparable strategy is seen in S. aureus, Garcia et al 2016).


I think I got the thought from this article here:

Coxilla burnettii Superoxide Dismutase Gene: Cloing, Sequencing, and Expression in [E. coli] Heizen et al 1992


But this one, which I just have found, looks interesting, too:

Supervision of Monocytes Functions by Coxilla burnettii: Impairent of the Cross- Talk between avb3 Integrin and CR31 Capo et al 1999
 
Grigor said:
Interesting about the separating as this study suggests that van der Meer' buddies Blijenberg and Knoop were all about lumping.

https://psycnet.apa.org/record/2018-23402-001

Who's going to win? :)
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For sure I know who's going to lose while these people are jerking each other over imaginary philosophical conundrums: the patients. As usual. It's always the patients who lose.
 
I thought it was interesting that they highlighted 4E-BP1 as being significantly increased. @DMissa reported the same thing in his Complex V papers quoted below.
Section 3.7
"4E-BP1 is often used as a marker of TORC1 activity. We found that 4E-BP1 phosphorylation levels were significantly elevated in ME/CFS lymphoblasts and were accompanied by a correspondingly increased response to the mTOR inhibitor, Torin2. "
EDpYKQxU8AAGw0O.png

"This chronic elevation of TORC1 activity could explain the increased expression of mitochondrial proteins and respiratory capacity that we found in ME/CFS lymphoblasts"
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wigglethemouse said:
I thought it was interesting that they highlighted 4E-BP1 as being significantly increased. @DMissa reported the same thing in his Complex V papers quoted below.
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It is interesting. These are, however, related but different measurements. In this thread's paper, from what I can see, the levels of 4E-BP1 in plasma were measured and elevated.

In our paper, it is the intracellular ratio of phosphorylated 4E-BP1 to total 4E-BP1 reported in the figure which you shared (reflecting elevated TORC1 activity, since the phosphorylated 4E-BP1 is normalised to total 4E-BP1 in the same samples).

So, two related but separate conclusions.

In brief, for those who are foggy or find my explanation too wordy regarding 4E-BP1 comparisons:

The paper here: elevated levels of 4E-BP1 in plasma.

Our paper: elevated phosphorylation of 4E-BP1 by TORC1 in lymphoblasts (internally accounting for total 4E-BP1 levels).
 
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DMissa said:
It is interesting. These are, however, related but different measurements. In this thread's paper, from what I can see, the levels of 4E-BP1 in plasma were measured and elevated.

In our paper, it is the intracellular ratio of phosphorylated 4E-BP1 to total 4E-BP1 reported in the figure which you shared (reflecting elevated TORC1 activity, since the phosphorylated 4E-BP1 is normalised to total 4E-BP1 in the same samples).

So, two related but separate conclusions.

In brief, for those who are foggy or find my explanation too wordy regarding 4E-BP1 comparisons:

The paper here: elevated levels of 4E-BP1 in plasma.

Our paper: elevated phosphorylation of 4E-BP1 by TORC1 in lymphoblasts (internally accounting for total 4E-BP1 levels).
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Hi,

thank you for being here!

Could you give us an update about your next steps and a timescale for these plans?

Also are you looking for funding?

Is there any antioxidant that you see could help in the pathology you and your colleagues found?

Thank you!
 
butter. said:
Hi,

thank you for being here!

Could you give us an update about your next steps and a timescale for these plans?

Also are you looking for funding?

Is there any antioxidant that you see could help in the pathology you and your colleagues found?

Thank you!
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I will PM you so as not to derail the thread.
 
Interesting. This is a Dutch study. The Netherlands experienced a "Q Fever epidemic" (link) between 2007-2011. Some 20% of patients went on to develop so-called "Q Fever Fatigue Syndrome" (QVS). I took a look at the official government guidelines on QVS (link to document, in Dutch). It describes fatigue as the primary symptom of QVS, in addition to:

- Unrefreshing sleep (93%)
- Increase in symptoms following exertion, also known as PEM (93%)
- Concentration and memory problems (80-87%)
- Headaches (83%)
- Muscle pains (73%)
- Joint pains (63%)
- Sore throat and/or tender lymph nodes (24-39%)
- Depression (26%)

The document even says that where clinical depression is suspected, it should not be considered mutually exclusive with QVS. And yes, the term "PEM" is used, literally and unapologetically. One could seamlessly transplant this paragraph into a text on the clinical presentation of MECFS, and nobody would suspect that it originally described QVS.

I would comment what a difference it makes to know the original pathogen - but we often do know the precise viral / bacterial trigger in individual cases of MECFS...

Screenshot attached.
 

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I don't have enough concentration to figure out the overall pattern right now (it is complex!).

Despite only a brief mention in the discussion, the common link of 4EBP1, MMP1, AXIN1 is relationship between cellular adhesions (cell-cell and cell-extracellular matrix interactions) and metabolism through WNT signalling pathways.

I note the following:

Axin1 is a negative regulator of WNT signalling pathway
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3967064/

Integrins regulate mmp1/collagen balance during tissue development or repair: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3460049/

Integrin signalling can regulate WNT signalling https://www.nature.com/articles/srep20395

Elevated expression of eIF4E translationally activates the transforming growth factor β (TGF-β) pathway(...)

Overexpression of eIF4E is shown to facilitate the selective translation of integrin β1 mRNA, which drives the translationally controlled
assembly of a TGF-β receptor signaling complex containing α3β1 integrins, β-catenin, TGF-β receptor I, E-cadherin, and
phosphorylated Smad2/3
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(from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4524117/)
(note β-catenin and E-cadherin are part of the WNT signalling pathway)

The WNT pathway is also a key regulator of mTOR, in more ways that mentioned in the discussion of the Q fever study.
https://en.wikipedia.org/wiki/Wnt_signaling_pathway
Also side note:
https://en.wikipedia.org/wiki/TGF_beta_Activation
(integrins are often involved in TGF-β activation and signal transduction)

Lastly, I'd like to point out that at least one integrin has been shown to be a key cell entry receptor for Coxiella burnetii
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5619019/

I have previously noted on this forum that integrins are key entry receptors for a variety of viruses including SARS-CoV-2, certain enteroviruses (Coxsackievirus) and certain herpesviruses (such as EBV and CMV). Even when not absolutely necessary for cell entry, there is still a possibility of altered regulation due to surface receptors (or fragments) of the virus or bacteria interacting with these integrins. The question is whether this can induce (or "kindle") long term persistent feedback loops or long-term damage due to dysregulation during the tissue repair process (in the capillary endothelium, or peripheral sensory axons, for example, leading to persistent sensitisation)
 
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