Harvard Medical School scientists have shown for the first time that a common skin bacterium — Staphylococcus disease — can cause itching by acting directly on nerve cells.
The findings, based on research in mice and human cells, are reported Nov. 22 Cell. The research adds an important piece to the long-standing itch puzzle and explains why common skin conditions such as eczema and atopic dermatitis are often accompanied by persistent itching.
In such conditions, the balance of microorganisms that keep our skin healthy is often thrown off, allowing S. aureus to flourish, the researchers said. Until now, the itching that occurs with eczema and atopic dermatitis was thought to come from the accompanying inflammation of the skin. But the new findings show it S. aureus alone causes itching by inciting a molecular chain reaction that results in the urge to scratch.
“We’ve identified an entirely new mechanism behind the itch — the bacterium Staph aureus, which is found in almost every patient with the chronic condition atopic dermatitis. We show that the itch can be caused by the microbe itself,” said senior author Isaac Chiu, associate professor of immunology at the Blavatnik Institute at HMS.
The experiments of the study showed that S. aureus it releases a chemical that activates a protein in the nerve fibers that transmit signals from the skin to the brain. Treating animals with an FDA-approved anticoagulant drug successfully blocked the activation of the protein to interrupt this key step in the itch-scratch cycle. The treatment relieved symptoms and minimized skin damage.
The findings can inform the design of oral medications and topical creams to treat persistent itching that occurs with various conditions linked to an imbalance in the skin microbiome, such as atopic dermatitis, pruritus nodosa, and psoriasis.
The repetitive scratching that is characteristic of these conditions can damage the skin and increase inflammation.
“Itching can be quite debilitating in patients suffering from chronic skin conditions. Many of these patients carry on their skin the very microbe that we have now shown for the first time can cause itching,” said study first author Liwen Deng , postdoctoral research. collaborator in the Chiu lab.
Identification of the molecular spark that causes itch
The researchers exposed the skin of mice to S. aureus. The animals developed intense itching for several days, and repeated scratching caused worsening skin damage that spread beyond the initial point of exposure.
In addition, mice exposed to S. aureus became hypersensitive to harmless stimuli that normally did not cause itching. Exposed mice were more likely than unexposed mice to develop abnormal itching in response to a light touch.
This hyperkinetic response, a condition called allocnosis, is common in patients with chronic skin conditions characterized by persistent itching. But it can also happen to people without underlying conditions — think of that scratchy feeling you might get from a wool sweater.
To determine how the bacterium triggered itching, the researchers tested several modified versions of it S. aureus microbe engineered to lack specific parts of the bug’s molecular makeup. The team focused on 10 enzymes known to be released by this microbe upon skin contact. One by one, the researchers eliminated nine suspects — showing that a bacterial enzyme called V8 protease was itself responsible for triggering the itch in the mice. Human skin samples from patients with atopic dermatitis also had more S. aureus and higher levels of V8 than healthy skin samples.
The analyzes showed that V8 causes itch by activating a protein called PAR1, which is found in skin neurons that originate in the spinal cord and carry various signals – touch, heat, pain, itch – from the skin to the brain. Normally, PAR1 is inactive, but upon contact with certain enzymes, including V8, it is activated. The research showed that V8 cuts off one end of the PAR1 protein and wakes it up. Experiments in mice have shown that once activated, PAR1 initiates a signal that the brain eventually perceives as an itch. When the researchers repeated the experiments in lab dishes containing human neurons, they also responded in V8.
Interestingly, several immune cells involved in skin allergies that are classically known to cause itch — mast cells and basophils — did not trigger itch after bacterial exposure, the experiments showed. Neither are inflammatory chemicals called interleukins, or white blood cells, which are activated during allergic reactions and are also known to be elevated in skin conditions and even some neurological disorders.
“When we started the study, it was not clear whether the itching was a result of inflammation or not,” Deng said. “We’re showing that these things can be disconnected, that you don’t necessarily have to have inflammation for the microbe to itch, but that itching exacerbates inflammation in the skin.”
Stopping the itch-scratch cycle
Because PAR1 — the protein activated by S. aureus — involved in blood clotting, the researchers wanted to see if an already approved anticoagulant drug that blocks PAR1 would stop the itching. He did it.
Itchy mice exposed to skin S. aureus showed rapid improvement during treatment with the drug. Their desire to scratch was dramatically reduced, as was the damage to the skin caused by scratching.
Furthermore, after being treated with PAR1 inhibitors, the mice no longer exhibited abnormal itching in response to innocuous stimuli.
The PAR1 inhibitor is already used in humans to prevent blood clots and could be repurposed as an anti-itch drug. For example, the researchers noted, the drug’s active ingredient could become the basis for topical anti-itch creams.
An immediate question the researchers plan to explore in future work is whether in addition to other microbes S. aureus may cause itching.
“We know that many microbes, including fungi, viruses and bacteria, are accompanied by itch, but how they cause itch is not clear,” Chiu said.
Beyond that, the findings raise a broader question: Why does a microbe itch? Evolutionarily speaking, what is this about the bacterium?
One possibility, the researchers said, is that pathogens may exploit itch and other nerve reflexes to their advantage. For example, previous research has shown that the tuberculosis bacterium directly activates vagal neurons to trigger coughing, which could allow it to spread more easily from one host to another.
“It’s speculation at this point, but the itch-scratch cycle could benefit the microbes and allow them to spread to distant areas of the body and to uninfected hosts,” Deng said. “Why do we itch and scratch? Is it helping us or helping the microbe? That’s something we could watch in the future.”
The work was funded by the National Institutes of Health (grants R01AI168005, R01AI153185, R01NS065926, R01NS102161, R01NS111929, R37AI052453, R01AR076082, U0381AI, U03100 85, R01JL160 582, F32AI172080, T32AI049928, 1R21AG075419), Food Allergy Science Initiative (FASI), Burroughs Wellcome Fund, Drako Family Fund, Jackson-Wijaya Research Fund, Canadian Institutes of Health Research (CIHR) (grants 376560 and 469411) and ANR-PARCURE (PRCE-CE18, 2020).
Chiu serves on the scientific advisory board of GSK Pharmaceuticals. Provisional patent application serial number 63/438,668, in which several authors are named as inventors, was filed based on these findings.