Scientists at Harvard Medical School have shown for the first time that the common skin bacterium, Staphylococcus aureus, can cause itching by acting directly on nerve cells. The new findings, based on research in mice and in human cells, add an important piece to the long-standing puzzle of itch and helps explain why common skin conditions like eczema and atopic dermatitis (AD) are often accompanied by persistent itch.

The team’s study showed that S. aureus releases a protease enzyme, known as V8, which activates a receptor on the nerve fibers that transmit signals from the skin to the brain. Treating animals with an FDA-approved anti-clotting drug vorapaxar successfully blocked activation of the receptor, and so interrupted this key step in the itch-scratch cycle. Tests showed that the treatment relieved symptoms and minimized skin damage. The study findings could help inform the design of oral medicines and topical creams to treat persistent itch that occurs with various conditions linked to an imbalance in the skin microbiome, such as atopic dermatitis, prurigo nodularis, and psoriasis.

“We’ve identified an entirely novel mechanism behind itch—the bacterium Staph aureus, which is found on almost every patient with the chronic condition atopic dermatitis,” said Isaac Chiu, PhD, associate professor of immunology at the Blavatnik Institute at HMS. “We show that itch can be caused by the microbe itself.” Chiu is senior author of the team’s published paper in Cell, which is titled “S. aureus drives itch and scratch-induced skin damage through a V8 protease-PAR1 axis,” in which the scientists concluded, “… our study reveals a distinct bacterial-driven itch mechanism that contributes to skin pathology and may be targeted for therapeutic treatment of itch.”

Pruriceptors are sensory neurons that mediate itch and a desire to scratch. And persistent itch commonly accompanies conditions such as eczema and atopic dermatitis. The repeated scratching that is a hallmark of these conditions can cause skin damage and amplify inflammation. Also, in conditions such as eczema and AD, the equilibrium of microorganisms that keep the skin healthy is often thrown off balance. “Microbes that colonize the skin play key roles in tissue homeostasis and physiology,” the authors wrote, but to date, “… a causative role for microbes in driving itch was unknown.”

Up until now, it was thought that the itch associated with eczema and atopic dermatitis arose from the accompanying inflammation of the skin. But the new findings show that S. aureus single-handedly causes itch by instigating a molecular chain reaction that culminates in the urge to scratch. “Itch can be quite debilitating in patients who suffer from chronic skin conditions,” said study first author Liwen Deng, PhD a postdoctoral research fellow in the Chiu Lab. ”Many of these patients carry on their skin the very microbe we’ve now shown for the first time can induce itch.”

For their reported study, researchers exposed the skin of mice to S. aureus. The animals developed intensifying itch over several days, and the repeated scratching caused worsening skin damage that spread beyond the original site of exposure. Mice exposed to S. aureus in addition became hypersensitive to innocuous stimuli that would not typically cause itch. The exposed mice were more likely than unexposed mice to develop abnormal itching in response to a light touch.

This hyperactive response, a condition called alloknesis, is common in patients with chronic conditions of the skin characterized by persistent itch. “Alloknesis can potentiate the itch-scratch cycle in AD patients,” the investigators noted. But it can also happen in people without any underlying conditions.

To determine how the bacterium triggered itch, the researchers tested multiple modified versions of S. aureus that were engineered to lack the genes for the organism’s 10 protease enzymes that are known to be released upon skin contact. Having eliminated S. aureus production of one protease at a time, the researchers showed that the bacterial enzyme called protease V8 was single-handedly responsible for initiating itch in mice. Human skin samples from patients with atopic dermatitis also had more S. aureus and higher V8 levels than healthy skin samples. Interestingly, administering V8 to mice induced robust itching, though not pain. “V8 protease injection was also sufficient to cause alloknesis,” the scientists noted.

