What is in tick spit, and how does it help the creepy-crawlies stick to their hosts?

Few things are more disgustingly satisfying than pulling a half-bloated tick out of its victim’s skin, head still intact. But seeing a chunk of flesh apparently still gripped in the arachnid’s maw may cause pause. How can a tick be so firmly attached that removing it also rips skin from the host? The short answer: tick cement, a protein-rich secretion in a tick’s spit that polymerizes to form a solid plug of glue.

After decades of tick research, veterinary parasitologist Albert Mulenga of Texas A&M University loves the widely despised animal’s biology. “If you see a flat tick, it’s very, very small,” he says, “but by the time she has finished feeding, she has ballooned up.” To suck up its fill of blood, the tick needs to firmly stick to a host.

Unlike other bloodsuckers such as mosquitoes and bedbugs, ticks don’t simply dip their mouthpart into a host, slurp up a meal, and zip away. Instead, a tick buries its barbed, tubelike mouth into its host’s skin and then stays in place for days or even weeks. Over time, a pool of the host’s blood will form in the cavity around the tick’s mouthpart. The parasite will drink deeply from this pool, swelling before falling from its host’s skin, satiated. But a blood meal will be successful only if the tick stays attached and unnoticed by its host and the host’s immune system.

“When a tick bites, it’s super important early in feeding to attach quickly and to solidify that attachment,” says Jacquie Berry, a graduate student in Mulenga’s lab in the College of Veterinary Medicine and Biomedical Sciences and a self-described “tick person.” Although the parasite’s barbed mouthpart helps it keep its head buried in flesh, the barbs alone are no match for a host’s vigorous grooming and movement. “That’s what the cement is for,” Berry says.

Tick cement is secreted in two phases. Within 5–30 min of an initial bite, a tick will begin spitting out the first layer of a cement cone into the gap between its mouth and the host’s skin, sealing the space, gluing the tick in place, and offering the pest some protection from the host’s immune system. “They’ll continue secreting the inner core layer for 24 hours,” Berry says, “and this layer hardens really quickly.” After 24 h, the tick will transition to releasing an outer layer of cement that takes much longer to harden. “[The cement is] very mobile, so it moves out into the skin and spreads out over more surface area to solidify the attachment,” Berry says.

But if the inner core of cement is never formed, the outer layer will never form either. “Ideally, if you are able to disrupt that process, it means that the tick cannot start feeding, and therefore it cannot acquire or transmit pathogens,” Mulenga explains. Teasing apart the mechanism behind cement formation might offer a new route for vaccinating against tick-borne disease, a long-term goal of his research. So, in 2010, well before Berry joined his lab, Mulenga shifted part of his group’s focus toward identifying the molecular makeup of tick cement and elucidating what makes the substance so sticky.

He is not the first scientist who’s been interested in the bioadhesive. In the 1960s, scientists discovered that tick cement is composed primarily of glycine-rich proteins, Mulenga says, but the identities of individual proteins remained elusive. Without more detailed information, it is impossible to create an antigen targeting tick cement and thus impossible to make a vaccine. So Mulenga decided to try to identify the specific protein composition of the substance.

Sourcing tick cement is not trivial. In his lab, Mulenga starts by feeding lab-grown ticks—they cost a few dollars apiece, he says—on rabbits and cattle. After the ticks attach, researchers have a couple options to get to the cone of tick cement.

During one experiment, Mulenga says, a student realized that the cement cone was often still present on a tick’s mouth if the tick had been manually removed from a host. After carefully plucking 20 lone star ticks (Amblyomma americanum) from rabbits and then separating the ticks from their cement cones, the team used mass spectrometry to identify the proteins contained within the tick cement. They found a complex mixture of 160 unique proteins but could only speculate at the proteins’ function (Int. J. Parasitol. 2017, DOI: 10.1016/j.ijpara.2017.08.018).

In another study, on black-legged ticks (Ixodes scapularis), rather than removing the cones of cement from ticks pulled from their bunny hosts, Mulenga’s team cut the embedded bioadhesive plugs directly from the host rabbits’ skin for analysis. In this case, the team found almost 140 unique cement proteins. Some are nearly identical to those found in lone star tickcement (Sci. Rep. 2022, DOI: 10.1038/s41598-022-24881-4).

Unfortunately, even with this more detailed look at the protein composition of tick cement, the mystery of which of those proteins polymerize into a bioadhesive, and how that polymerization is triggered, remains. “My hypothesis is that the most important proteins are going to be common to both species,” Mulenga says.

Now Berry is working to dive more deeply into the composition of the two species’ cement, searching for the proteins that trigger cement formation. “Once we identify the key proteins in polymerization, then we can recreate the cement,” Mulenga says. The work is ongoing, but Mulenga says Berry might have found one such protein. Such a discovery could provide the target for an antitick vaccine able to block ticks from attaching to a host.

Recreating tick cement could also enable researchers to develop a new nature-inspired bioadhesive. Evolution has provided ticks with a relatively strong adhesive that easily integrates into animal skin, explains Mulenga, meaning a synthetic version would likely have minimal side effects. Only more research will reveal whether Berry has found a catalyst for tick cement formation, but if she has, it “could have major implications in surgery,” Mulenga says, possibly providing medicine with another, minimally invasive tool for sealing wounds. The work is “miles away from that point,” he says, “but I think that what Jacquie is doing could help get us there.”

Tick cement is not the only interesting substance hiding in tick spit that could have uses in medicine. “There are so many different protein families that are secreted,” says Shahid Karim, a vector biologist at the University of Southern Mississippi. In his lab, researchers collect saliva directly from the mouths of blood-bloated ticks and analyze it, revealing its wealth of pharmacologically active proteins.

Cysteine protease inhibitors are one such class of proteins and are key to a tick’s stealthy feeding because they shut down the host’s immune system. “We have identified 25 of them in the salivary glands,” Karim says. Other proteins in a tick’s spit prevent inflammation and so prevent the bite site from becoming itchy until after a tick has finished its meal and removed itself from any danger of being scratched off. Anticoagulation proteins secreted by the parasite keep the host’s blood flowing during the entirety of that blood meal, ensuring that no scab will form until after a tick drops off its host’s skin.

The point is that tick saliva is amazingly complex, the tick researchers say. This makes revealing the mystery of tick cement and all the other components of tick saliva—many of which might be used to invent new vaccine targets or nature-inspired therapies—incredibly challenging. And the area can’t be explored by biologists alone. “We have to collaborate with the chemists, the folks who have the knowledge of molecular structures,” Karim says. Ultimately, those collaborations will be key to unraveling the sticky secrets of tick spit.