Enterococcus faecalis redox metabolism activates the unfolded protein response to impair wound healing E. faecalis EET generates ROS, which induces the UPR in keratinocytes, inhibiting in vitro migration.

We’ve discovered how the superbug E. faecalis prevents chronic wounds from healing.

It’s not a toxin. It’s metabolism.

The bacteria use extracellular electron transport (EET) to electrochemically generate ROS, effectively "freezing" skin cells in place.

doi.org/10.1126/sciadv.aeb5297

Enterococcus fans: Check out our latest on E. faecalis EET, advancing our understanding of both the fundamental physiology of this bug and new mechanisms of its virulence. This is the product of a thrilling collaboration with friends in Singapore @gthibault.bsky.social led by @aarontan.bsky.social.

Trouble at the border: An invading gut bacterium can break tolerance to self-RNA Mouse anti-RNA antibodies triggered by gut E. gallinarum correlate with self-RNA autoantibodies and lupus severity in humans.

www.science.org/doi/10.1126/...

Research highlight📖
“…colonizing the gut of autoimmune-prone mice with E. gallinarum led to dissemination of living E. gallinarum to the lymph nodes, liver, and spleen, accompanied by ⬆️TH17 cells at these sites and production of anti-RNA #autoantibodies. “

Within-host evolution of a gut pathobiont facilitates liver translocation - PubMed Gut commensal bacteria with the ability to translocate across the intestinal barrier can drive the development of diverse immune-mediated diseases^1-4. However, the key factors that dictate ...

NZWxBXSB F1 will eventually succumb to disease even after anti-E. Gall treatment (but much later).
Another factor could be intra-host evolution (pubmed.ncbi.nlm.nih.gov/35831502/)

There is probably still a genetic (?) component that determines if someone develops the full disease. There are studies detecting E.gall in ~5-10% of the population (luckily autoimmunity is rarer) . We also saw that "normal" B6 mice will recover after stopping IMQ induction of pathology,.. while

"All disease begins in the gut" - Hippocrates, next to picture of his sculptured face

..where it leads to B cell maturation and autoantibody production. We observe a strong correlation between anti-E.gall antibodies and autoantibodies of the IgG3 subclass in SLE patients. To conclude with Hippocrates: all disease starts in the gut!

a man in a suit and tie says in conclusion in front of flowers Alt: a man in a suit and tie says in conclusion in front of flowers

To summarize: We characterize E.gall as one of the few confirmed human pathobionts that can induce extraintestinal Th17 immunity. The mechanism involves TLR8 activation in APCs and CD86 induction. E.gall has the ability to translocate to systemic sites,..

a cartoon character is smiling with the words oh yeah it 's all coming together below him Alt: a cartoon character is smiling with the words oh yeah it 's all coming together below him

To put it all to a mechanistic test, we transferred E.gall into B6-SPF mice and used IMQ to induce an SLE-like pathology. The presence of E.gall aggravated proteinuria and lead to IgG3 deposits in the kidney

a man in a red tuxedo and bow tie is sitting on a couch and making a funny face . Alt: a man in a red tuxedo and bow tie is sitting on a couch and making three finger sign.

We saw that IgG3-reactivities against human autoantigens and E.gall RNA strongly correlated with each other, while anti-E.coli RNA antibodies did not. We confirmed this in another independent patient cohort. We also observed that the strongest reactivity was seen in patients with more severe disease

two men standing next to each other with the words an-ti-bod-ies Alt: Cpt James T Kirk says an-ti-bod-ies on the enterprise

Next we looked at autoantibodies from patients with SLE or AIH. All patients with SLE had antibodies targeting E.gall RNA, while there was no increase in anti-E.coli RNA antibodies compared to healthy donors. Next we looked at IgG subclasses.

a man with long blonde hair and a beard is wearing glasses and a pink and white plaid shirt . Alt: Didier Raoult - who is known for fake studies claiming the use of hydroxychloroquine for COVID - shrugs his shoulders and says "what else"

Interestingly, blocking lysosome activity via hydroxychloroquine - a drug commonly used as medication in SLE - had a comparable effect. RNA is considered an autoantigen in SLE, suprisingly E.gall-RNA was much more potent in IFNa induction compared to human RNA.

a man is touching his face with his hands while smiling . Alt: a man is smiling and saying "it is free real estate"

What part of E.gall is activating the APCs? Destruction of proteins or cell wall did not have any effect, but blockade of the RNA-sensor TLR8 abrogates all Th17 inducing activity of E.gall. But to reach TLR8, bacteria need to be inside the APC - and indeed we could observe live E.gall in monocytes.

a man in a blue shirt and tie is pointing at a board with papers on it . Alt: a man in a blue shirt and tie is pointing at a board with papers on it .

And mechanistically? It only works if you have antigen-presenting cells present. E.gall specifically induced CD86, and blockade of CD86, but not CD80, prevents Th17 induction. Emphasizing that CD80 and CD86 are distinct! We also see a TCR activation and expansion of cytokine producing T cell clones.

a man in a suit and tie is standing in front of a building and saying `` you 're special '' . Alt: a man in a suit and tie is standing in front of a building and saying `` you 're special '' .

What's so special about E.gall? We saw that it can move through the intestinal wall and was the only bacterium that bypassed the firewall Organs (MLN, Liver) and ended up in the spleen, where it induced B cell maturation and autoantibody production.

a bald man in a suit and tie is sitting in front of a blue wall . Alt: a bald man in a suit and tie is sitting in front of a blue wall saying "mild shock" ironically.

We now wondered how exactly E.gall would induce Th17 immunity and if this would also work in humans. We observed that E.gall is a potent inducer of human Th17 cells. Surprisingly, also other Enterococci were able to do so.

a man in a suit says " i finally have a case of lupus ! " Alt: Dr. House says " i finally have a case of lupus ! "

We previously identified the intestinal pathobiont Enterococcus gallinarum in autoimmune-prone mice and in tissue biopsies from patients with systemic lupus erythematosus (SLE) or autoimmune hepatitis (AIH). E.gall induced Th17 Responses in mice, and its eradication ameliorated SLE-like pathology.

Translocating gut pathobiont Enterococcus gallinarum induces TH17 and IgG3 anti-RNA–directed autoimmunity in mouse and human Translocating pathobiont Enterococcus gallinarum promotes human TH17 and anti-RNA IgG3 autoantibody responses in patients with autoimmune disease.

Have you ever wondered how pathobionts contribute to autoimmunity? In this week's issue of Science Translational Medicine @science.org we elucidate the mechanism how E.gallinarum influences systemic immune responses and aggravates autoimmunity.. #ImmunoSky #Microbiome
www.science.org/doi/10.1126/...