Peptidoglycan of Borrelia burgdorferi can persist in discrete tissues and cause systemic responses consistent with chronic illness, McClune et al,2025

[PeterW]

Saw this posted from
Science Translational Medicine (a reputable journal), and thought it looked exciting.

I also note liver involvement - there are some reports of liver issues in some people with ME…

Interested to know what people think.

Abstract
Persistent symptoms after an acute infection is an emerging public health concern, but the pathobiology of such conditions is not well understood. One possible scenario involves the persistence of lingering antigen. We have previously reported that patients with postinfectious Lyme arthritis often harbor the peptidoglycan (PG) cell wall of Borrelia burgdorferi, the Lyme disease agent, in the synovial fluid of their inflamed joints after treatment. However, it is not yet known how B. burgdorferi PG persists, in what form, or if it may play a role in other postinfectious complications after Lyme disease. Using a murine model, we developed a real-time in vivo system to track B. burgdorferi PG as a function of cell wall chemistry and validated our findings using both molecular and cellular approaches. Unlike typical bacterial PG, the unique chemical properties of polymeric B. burgdorferi PG drive murine liver accumulation, where the cell wall material persists for weeks. Kupffer cells and hepatocytes phagocytose and retain B. burgdorferi PG and, although liver occupancy coincides with minimal pathology, both organ-specific and secreted protein profiles produced under these conditions bear some similarities to reported proteins enriched in patients with chronic illness after acute infection. Moreover, transcriptomic profiling indicated that B. burgdorferi PG affects energy metabolism in peripheral blood mononuclear cells. Our findings provide mechanistic insights into how a pathogenic molecule can persist after agent clearance, potentially contributing to illness after infection.

link: https://www.science.org/doi/10.1126/scitranslmed.adr2955

 

[jnmaciuch]

I've just read the abstract so far, but if the findings are solid (and I generally trust this journal), this is a BIG finding. Unfortunately it looks like I don't have institutional access

Unlike typical bacterial PG, the unique chemical properties of polymeric B. burgdorferi PG drive murine liver accumulation, where the cell wall material persists for weeks.

Moreover, transcriptomic profiling indicated that B. burgdorferi PG affects energy metabolism in peripheral blood mononuclear cells.

Particularly this part

 

[Nightsong]

Fresh human peripheral blood mononuclear cells (PBMCs) from multiple donors were pooled and stimulated with an equal amount of polymeric, unlabeled PG from multiple sources, in duplicate. Given the scalability of RNA sequencing (RNA-seq), we were able to expand our assessment to include host responses as a function of PG chemistry and include other variants [e.g., E. coli (m-DAP), S. aureus (l-Lys-Gly5), Streptococcus mutants (l-Lys), and Bacillus subtilis (amidated m-DAP)]. Comparative transcriptomic analysis indicated that more than 10,000 genes were coexpressed upon stimulation with each PG preparation, which makes sense for a common pathogen-associated molecular pattern (PAMP); however, PGBb caused the greatest number of genes to be significantly differentially expressed (Fig. 3H, P < 0.01).

One intriguing pattern emerged within these differentially expressed loci; energy metabolism–related genes were among the most differentially expressed (e.g., electron transport chain; tricarboxylic acid, longevity regulating pathway), and most of these genes were specifically down-regulated by pPGBb (fig. S12, A to C). In addition, C-C motif chemokine ligand 19 (CCL19) and interleukin-23 (IL-23) have been implicated in PTLDS (30–32), and transcripts for both CCL19 and IL-23 were significantly increased upon pPGBb stimulation. This immunological response, however, was not specific for a particular type of PG (fig. S12D, P < 0.0001).

...

A common complaint is chronic fatigue, much like other postacute infection syndromes (5–9). Therefore, it was interesting to us that many of the specific transcriptomic responses attributed to the unique features of pPGBb were associated with energy metabolism (fig. S12, A to C). One caveat is that these data were collected from healthy human PBMCs instead of myocytes, glial cells, or even PBMCs from patients with PTLDS. That said, if our preliminary model above describing transient reentry of pPGBb into the serum is correct, PBMCs may be temporarily but repeatedly exposed

 

[Hutan]

@duncan

Unlike typical bacterial PG, the unique chemical properties of polymeric B. burgdorferi PG drive murine liver accumulation, where the cell wall material persists for weeks.

'weeks' probably isn't long enough though.

I'd love the title of this paper
'Peptidoglycan of Borrelia burgdorferi can persist in discrete tissues and cause systemic responses consistent with chronic illness'
to be true for long enough that it is relevant to chronic disease. Looking forward to more thoughts/excerpts from people who can see the paper.

 

[Wanted! Alive]

In StatNews:

https://www.statnews.com/2025/04/23/lyme-disease-clues-to-chronic-form-treatment-antibiotics/

We found that the unusual chemical features of the Borrelia burgdorferi peptidoglycan is what makes it able to persist,” Jutras said. “It looks like the liver is acting as a sink for these unusual pieces of peptidoglycan.”

