Ingested plant viruses, friend and/or foe?

[circular]

I first came across the notion of plant viruses in the Viome Testing thread. I wondered if all plant viruses that get in us from eating plants are necessarily bad. Apparently they've been thought not to be pathogenic in people because we don't have the receptors necessary for the virus to replicate in us. In fact, they're being employed to help solve health problems, including using them in vaccines. However, papers have been coming out showing that people produce antibodies to them. Doesn't sound good.

This paper left me pretty darn confused. It's over my head for starters, but it also seems to imply paradoxical possibilities for how just one plant virus might influence neurodegenerative diseases. The common plant virus Tobacco Mosaic Virus (TMV) might help prevent Parkinson's when it stimulates antibodies that then attack the TOMM40L protein through molecular mimicry (possibly explaining why smokers have lower rates of Parkinson's).

But first, the study limitations! No one with any sense would even bother reading until further studies are done, but I forget to check the limitations until my eyelids were at half-mast.

Our study has a number of limitations. The study’s sample size is small, with only 20 people in each group ( ), with uneven distribution of African American subjects ( ). The measurement of anti-TMV antibody in serum by ELISA is semi-quantitative, and we were unable to quantitatively measure antibody levels ( ). The study population included relatively young subjects and aged adults are at higher risk for PD, so we are unable to draw a firm conclusion regarding PD ( ). Further studies are needed to evaluate the relationships among anti-TMV and anti-TOMM40L antibodies and the development of PD, and to determine the role of TOMM40L in pathogenesis of PD (ya think?). Future study of the effects of TMV exposure on human health and disease may provide a possible therapeutic strategy against Parkinson’s disease. Finally, TMV is being used as a vector for antigen delivery in bioengineered vaccines [49]. Our data suggests that immune responses to TMV antigens deserve investigation because of their potential to interfere with vaccine biodistribution or cellular metabolism. [Emphasis added]

I gather TOMM40L isn't exactly the same as TOMM40, but both are part of the TOM complex. A mutation on TOMM40 (not TOMM40L to my knowledge) is usually but not always found with the apoe4 variant and is thought to contribute to or even at least partially drive the Alzheimer's risk we see with apoe4. So I'm confused, does the fact that TMV antibodies might protect against Parkinson's via molecular mimicry with TOMM40L rule out downside effects its antibodies may have on TOMM40 with respect to Alzheimer's? I'm assuming smoking is associated with increased Alzheimer's even if it's associated with decreased Parkinson's (?), so could TMV or other plant viruses be having molecular mimicry fun with TOMM40 in an adverse way, whether or not one has the mutation there along with their apoe4?

Apparently this plant virus is in over 150 plants, including tomato and pepper.

Humans Have Antibodies against a Plant Virus: Evidence from Tobacco Mosaic Virus

The abstract concludes:

Our results showing molecular mimicry between TMV and human TOMM40L raise the question as to whether TMV has a potential role in smokers against Parkinson’s disease development. The potential mechanisms of molecular mimicry between plant viruses and human disease should be further explored.

The introductions states:

Although the health risks of tobacco smoking are well documented, increasing evidence suggests that smokers have a lower incidence of some inflammatory and neurodegenerative diseases.

Dig deeper and things get complex as usual.

In the case of the observed sequence homology between TMV coat protein epitope 36–41 and human TOMM40L protein p60–65, it may be that anti-TMV antibodies influence mitochondrial function to alter disease processes. Although it might be expected that antibodies to mitochondrial proteins will not have access to the intracellular space, it should be noted that antinuclear antibodies are known to play an important part in autoimmune diseases including systemic lupus erythematosis and hepatitis C [43], [44]. The alteration of mitochondrial function induced by the TMV related molecular mechanism we have discussed may be secondary to cytotoxicity (and the disruption of cellular integrity) caused by amyloid aggregates, including out-of-register Beta–sheets as recently reported by Liu et al [45]. It may also be the case that anti-TMV antibodies cross-react with other proteins important in neurodegenerative disorders. The molecular mimicry process we describe here may be primarily in the CNS or may be a systemic mechanism, as alpha-synuclein is also expressed in lymphocytes [46]. Furthermore, the mechanisms of molecular mimicry we discuss could take place in microglia, which are believed to play a role in PD. Impaired mitochondrial metabolism in microglia will impair neuroinflammation and modify risk. We acknowledge that the specific influence of the molecular mimicry we report on mitochondrial function is difficult to predict. It may be that abnormalities in mitochondrial processes in PD are improved by the antibody interactions. A protective role for antibodies against a plant virus (potato virus Y) in the development of Alzheimer’s disease has been proposed [47]. It is also possible that the presence of anti-TMV antibodies elicits immune responses in the brain involving toll like receptors or other immune response elements involved in the pathogenesis of PD [48]. [Emphasis added]

