Coxsackievirus B ramps up glycolysis in cells for its own purposes, but glycolysis inhibitors reduce CVB viral replication

[Hip]

A 2022 in vitro study says that coxsackievirus B infection increases glycolysis inside cells, and found that glycolysis inhibitors like reduced CVB3 viral replication in vitro:

Study: Metabolic reprogramming as a novel therapeutic target for Coxsackievirus B3

They tried two glycolysis inhibitors: 2-deoxy-D-glucose (2-DG) and sodium oxamate (SO).

2-DG worked better, resulting in a more than 10-fold reduction in viral levels in vitro. But 2-DG has safety issues, because it actually makes influenza infection worse, and 2-DG kills mice with influenza. Plus 2-DG has a short half-life. Thus SO looks the better option.

The paper says:

SO has been used and has shown effective results in co trolling viral replication and propagation (Zhang et al. 2019; Icard et al. 2021; Zhou et al. 2021). For example, SO inhibited hepatitis B virus infection without being limited to one cell type (Zhou et al. 2021).

Moreover, SO suppressed the replication of Vesicular stomatitis virus and Herpes simplex Virus-1 through decreasing lactate level (Zhang et al. 2019).

Furthermore, there are no reports yet that SO can cause side effects while controlling viral infection. Given the low side effects of SO, we propose that the use of SO could be an effective treat- ment for CVB3 therapy.

The fact that sodium oxamate inhibits hepatitis B infection in mice (in the Zhou 2021 paper) is interesting here, as it shows sodium oxamate works in vivo.


A paper from Zhang 2019 indicates that lactate from glycolysis inhibits RIG-I signalling. RIG-I is a part of the intracellular immune response to coxsackievirus B.


Thanks to @Rim1 for bringing to my attention the fact that some viruses may up-regulate glycolysis in order to thwart the immune response.

 

[Murph]

could this be why keto works for some people: reduced glycolysis inhibiting viral replication ?

 

[Hip]

could this be why keto works for some people: reduced glycolysis inhibiting viral replication ?

Yes, I was thinking that too. Perhaps the ketogenic diet, which inhibits glycolysis, has antiviral effects.

Just now came across this paper which tested the keto diet on mice with influenza, and found four days into the infection, all the mice fed a high-carb died, but half the mice on a keto diet survived.


I was not previously aware of the changes in glycolysis in viral infection. It seems that many viruses induce glycolysis in the cells they infect (similar to the way cancer cells induce glycolysis, which is called the Warburg effect).

 

[Consul]

Sounds like keto diet affects lactate affects rig1 affects interferon affects virus is the link then.

 

[Rim1]

Looks like latent viral infections also induce aerobic glycolysis and its inhibition could lead to cell apoptosis:

"Unexpectedly, latent viral infections can also induce glycolysis. During latent herpesvirus infection there is little or no production of virions and limited viral gene expression and therefore less obvious need for rapid metabolic changes.

Kaposi׳s sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi׳s sarcoma, an endothelial based tumor. Upon infection of endothelial cells, KSHV establishes a predominantly latent infection. A metabolomics study of endothelial cells latently infected with KSHV found that glycolytic metabolites are induced during latency (Delgado et al., 2012).

KSHV induces the uptake of glucose at least in part through induction of glucose transporter3 (Delgado et al., 2010). Hexokinase 2, the first rate-limiting enzyme of glycolysis is upregulated during latent infection by KSHV and there are also increases in the production of lactic acid leading to increased acidification of the media following infection.

Oxygen utilization is decreased in latently infected endothelial cells indicating that oxidative phosphorylation is diminished. The induction of glycolysis is essential for the survival of latently infected cells as inhibition of this pathway led to death of latently infected cells due to apoptosis (Delgado et al., 2010). Therefore, the switch to glycolysis induced by viruses is not solely required for nucleic acid replication or virion assembly and egress but may play a role in cell survival as well. KSHV is also the etiologic agent of primary effusion lymphomas (PEL), a pleural cavity lymphoma.

The level of glycolysis is very high in PEL cells as compared to primary B-cells (Bhatt et al., 2012). PEL cells are isolated from a human tumor so it is formally difficult to separate out if glycolysis is altered due to viral infection or to tumor formation in general. However, the PEL cell data is consistent with viral induction of glycolysis."

 

[Rim1]

Continuation for those interested:

"Recently, it was shown that the KSHV encoded microRNAs are sufficient to induce aerobic glycolysis (Yogev et al., 2014). KSHV encodes over 17 distinct microRNA species from 12 loci. The microRNAs are encoded in the major latent locus and are expressed during latent infection. Ten of the 12 KSHV miRNA loci are intergenic.

