Saturday 24 February 2018

Endogenous Retroviruses (ERVs) and autism continued

It's been a while since I last mentioned Human Endogenous Retroviruses (HERVs) in the context of autism (see here) on this blog. I still however retain an interest in how these 'fossil viruses' - remnants of our ancient battle with various viruses down the ages that are still present in the genome - *might* impact on our health and well-being for all-manner of reasons.

One name in particular has been at the forefront of the work on HERVs with particular reference to autism (and ADHD and beyond) - Emanuela Balestrieri - and alongside, quite a significant peer-reviewed research record has been built up (see here). A new paper from the Balestrieri 'research group' (if I can call it that) continues their research journey in this area, from Chiara Cipriani and colleagues [1]. The aim of the research game this time around was to look at two popular mouse models of autism - "inbred BTBR T+tf/J mice and CD-1 outbred mice prenatally exposed to valproic acid (VPA)" - and examine the transcriptional activity of various ERVs (that's ERVs not HERVs 'cos these were mice) compared with control mouse strains ("C57BL/J and CD-1 untreated mice").

From what I gather, there were two main elements to the Cipriani study: (1) assessing intracisternal A-particle elements (IAPs) and Type II early transposons (ETns) in blood and brain samples of those autism-related mouse models, and (2) evaluating "the transcriptional activity of proinflammatory cytokines (IL-1β, IL-6, TNF-α) and Toll-like receptors (TLR3 and 4)... in whole embryos and, from the offspring at different time after birth, in blood and brain samples to investigate on the hypothesised link between the ERVs transcriptional activity and the immune system." If much of that sounds like a foreign language to you, well, you're not alone. From what I gather, intracisternal A-particle elements (IAPs) are "endogenous retroviral sequences" that can "induce genomic mutations and cell transformation by disrupting gene expression." Type II early transposons (ETns) are "mobile members of the repetitive early transposon family of mouse long terminal repeat (LTR) retroelements and have caused a number of mutations by inserting into genes" [2]. Clear as mud right?

Results: "In the two distinct mouse models analysed, the transcriptional activity of the ERV families was significant higher in comparison with corresponding controls, in whole embryos, blood and brain samples." Taking the BTBR mice first, in comparison to control mice (C57BL6/J), pretty much all of the expression levels of the ERV genes looked at were higher in embryos. In both blood and brain, over the course of 120 days post-natally, ERV expression was also higher than that in control mice. I say all this acknowledging that absolute number of 'mouse participants' in this study was relatively small.

Also, compared with 'vehicle treated' control mice, those offspring embryos exposed to maternal VPA ("VPA mice were produced by treating outbred pregnant CD-1 female mice with a single dose of VPA (500 mg/kg, sc) at gestational day (GD) 10.5") also saw higher transcriptional activity of 'most' ERVs. The data from blood and brain samples were similarly interesting; in brain samples in particular, those exposed to VPA always showed higher ERV transcriptional activity than non-exposed controls, and notably so. Insofar as the inflammatory cytokine look-see side of things, well in both autism-related mouse models, "the expression levels of the proinflammatory cytokines and TLRs [Toll-like receptorswere significantly higher than controls."

What does this all mean? Well, bearing in mind that mice are mice and not humans (see here), researchers conclude that "results are in agreement with our previous data showing a distinctive expression profile of some human HERV families in blood samples from two different cohorts of young autistic patients and support the hypothesis that ERVs could be implicated in ASD." The fact that authors used not one but two mouse models of autism - including something akin to an 'acquired' autism phenotype in that VPA mouse model - and found similar things adds something a little extra to their findings. The possibility of a tie-up between ERV expression and immune system 'activation' requires more investigation save any sweeping generalisations about linkage. I am wondering if autism research in this area might however benefit from looking at some initial research on myalgic encephalomyelitis (ME) (see here) and onward some chatter about a possible link between HERV proteins acting as 'superantigens' in immune system terms.

Hopefully further research will be forthcoming sooner rather than later...


[1] Cipriani C. et al. High expression of Endogenous Retroviruses from intrauterine life to adulthood in two mouse models of Autism Spectrum Disorders. Sci Reports. 2018; 8: 629.

[2] Baust C. et al. Structure and Expression of Mobile ETnII Retroelements and Their Coding-Competent MusD Relatives in the Mouse. Journal of Virology. 2003; 77: 11448-11458.


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