The investigators hypothesized that specific host receptors may mediate neuronal recognition of V8 protease to drive itch.  They focused on  G-protein coupled receptors known as PARs. Their analyses showed that V8 triggers itch by activating PAR1, which is found on skin neurons that originate in the spinal cord and carry various signals—touch, heat, pain, itch—from the skin to the brain. “PARs are expressed in pruriceptive neurons and their activities linked to itch,” they pointed out. Normally, PAR1 lies dormant but upon contact with certain enzymes, including V8, it gets activated. The study results showed that V8 snips one end of the PAR1 protein to activate it.

Experiments in mice also demonstrated that once activated, PAR1 initiates a signal that the brain eventually perceives as itch. In vitro experiments also showed that human neurons also responded to V8. “Non-microbial proteases have been linked to itch,” the scientists pointed out. “Our study adds a bacterial protease as a pruritogen that acts through PAR1.”

Interestingly, various immune cells implicated in skin allergies and classically known to cause itch—mast cells and basophils—did not drive itch after bacterial exposure, the experiments showed. Nor did inflammatory chemicals called interleukins, or white cells, which are activated during allergic reactions and are also known to be elevated in skin diseases and even in certain neurologic disorders. “Overall, we ruled out a role for MYD88, mast cells, basophils, IL31RA, IL4RA, and lymphocytes in itch,” the team reported.

“When we started the study, it was unclear whether the itch was a result of inflammation or not,” Deng said. “We show that these things can be decoupled, that you don’t necessarily have to have inflammation for the microbe to cause itch, but that the itch exacerbates inflammation on the skin.”

Because PAR1—the protein activated by S. aureus—is involved in blood-clotting, researchers wanted to see whether an already approved anticlotting drug that blocks PAR1 would stop itch. “We next investigated the therapeutic potential of PAR1 blockade in blocking itch and skin pathology … vorapaxar is an FDA-approved PAR1 antagonist and drug used for reducing the risk of thrombotic cardiovascular events.” Tests in mice showed that the drug did stop itching. The itchy mice whose skin was exposed to S. aureus experienced rapid improvement when treated with the drug.

“We found that co-administration of V8 and vorapaxar resulted in significantly reduced scratching for all doses of vorapaxar tested,” the scientists stated. The animals’ desire to scratch diminished dramatically, as did the skin damage caused by scratching. Moreover, once treated with PAR1 blockers, the mice no longer experienced abnormal itch in response to innocuous stimuli. “Vorapaxar also significantly reduced V8 protease-induced alloknesis,” the team further commented. “We found that vorapaxar treatment reduced alloknesis responses up to 3 h after V8 injection.” In summary, they concluded, “… pharmacological inhibition of PAR1 in mice significantly reduces itch behaviors that drives skin damage during bacterial exposure.”

The PAR1 blocker is already used in humans to prevent blood clots and could be repurposed as anti-itch medication. For example, the researchers noted, the active ingredient in the medicine could become the basis for anti-itch topical creams.

“PAR1 could be an attractive candidate to target for itch therapies,” they noted in their paper. “Vorapaxar is currently FDA-approved for prevention of thrombotic cardiovascular events. Future development of topical application of such PAR1 antagonists could avoid adverse events caused by systemic delivery.”

One immediate question that the researchers plan to explore in future work is whether other microbes besides S. aureus can trigger itch. “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 would a microbe cause itch? Evolutionarily speaking, what’s in it for the bacterium?

One possibility, the researchers said, is that pathogens may hijack itch and other neural reflexes to their advantage. “S. aureus induces itch and scratching behaviors that mediate skin damage,” they pointed out. “This may impact bacterial spread deeper in the skin or result in dissemination to distant body sites. Scratching could also facilitate bacterial spread to other hosts.” Previous research also has shown that the bacterium that causes tuberculosis directly activates vagal neurons to cause cough, which might enable it to spread more easily from one host to another. The authors concluded, “Further investigation into how bacteria induce maladaptive behaviors to mediate invasion and dissemination is needed.”

Deng said, “It’s a speculation at this point, but the itch-scratch cycle could benefit the microbes and enable their spread to distant body sites and to uninfected hosts. Why do we itch and scratch? Does it help us, or does it help the microbe? That’s something that we could follow up on in the future.”

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