When these 10 intergenic viral microRNAs were overexpressed in endothelial cells there was an increase in lactic acid production and a decrease in oxygen utilization. The microRNA cluster also induces hypoxia induced factor 1 and upregulates the expression of glucose transporter 1. These effects appear to be due to the microRNA repression of two metabolic regulatory genes, EGLN2 and HSPA9 (Yogev et al., 2014).

It remains to be seen if the KSHV miRNAs are necessary for the induction of glycolysis in the context of KSHV infection or if other latently expressed genes are also able to induce glycolysis. Regardless, these results show that KSHV has evolved functions to induce glycolysis and the induction of glycolysis is not a simple cellular response to infection.

Epstein-Barr virus (EBV) is the causative agent of infectious mononucleosis and also causes a number of malignancies including Burkitt׳s lymphoma and nasopharyngeal carcinoma (NPC). EBV infected NPC cell lines have high levels of glycolysis, an effect recapitulated by the expression of a known EBV oncogene expressed during many forms of latency, latent membrane protein 1 (LMP-1) (Xiao et al., 2014). LMP-1 induces the expression of HK2, leading to the induction of glycolysis. Knockdown of HK2 in the LMP expressing NPC cells leads to an increase in cell death, indicating that the induction of glycolysis is necessary for survival of the cells.

The importance of glycolysis during latent infection is highlighted by the fact that both KSHV and EBV induce glycolysis during latent infection. In both cases, latently expressed genes are sufficient to induce the effect indicating that latent viral infection directly induces glycolysis. Both KSHV and EBV are oncogenic viruses in specific environments and both viruses induce metabolic pathways induced in most cancer cells while keeping the infected cell alive, leading to speculation as to the role of virus induced metabolism in viral oncogenesis.

While many viruses induce and require glycolysis, its exact role in viral replication and during latent infections is not entirely clear. If glucose uptake and utilization is increased, ATP can be produced more rapidly through aerobic glycolysis. Therefore, viruses may have evolved to induce glycolysis for a rapid source of ATP for replication. In the cancer field, it has been postulated that ATP is not generally limiting and that aerobic glycolysis increases biomass for a growing cell (DeBerardinis et al., 2008).

Viruses may require this biomass for replication or for the maintenance of latently infected cells. Increased glucose uptake may also be required to feed other metabolic pathways during viral infection. Importantly, fatty acid synthesis is required for the replication of many viruses and increased glucose may feed this pathway in many virus-infected cells.

The need for glycolysis for different viruses ranges widely as exemplified by the comparison of HSV-1 and CMV in the same cell type (Vastag et al., 2011). Determining which aspects of glycolysis are necessary for each virus studied will be important for understanding the different requirements for the induction of glycolysis by distinct viruses."

 

[Hip]

Four ME/CFS research groups found "something in the serum" affecting the energy metabolism of ME/CFS patient cells.

Fluge and Mella's work on the "something in the serum" discovered that in vitro, healthy cells exposed to ME/CFS patients' serum developed energy metabolism changes.

These changes include triggering excessive lactate secretion in cells, which would suggest ME/CFS patient cells are using anaerobic glycolysis to produce energy.


I wonder whether this "something in the serum" is one and the same as the high level of bacterial toxins that Dr Markov has found in the blood of ME/CFS patients. One bacterial toxin, LPS, is known to ramp up glycolysis.

Anyway, if there is a factor constantly present in the blood of ME/CFS patients which is ramping up glycolysis, this could explain why ME/CFS patients have trouble fully clearing viral infections from their cells.

ME/CFS patients can usually handle acute viral infections (like catching a cold) without much trouble, but cannot seem to clear the low-level lingering intracellular infections in their cells, such as non-cytolytic enterovirus infections which have been found in the muscles, intestines and brain tissues of ME/CFS patients.


If there is a factor in the blood which is constantly ramping up glycolysis in ME/CFS patients' cells (such as Dr Markov's bacterial toxins leaking into the blood), then this would hamper the intracellular immune system in all cells of the body, preventing the immune system from clearing these low-level lingering intracellular viral infections.

Increased glycolysis in in cells can reduce the interferon response, and interferon is part of the intracellular immune system that helps clear out lingering bits of virus.



This paper details the immune suppressing effects of glycolysis on interferon:

Viral infection causes the host to activate an antiviral response that, in part, is dependent on mitochondrial antiviral signaling protein (MAVS) to stimulate type I interferons. Zhang et al. (2019) demonstrate that glucose-generated lactate interacts with MAVS to suppress type I interferons.

