A joint research effort has uncovered how a particular type of parasitic worm that targets mammals has found a way to avoid causing itchiness, providing new insights into why mammals feel the urge to scratch.
Have you ever experienced an itchy nose or, even more frustrating, a spot on your back that you just can’t reach? Now, imagine having an itch that just won’t go away, no matter how much you scratch. This persistent itch, known as pruritus, might actually serve as one of the skin’s primary defenses against harmful invaders, according to neuroimmunologist Juan Inclan-Rico from the University of Pennsylvania.
“While it’s annoying and inconvenient, sensations like pain and itch are crucial for survival. They are especially prevalent in the context of skin infections,” explains Inclan-Rico, a postdoctoral researcher in the Herbert Lab at Penn’s School of Veterinary Medicine. He has been researching the concept of “sensory immunity,” which is the idea that if we can feel something, we can respond to it. Itchiness, he notes, is the body’s way of realizing potential threats, such as skin infections, before they become a problem.
However, a recent study published in Nature Immunology, led by De’Broski Herbert, a professor of pathobiology at Penn Vet, challenged that notion. Their research illuminated how the parasitic worm Schistosoma mansoni manages to infiltrate the human body by circumventing this very itch defense mechanism, effectively evading the scratch response. Although there are preventative treatments for potential encounters with S. mansoni, actual treatment options for those who unknowingly come into contact with it are limited, making these findings significant.
“These blood flukes are among the most common human parasites, infecting around 250 million people worldwide. They appear to have evolved ways to block the itch sensation, allowing them to enter the body without being noticed,” Inclan says. “Our goal was to uncover how they manage to do that. What are the molecular mechanisms that dampen such a crucial sensory alert? And what can this teach us about the sensory processes that drive our need to scratch an irritating itch?”
Understanding the differences
Inclan-Rico shared that their research was prompted when they discovered certain mouse strains were more prone to S. mansoni infections. “In particular, we noticed some mice had a higher concentration of parasites successfully moving through their bodies after skin penetration,” he noted.
Heather Rossi, a senior research investigator in the Herbert lab and a co-author on the paper, stated that this discovery spurred the team to delve into the neural activity involved, focusing particularly on MrgprA3 neurons, which are typically linked to itchiness and immune responses.
Next, they examined a relative of S. mansoni commonly found in birds but also known to cause swimmer’s itch in humans, and they observed a marked difference in how mice reacted—or didn’t react—to it.
“The avian schistosomes caused a significant itch reaction in the skin, whereas S. mansoni did not trigger this response,” Rossi reports. “Furthermore, when we introduced chloroquine —an anti-malarial medication known to induce itch by interacting with MrgprA3—to the mice treated with S. mansoni antigens, we found that the itch sensation was almost completely blocked.”
Examining the details
To gain deeper insight into the biochemistry that allows S. mansoni to evade the MrgprA3 neurons, the researchers utilized a three-pronged approach: employing light to genetically stimulate these neurons on the skin of the ears before infection, administering chloroquine, and genetically reducing the number of MrgprA3 neurons in the mice.
“We found that activating these neurons actually blocks parasite entry,” Inclan-Rico explains. “It seems to create an inflammatory response in the skin that deters the parasites from entering and spreading, which is quite fascinating.”
Members of the Herbert lab (Left to right): Ulrich Femoe, Heather Rossi, Adriana Stephenson, Evonne Jean, Annabel Ferguson, De’Broski Herbert, Juan Inclan Rico, Heidi Winters, Camila Napuri, Li-Yin Hung, Olufemi Akinkuotu. (Credit: Adriana Stephenson)
The team has been investigating parasites that penetrate the skin, navigating through connective tissues until they reach a blood vessel, which allows them to travel to the lungs. There, they undergo molting into another larval form before moving to the liver and portal vein, eventually reaching the intestines as adults, where they lay eggs that cause symptoms in humans, such as abdominal swelling, fever, and pain.
“Therefore, if there are fewer parasites entering the body during the initial infection and fewer parasites reaching the lungs,” Inclan-Rico states, “it suggests two things: the activation of these neurons is preventing parasites from getting in and is also stopping their spread throughout the body.” The researchers also discovered that mice lacking MrgprA3 had an increased incidence of lung infections from the parasites.