I'm worn out so I hope some others have enough interest to try and digest this and hopefully restate the quandaries better than I have. Maybe dig up some more goodies, since this paper doesn't address my questions.

You can find more on plant viruses and how they're being used in modern medicine, including vaccines, here:

Plant Virus Expression Vectors: A Powerhouse for Global Health

Oh, but WAIT! I, half asleep, had to find this old as the hills 2008 paper on a plant virus antibody that's possibly protective for Alzheimer's:

Antibodies to Potato Virus Y Bind the Amyloid β Peptide

wherein:

Plant viruses are found throughout the world, frequently infect crops used for human consumption, and have no known effects on human health. We propose that the development of antibodies to PVY following oral exposure is protective against the development of AD because of the beneficial effects of binding of the antibody to the Aβ protein. A model for this interaction may be supplied by the relationship between vaccinia infection (related to cowpox) and the resultant immunity to variola (smallpox). There are naturally occurring proteins other than PVY that bear significant homology to Aβ and that may influence the development of AD. For example, several proteins of Enterococcus contain sequences homologous to Aβ (NCBI and National Institutes of Health). The mechanism we propose may influence the pathophysiology of other conditions as well. Antibodies developed in response to naturally occurring plant or animal viruses, bacteria, or other agents may interact with protein trafficking in the brain and blood to influence handling and deposition of pathological proteins. This approach may be valuable for AD immunotherapy because of the relatively low inflammatory potential with intestinal immunogen delivery and the efficacy of antibody binding to pathogenic Aβ monomers.

It is of interest to note as well that circulating antibodies against both unphosphorylated and phosphorylated Tau proteins have also been observed (58), and active immunization with a phosphorylated Tau epitope in P301L tangle model mice reduced brain aggregated Tau and slowed progression of behavioral deficits (59). Also, antibodies generated against soluble oligomeric Aβ have been shown to neutralize oligomers of the prion protein and α-synuclein, suggesting that shared epitopes of these pathogenic proteins may play a role in several neurodegenerative illnesses (52, 60). [Emphasis added]

I wonder if some of the same plant viruses that Viome is having customers avoid are ones that are being used in AD immunotherapy trials. I'm concluding for now that just because Viome finds plant viruses in one's poo does not mean we should stop eating the associated plant. This area may well be as complex as black hole collisions and everything else in the universe.

[SusanJ]

Our results showing molecular mimicry between TMV and human TOMM40L raise the question as to whether TMV has a potential role in smokers against Parkinson’s disease development.

Hey Circ, interesting stuff. A lot of speculation. I'd guess we need to see more research in more people.

I would point out that there was a big buzz about Parkinson's and the vagus nerve a few years back. "Parkinson's starting in the gut" as it were, e.g., https://neurosciencenews.com/parkinsons ... logy-2150/

The tobacco connection could be the known impact of nicotine on the vagus nerve (versus the proposed TMV effects) to reduce inflammation.

Activation of the macrophage α7 receptor by acetylcholine, nicotine, or other agonists, selectively inhibits production of pro-inflammatory cytokines while leaving anti-inflammatory cytokines undisturbed...When afferent vagus nerve terminals are activated by cytokines or other pro-inflammatory stimuli, the message travels through the afferent vagus nerve, resulting in action potentials traveling down efferent vagus nerve fibers in a process that eventually leads to macrophage α7 activation by acetylcholine and inhibition of pro-inflammatory cytokines production.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4546521/

I've always felt keeping good vagal tone was important for those of us with inflammation issues and especially those of us with susceptibility to neuroinflammation.

[circular]

Thanks Susan. I agree the TMV = protection vs PD is going way out on a limb due to all the study limitations I quoted, and the paper did mention the nicotine explanation.