As @Consul said above, the cell's internal immune response to a virus involves this mechanism:

RLR detects viral RNA in the cell ➤ then signals MAVS ➤ which triggers release of type 1 interferons

Where:
RLR = RIG-I-like receptor
MAVS = mitochondrial antiviral signalling protein (MAVS is found on the outer membrane of the mitochondria)

But Zhang 2019 found that lactate produced during glycolysis as a potent suppressor of RLR antiviral signalling.

Zhang found that lactate directly binds to MAVS, and thereby blocks the signal from RLR, which means that interferon secretion is inhibited.

 

[Hip]

@Rim1, you might like to edit your posts to divide your text into paragraphs of about 3 or 4 lines, separated by a blank line, because many ME/CFS patients find it very hard to read long paragraphs. I find it almost impossible to penetrate long paragraphs.

Also, if you like, you can place quoted text in a quote box using this menu option (just highlight the text and then select the quote option):

 

[Hip]

Let me just try to summarise the ideas mentioned in my above post:

Many viruses ramp up glycolysis in the cells they infect, for their own purposes (such as thwarting the cell's immune response).

But my speculation is that in ME/CFS, there could be additional factors (like bacterial toxins for example) that are also ramping up glycolysis.

So you may have two factors increasing glycolysis: the virus itself, and the additional factors like bacterial toxins. So this double boost of glycolysis may help the virus survive and reproduce.

Although viruses boost glycolysis on their own, the healthy immune system is usually still able to clear viruses, even with the viral increase in glycolysis. But if you add an additional factor like a toxin which ramps up glycolysis even further, maybe this overwhelms the immune system, and it no longer is able to clear the viruses.

 

[Hip]

If elevated glycolysis is the factor preventing ME/CFS patients from clearing their viruses, then trying some glycolysis inhibitors might be a worthwhile experiment.

The glycolysis inhibitor sodium oxamate mentioned above is one option. And this paper details some natural glycolysis inhibitors (for use in cancer treatment, where glycolysis inhibition can be helpful):

Natural products, such as resveratrol mostly found in red grape skin, licochalcone A derived from root of Glycyrrhiza inflate, and brusatol found in Brucea javanica and Brucea mollis, largely derived from plant or animal material, can affect glycolysis pathways in cancer by targeting glycolytic enzymes and related proteins, oncogenes, and numerous glycolytic signal proteins.

Resveratrol is the only one which is easily available as a supplement. However, resveratrol is broken down in the gut, and is not absorbed systemically, so oral resveratrol will not work. Though you can buy resveratrol powder, and apply that transdermally.

 

[BrightCandle]

Professor Kell working on Microclots found that ME/CFS patients have microclots like Long Covid patients do, but they are bigger and less numerous. He also speculated that this could be due to LPS and they added tiny amounts of LPS to control blood and it produced the same types of clots to that of ME/CFS patients. Its about as close as anyone has gotten to showing LPS is in the blood. LPS could just be another thing that causes microclots to form and it could be a coincidence it minics a similar clotting profile to that of ME/CFS, many conditions have these microclots with varying quantities and size and type. Still its a mark of evidence towards LPS being the cause of the odd metabolism and cellular response from the blood. Even small amounts of LPS causes neurological and cellular issues its a very potent toxin so it would explain everything.

 

[godlovesatrier]

Hmm.

Glycine lowers glycation (https://pubmed.ncbi.nlm.nih.gov/30944692/). Glycation promotes ROS levels in the body (https://pubmed.ncbi.nlm.nih.gov/35487443/)

Oral glycine may lower RAGE (see first link) and then this ME/CFS study re "RAGE" (https://www.simmaronresearch.com/bl...p-in-mecfs-may-be-impairing-energy-production)

"In “Elevated ATG13 in serum of patients with ME/CFS stimulates oxidative stress response in microglial cells via activation of the receptor for advanced glycation end products (RAGE)”, the Simmaron Foundation research team just added a new possibility to that list - and a rather fundamental one at th"

"Here we demonstrate that autophagy-related protein ATG13 is strongly upregulated in the serum of ME/CFS patients, indicative of impairment in the metabolic events of autophagy."

These are from my notes earlier in the year. So I figured the reason glycine helps me is because it lowers ROS and rebalances the imbalcen with glycation. It makes sense to me that a virus would cause metabolic problems, after someone posted a link to a study (recently??) showing that coxsackie impairs metabolism/lipid profiling...my memory is spotty on this sorry!

Now the difference between glycation and https://en.wikipedia.org/wiki/Glycolysis

"In contrast with glycation, glycosylation is the enzyme-mediated ATP-dependent attachment of sugars to protein or lipid.[1]"

So as I read it it's the same thing but it happens in two distinctly different ways.