Cellular interactions
With the knowledge that MrgprA3 neurons help block parasite entry, the research team explored whether these neurons communicated with immune cells, delving into the interaction between these two cell types.
“When we activated MrgprA3, it resulted in more macrophages in the skin,” Inclan-Rico says. “Macrophages are the white blood cells that typically engulf infectious agents, and when we reduced their numbers, it became clear that there is a direct link between the neurons and the macrophaging response, as the worm infection was not blocked at all without them.”
The Herbert team then aimed to pinpoint the specific signaling molecules involved and discovered that when MrgprA3 is activated, the neuropeptide CGRP is released, thereby playing a crucial role in communication between neurons and immune cells.
“CGRP acts as a messenger between the neurons and macrophages,” Inclan-Rico notes, “triggering the activation of immune cells near the infection site, which helps contain the parasite.”
Interestingly, they found that the nuclear protein IL-33, usually recognized as an alarm signal released by damaged cells, also plays a surprising role. Upon examining the macrophages, the team discovered that IL-33 was not merely being diminished but was actively residing within the cell nucleus.
“Until now, it was believed that IL-33 was a nuclear protein, but its exact function was unclear. It was thought to be a secreted factor resulting from cell death or possibly from immune cells themselves,” Rossi said. “However, through various experiments, we established that IL-33 in macrophages modifies DNA accessibility, opening up the tightly packed DNA and enabling pro-inflammatory cytokines like TNF to be produced.”
This pro-inflammatory setting is critical for establishing a protective barrier that keeps the parasite from advancing deeper into the body.
“This is a two-step process,” Inclan-Rico explains. “First, MrgprA3 neurons release CGRP, signaling to the macrophages. Then, IL-33 residing in the macrophages’ nuclei is notably reduced, boosting the inflammatory response and aiding in blocking the parasite’s entry.”
Notably, the researchers found that when IL-33 was genetically removed from macrophages, the protective response triggered by the itchy neurons disappeared.
“This indicates that the neurons coordinate this entire defense mechanism, but they require the macrophages—and specifically IL-33 in those macrophages—to execute a complete immune response,” Herbert points out.
Looking forward, the Herbert lab intends to investigate more about the mechanisms behind this interaction between neurons and immune cells.
“We are particularly interested in identifying the molecules that parasites manipulate to subdue the neurons and whether we can leverage this knowledge to improve our ability to prevent parasite entry,” Herbert states. They also hope to discover other molecules, aside from CGRP and IL-33, involved in this signaling pathway.
“If we can identify exactly which components parasites target to escape the itch response, we could develop innovative treatments for not just parasitic infections but also for other itch-related conditions like eczema or psoriasis,” Herbert adds.
De’Broski R. Herbert is the presidential professor of immunology and a professor of pathobiology at the School of Veterinary Medicine at the University of Pennsylvania.
Juan Manuel Inclan-Rico is a postdoctoral researcher in the Herbert Lab at Penn Vet.
Heather L. Rossi is a senior research investigator in the Herbert Lab at Penn Vet.
Other researchers include Ulrich M. Femoe, Annabel A. Ferguson, Bruce D. Freedman, Li-Yin Hung, Xiaohong Liu, Fungai Musaigwa, Camila M. Napuri, Christopher F. Pastore, and Adriana Stephenson of Penn Vet; Wenqin Luo and Qinxue Wu of the Perelman School of Medicine at Penn; Cailu Lin and Danielle R. Reed of the Monell Chemical Senses Center; Petr Horák and Tomáš Macháček of Charles University, Czech Republic; and Ishmail Abdus-Saboor of Columbia University.
This research was supported by the National Institutes of Health (grants T32 AI007532-24, R01 AI164715-01, U01 AI163062-01, P30-AR069589, and R01 AI123173-05 and contract HHSN272201700014I), Charles University (Cooperatio Biology, UNCE24/SCI/011, SVV 260687), and the Czech Science Foundation (GA24-11031S).