And back to those ticks: The scientists can’t say for certain, but they suspect a sugar carried by ticks may penetrate the cell walls shed by the bacteria in ways that trap them in the liver, keeping the immune system on high alert. Those antigens from the discarded cell walls that remain may trigger post-treatment Lyme disease, which has similarities to long Covid and other infection-associated illnesses.

Proal said it’s possible the antigens are being actively produced by bacteria lingering in hidden reservoirs, as is the case with the SARS-CoV-2 virus in long Covid.

In response, Jutras said purified peptidoglycan, alone, persists in mice, asserting that this work suggests that Lyme can persist without the bacteria still present, because of the peptidoglycan’s unusual features.

 

[PeterW]

@duncan

'weeks' probably isn't long enough though.

Depends how long they kept looking for it I suppose. Even if it doesn't persist for years and decades (though if something persists in a mouse for decades, it would be a very significant breakthrough in its own right).

It might shed some light on medium-term post-infectious symptoms (think all those who recover from LongCovid in year 1), and there could be variation in persistance from mouse to mouse.

In StatNews:
Jutras said purified peptidoglycan, alone, persists in mice, asserting that this work suggests that Lyme can persist without the bacteria still present, because of the peptidoglycan’s unusual features.

I thought this was quite interesting. There are whole facebook cults telling people they have Chronic Lyme and advising them to send off their blood to Armin labs in Germany for a mysterious £600 blood test. Everyone seems to get a positive result, and is then advised to go on IV doxycycline for months on end (at vast cost), or take months of antibiotics.
It would be great to better understand these post-lyme, ME-like syndromes, and also put and end to the crazy and exploitative false therapies.

 

[mariovitali]

Below are AI-assisted suggested ways to clear persistent peptidoglycans. @Jonathan Edwards would you like to comment ? I also asked whether UDCA can be used for this purpose.


https://chatgpt.com/share/6809de33-95e0-8006-8c2a-1a0de437130c

 

[mariovitali]

Sorry, for the double post I couldn't edit the post above. Here is the response from a mixture of AI agents on the subject. The potential use of piperaciline is mentioned (which is discussed in the StatNews article linked above)

 

[Midnattsol]

I have access to the paper, send me a pm if you want it

 

[PeterW]

Here is another article about the study, which include some discussion with the laboratory leader:

Science Daily:
• "Lyme and long COVID-19 are clearly vastly different diseases, but it's possible that they share a more general mechanism of inappropriate inflammation caused by remnants of a previous infection," said Jutras, who led the research. "The maladaptive response is a product of an infection, but perhaps not necessarily an active one in all cases."
• "In the context of Lyme arthritis, if you give patients anti-inflammatory, disease-modifying antirheumatic drugs, they get better," Jutras said. "Some of these very same patients do not get better after oral and IV antibiotics, which implies there is something unique about how patients respond at a genetic level."
https://www.sciencedaily.com/releases/2025/04/250423164030.htm

 

[Jonathan Edwards]

Below are AI-assisted suggested ways to clear persistent peptidoglycans. @Jonathan Edwards would you like to comment ?

I have only seen the abstract and the bits people have cited. None of these observations seem particularly unexpected. We have known for a century that tissue macrophages and Kuppfer cells can hold on to garbage for years (tattoos). They found borrelia material in Kuppfer cells in mice with no pathology so the stuff didn't seem to be doing much. They gave it to monocytes, which changed metabolism, which, from what we have heard about PAMPs and itaconite sounds like expected.

But there is a big jump from junk sitting in tissue macrophages for weeks to its effects on monocytes fresh.

Junk like this might be very important but I am not persuaded that these observations tell us anything new. Proal of course suggested that there are live bacteria hiding away, but that is not suggested by the current experiments as far as I can see.

 

[duncan]

weeks' probably isn't long enough though.

It's always nice to see fresh TBD research. This one seems to resurrect the decades old debate over whether non-viable Bb cells or remnants can cause disease. There are plenty of arguments for both sides, and many are based on far more sophisticated subjects than mice - like monkeys and dogs. So why return to a murine model?

Perhaps more to the point, it's already been proven that even after long courses of antibiotics, persister cells have been found, and are indeed viable: https://journals.asm.org/doi/10.1128/aac.00864-15

That doesn't undo the curious penchant of BbPG cells for livers. Bbs most famous tropism is for brains. So the liver thing seems new, but it is tissue after all.

The point about the debris only appearing to last a few weeks isn't at all surprising when you take into consideration that one of the authors is Allen Steere.

ETA relevant study link

 

[jnmaciuch]

Having read the full paper now I’m a bit disappointed that they only examined PBMCs after external administration of the Lyme peptidoglycans—I had assumed from the abstract that they were looking at PBMCs from their PG-harboring-in-the-liver mouse condition.

What this experiment seems to show is just that PBMCs react more strongly to peptidoglycan from this bacterium. It doesn’t prove chronic transcriptional differences in PBMCs caused by a liver reservoir like I was hoping. It’s still a possibility, but this paper doesn’t show that.

 

[MeSci]

Even if it doesn't persist for years and decades (though if something persists in a mouse for decades, it would be a very significant breakthrough in its own right).

But mice only live for a couple of years.