So the two together might be even stronger maybe? I only take 5g in the morning now because takingit three times a day was getting to be a real pain. Plus so many symptoms are better now than they were in 2021/22.

Anyway just a thought!

 

[Hip]

Now the difference between glycation and https://en.wikipedia.org/wiki/Glycolysis

"In contrast with glycation, glycosylation is the enzyme-mediated ATP-dependent attachment of sugars to protein or lipid.[1]"

So as I read it it's the same thing but it happens in two distinctly different ways.

An interesting thought, but I just Googled, and could not find any suggestion that glycine can inhibit glycolysis.

If it could, I am sure we would have heard about it, as there is interest in finding glycolysis inhibitors in order to treat cancer (in cancer cells, glycolysis is increased — the Warburg effect).

 

[Consul]

Big difference between glycolysis and glycation/glycosylation though

 

[Hip]

Comparison of two glycolysis inhibitors, sodium oxamate and DCA:

Dichloroacetate (DCA) and sodium oxamate both inhibit glycolysis and lactate, and both can be used as a cancer treatment. DCA has been used as a ME/CFS treatment, see this study.

However, mechanisms are different: DCA inhibits the enzyme pyruvate dehydrogenase kinase, whereas sodium oxamate inhibits the enzyme lactate dehydrogenase (LDH), and the latter is the enzyme which directly converts pyruvate to lactate.

So LDH may be a better enzyme to inhibit in ME/CFS, since LDH is directly responsible for converting pyruvate to lactate. If you inhibit LDH, you inhibit the lactate which suppresses the intracellular immune response.

DCA by contrast inhibits lactate indirectly. DCA activates pyruvate dehydrogenase (PDH) by inhibiting pyruvate dehydrogenase kinase. This results in increased activation of the mitochondria, as PDH converts pyruvate into acetyl-CoA, which enters the mitochondria. By increasing mitochondrial functioning in this way, you can reduce anaerobic glycolysis and lactate production.

But if the mitochondria are blocked in ME/CFS, DCA may not be able to increase mitochondrial functioning effectively.

Note that pyruvate is the final product of glycolysis, and in anaerobic glycolysis (which does not involve mitochondria), this pyruvate is converted to lactate by LDH. Whereas in aerobic glycolysis (which involves mitochondria), the pyruvate is not converted, and instead the pyruvate is input into the mitochondria (via conversion to acetyl-CoA), where more energy is extracted.

 

[Hip]

There are some other lactate dehydrogenase inhibitors too, which might work similarly to oxamate:

• stiripentol (Diacomit, an anticonvulsant) available here
• δ-aminolevulinic acid (5-ALA)
• 1-(phenylseleno)-4-(trifluoromethyl) benzene (PSTMB)
• galloflavin
• quinoline 3-sulfonamides

 

[hapl808]

If elevated glycolysis is the factor preventing ME/CFS patients from clearing their viruses, then trying some glycolysis inhibitors might be a worthwhile experiment.

Might this explain why some people find metformin helpful?

 

[Hip]

Might this explain why some people find metformin helpful?

Just Googled it, and apparently metformin increases glycolysis and lactate release, so might promote the intracellular viral infections of ME/CFS, such as non-cytolytic enterovirus infections.

I never noticed any adverse effects when I took metformin for a few months, though, and I have enterovirus infections. However, some ME/CFS patients feel terrible when they take metformin.

 

[Consul]

Four ME/CFS research groups found "something in the serum" affecting the energy metabolism of ME/CFS patient cells.

Fluge and Mella's work on the "something in the serum" discovered that in vitro, healthy cells exposed to ME/CFS patients' serum developed energy metabolism changes.

Have you seen the last article by healthrising on the recover project? Possibly leaking some NMDA stimulans from the gut. Could explain hypersensitivities to sound and screen etc. Im very curious about the hypersensitivities in mecfs. For example people with MS have brain inflammation but they dont have the hypersensitivities like pwme do.

 

[Hip]

Have you seen the last article by healthrising on the recover project? Possibly leaking some NMDA stimulans from the gut. Could explain hypersensitivities to sound and screen etc. Im very curious about the hypersensitivities in mecfs. For example people with MS have brain inflammation but they dont have the hypersensitivities like pwme do.

Just had a quick read of Cort's article: seems that S-sulfocysteine is one of the NMDA agonists coming from the gut that might be able to cross the blood-brain barrier and stimulate the NMDA receptors in the brain.

Though I suspect the main source of NMDA agonism may come from the copious amounts of glutamate that are secreted by activated microglia. It's not a great evolutionary design that microglia pump out glutamate when activated. Studies have shown chronic activation of microglia in ME/CFS, so our brains may be bathed in glutamate.