Also agree re: the vagus nerve. It seems to sit at the intersection of important things, three coming to mind being the biome, choline and meditation/stress management. You're much more an expert on that. It would be interesting to work up a visual depicting it like a highway interchange or something, with routes in and out and signs showing where they lead

Interestingly this brings me to the notion that ingested plant viruses, even if they can't replicate, might travel up the vagus nerve (gut bugs do, right?) and stimulate reactions in or near the brain as well as other places. The paper I mention most importantly makes us aware that even though plant viruses don't replicate in us (a notion that has scientists quite possibly misled into thinking they're all good for vaccine production and other medical purposes), they are antigenic and can lead to cross-reactivity with our own body, not to mention mitochondria. In general, although the paper tries to identify a redeeming grace in this (TMV protects against PD?), my guess is that the process, whatever the plant virus, is potentially more detrimental than helpful. The notion that plant virus antigens might mess with the TOM complex (mitochondrial membrane) is, to me, alarming, and especially so for apoe4s, most of whom will already have a mutation on TOMM40 quite possibly not working in their favor to begin with.

I wondered how long such plant viruses can live in our gut; ie, whether their presence is certain to relate to recent ingestion. This page explains that unlike other plant viruses, TMV can live years even after its plant host cell dies, but I would think once in the human gut, dead or alive, a plant virus could stimulate antibodies that could cross-react with our tissues.

Interestingly, "Solanaceous, Tobacco Mosaic Virus" (perhaps a better name for it) is also common in the nightshade family of vegetables that many believe are to be avoided for autoimmune disease prevention and management. This page distinguishes between TMV and ToMV, tomato mosaic virus. It also has a list of tomatoes that are resistant to this viruses, for those who want their tomatoes.

This paper -- though it's title suggests a very specific topic -- appears to give a good overview of what's been shown so far on the plant virus/non-plant processes front.

Tobacco Mosaic Virus in the Lungs of Mice following Intra-Tracheal Inoculation

If anyone is interested I recommend the whole paper, but here's a snippet:

Until now, a major issue that precluded considering plant viruses as potential pathogens in humans was that they could not enter and replicate in vertebrate cells. A few aforementioned studies questioned the certainty of this paradigm [34], [35]. Moreover, mechanisms other than replication-induced pathogenicity may exist. For example, an alternative process may consist of deregulations through the micro-RNA (miRNA) regulatory pathway, which has been involved in pathogenicity in plants and in humans. Indeed, Bazzini et al. found that viruses that produce the most severe symptoms on tobacco (TMV and Tomato mosaic virus) altered miRNA accumulation to a greater extent than did viruses that produce mild symptoms (Tobacco etch virus and Potato virus Y) [41]. Additionally, the silencing suppressor activity of the TMV 126-kDa small replicase subunit is correlated with increased virus induced symptoms in tobacco [42] and it has been described that some phytoviruses RNA-silencing suppressors including the P38 protein of Turnip crinkle virus (TCV), the P19 protein of Tomato bushy stunt virus (TBSV) and the P15 protein of Peanut clump virus (PCV) were functional as silencing suppressors in human Hela cells [43] Furthermore, many human cancers appear to be induced by miRNA deregulation [44]. Therefore, the issue of interactions between plant viruses and the human body may be addressed by considering non-canonical mechanisms of diseases in vertebrate animals.

In summary, our findings and previous works suggest that the boundaries between Plantae and Vertebrata viruses may be less strict than currently accepted and they prompt a reevaluation of the potential pathogenicity of plant viruses for animals with modern microbiological tools. The role of these virions may be elucidated by analyzing the reprogramming of human cells inoculated by TMV. [Emphasis added]

I'm not about to extrapolate that a plant based diet is cancer causing, but I suppose if Viome found that I had a significantly high level of a particular plant virus, it might be expedient to replace that plant in my diet with another. I'm rethinking ordering Viome to see which plant viruses I may harbor and what the literature may show about those specific ones (and set up a Google alert), if not also eliminate the foods bringing the worst offenders, if there are any, into my system.

[SusanJ]

I'm rethinking ordering Viome to see which plant viruses I may harbor and what the literature may show about those specific ones (and set up a Google alert), if not also eliminate the foods bringing the worst offenders, if there are any, into my system.

Let us know if you do! It's interesting stuff for sure.