Over-representation of Torque Teno Mini Virus 9 (TTMV9) in a Subgroup of Patients with ME/CFS, 2024, Giménez-Orenga, Oltra et al

[John Mac]

Now published
Over-Representation of Torque Teno Mini Virus 9 in a Subgroup of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Pilot Study
Linked in post below
Karen Giménez-Orenga, Eva Martín-Martínez, Elisa Oltra



Preprint
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic disorder classified by the WHO as postviral fatigue syndrome (ICD-11 8E49 code). Diagnosing ME/CFS, often overlapping with Fibromyalgia (FM), is challenging due to nonspecific symptoms and lack of biomarkers. The etiology of ME/CFS and FM is poorly understood, but evidence suggests viral infections play a critical role. This study employs microarray technology to quantitate viral RNA levels in immune cells from ME/CFS, FM, or co-diagnosed cases, and healthy controls. The results show significant overexpression of the Torque Teno Mini Virus 9 (TTMV9) in a subgroup of ME/CFS patients which correlate with abnormal HERV and immunological profiles. Increased levels of TTMV9 transcripts accurately discriminate this subgroup of ME/CFS patients from the other study groups, showcasing its potential as biomarker for patient stratification and the need for further research into its role in the disease.

https://www.preprints.org/manuscript/202408.0073/v1

 

[Murph]

Fascinating little paper.

TTMV9 is an anellovirus. Wikipedia says:

"Their virome has been present in most humans. They enter in the cell early in life and replicate persistently.[8] This happens in the first month of life. It remains debated whether or not the first infection is symptomatic or not, however. They are probably repressed by host immunity, as the anelloviruses increase during host immunosuppression.[5]

The overall prevalence in the general population is over 90% and has been found in all continents.[2] They cause chronic human viral infections that have not yet been associated with disease. There is also no evidence of viral clearance following infection.[5] At least 200 different species are present in humans and animals.[9]

It has been shown that there are multiple methods of transmission such as saliva droplets and maternal or sexual routes.[2]

https://en.wikipedia.org/wiki/Anelloviridae

To me that hints that TTMv9 prevalence might be downstream of immunosuppression or immune dysregulation.

Separation between patients and controls is strong but not perfect:


Still this is an intriguing little clue, and if validated it could be a path towards defining a subgroup, which would be extremely helpful in running bigger studies.

 

[Hutan]

Active viral infections may cause immunological disturbances like autoimmunity or immunological dysfunction [15–17] and trigger dramatic changes in the epigenetic landscape [18], leading to viral reactivation of exogenous [19–21] or endogenous retroviruses [22]. This may contribute to the chronic immune activation and dysregulation observed in ME/CFS patients [23], as well as the persistence and exacerbation of symptoms.

It's an interesting theory.

In a previous work, we identified reactivation of human endogenous retroviral sequences in a subgroup of ME/CFS patients whose expression correlated with an altered immunological profile [9]. Those features allowed for perfect discrimination of that ME/CFS subgroup, suggesting alterations in patients’ epigenetic landscape.

The previous paper is discussed here:HERV activation segregates ME/CFS from FM and defines a novel nosological entity for patients fulfilling both clinical criteria, 2023, Gimenez-Orenga

The aim of this study was to identify candidate exogenous viral RNA sequences that may associate with the HERV activation profile and correlated immunological disturbances observed in the described subset of ME/CFS patients. To address this question, we performed a comprehensive analysis through microarray technology of viral RNA sequences present in the exact same RNA samples analyzed in our previous study, focusing on increased viral load in the subgroup of ME/CFS patients exhibiting altered HERV profiles as compared to FM, co-diagnosed cases and healthy controls.

To identify exogenous viral RNA potentially causing the activation of HERVs in a subgroup of ME/CFS cases, we analyzed by high-density microarray the expression levels in PBMC of up to 289 viruses belonging to eleven families (Figure 1A): (i) Retro-transcribing viruses: Hepadnaviridae, Retroviridae; (ii) ssRNA viruses: ssRNA-positive-strand viruses with no DNA stage, Coronaviridae; (iii)dsDNA viruses: Mastadenovirus, Chordopoxvirinae, Herpesviridae, Alphapapillomavirus, Betapapillomavirus, Gammapapillomavirus; and (iv) ssDNA viruses: Anelloviridae.

The study included 43 pre-pandemic female participants aged 42 to 58 years, with cases: n=8 ME/CFS, n=10 FM, n=16 ME/CFS + FM (co-diagnosed), and n=9 matched healthy controls. According to a previous study on the same cohort, ME/CFS cases were stratified into two subgroups based on gene and human endogenous retrovirus (HERV) expression, ME/CFS subgroup 1 (n=3) and ME/CFS subgroup 2 (n=5) [9]. Patient symptoms were assessed through the Fibromyalgia Impact Questionnaire (FIQ) [32], Multi Fatigue Inventory (MFI) for general fatigue [33], and Short-Form-36 Health Survey (SF-36) [34] for quality of life. Itemized questionnaire scores can be accessed in the reference study published by our group [9]. Significant differences were only found between ME/CFS subgroup 2 and co-diagnosed groups for MFI General fatigue (19 ± 1.7 vs 13.6 ± 3.2, respectively, p=0.035). Nonetheless, a tendency on lower scores with p<0.1 could be observed for other items of the MFI questionnaire in ME/CFS subgroup 2, suggesting worse health status for the patients included in the group.

Of course, a big problem with this study is the size of the samples e.g. only 8 ME/CFS people, and then they divide those 8 into two groups, based on gene and HERV expression from previous work. The dots in the chart posted above show the number of people in each group. With 289 viruses, to have one where the levels are different in the ME/CFS subgroup 2 could be just chance or sampling noise. I think it's another one for the replication pile.

Does this study tell us that all of the viruses that they tested for other than TTMV9 (so coronaviruses, dengue fever, herpes viruses) cannot be part of ME/CFS pathology except for possibly being hit and run triggers? I'm not sure. I haven't got to the discussion yet. Also, they only tested PBMCs. Presumably a virus causing ongoing pathology could be hanging out in other tissue.

 

[ME/CFS Skeptic]

Of course, a big problem with this study is the size of the samples e.g. only 8 ME/CFS people, and then they divide those 8 into two groups, based on gene and HERV expression from previous work. The dots in the chart posted above show the number of people in each group. With 289 viruses, to have one where the levels are different in the ME/CFS subgroup 2 could be just chance or sampling noise

Agree, there were only 5 patients in this subgroup.

 

[Dolphin]

Now published
https://www.mdpi.com/2076-0817/13/9/751