The Marvels of Tick Saliva!

José Ribeiro was 33 when he got his first tick bite, in the 1980s, and he remembers it as a momentous occasion. He had recently started studying tick saliva, a complex molecular cocktail that ticks inject into their hosts to inhibit pain, prevent blood clotting, and suppress the immune system—all so the tick can feed undetected for days and days and days. Ribeiro had been studying this in a lab, but now he was finally witnessing it in the flesh. In his flesh.

He marvelled at the bite. It did not hurt. It did not itch. “I was amazed at how they could be so stealthy,” recalls Ribeiro, who now studies disease-carrying insects and ticks at the National Institute of Allergy and Infectious Diseases. Ticks use saliva to manipulate the body of their hosts so their bites stay painless, itchless, and as unobtrusive as a bug swelling with blood can be. Scientists have since catalogued more than 3,500 proteins from the saliva of various tick species.

Ticks evolved this molecular cocktail because they, unlike virtually any other blood feeder, feed for days at a time on a single host. Most tick species feed only once during each stage of their life cycle (larva, nymph, adult), so they have to get a “voluminous blood meal” out of each host, says Sarah Bonnet, who studies ticks at the French National Institute for Agricultural Research. A tick might even wait years between feedings. In the meantime, it must subsist entirely on its previous blood meal. Each meal counts for a lot.

When a tick starts to feed, it doesn’t suck blood out of blood vessels. Instead, it secretes enzymes in its saliva that destroy a small ring of host tissue. This creates a “feeding cavity,” which Ribeiro likens to a “lake of blood.” “The tick sucks blood from that lake,” he says. For this strategy to work though, ticks also need to make proteins that prevent blood from clotting, as it normally wants to do in an injury site. Over the course of days, a host’s body will try to heal the wound by sending cells that make collagen. Normally, this would allow the wound to scar over, but tick saliva has molecules to counteract this, too.

Lastly, the tick has to evade a host’s immune system. Mammals, including humans, have complex immune systems with multiple lines of defence, and tick saliva can neutralise pretty much all of them. To start, ticks secrete molecular “mops,” which bind to and neutralise histamine. Histamine is best known for causing itching and redness, but it also plays an important role in opening up blood vessels to allow immune cells to get to a site of injury. Tick saliva prevents this, so tick bites don’t itch and immune cells can’t get to the bite. Tick saliva also degrades pain-inducing molecular signals in a host. That’s why tick bites also do not hurt. Ticks then inject molecules that neutralize or evade a suite of white blood cells that would otherwise be eating or attacking an invader.

The exact cocktail of a tick’s saliva proteins changes every few hours, Ribeiro says. The thousands of proteins in its saliva are highly redundant in function, and the tick cycles through them as a way of circumventing a host’s immune system. Immune systems take time to recognise and react to a foreign tick protein, and this strategy simply doesn’t give a host’s cells a chance to do that. Suppose, Ribeiro says, “Monday a tick starts feeding on you and injecting the saliva in you.” By Friday, when your body can mount a proper immune response against those first proteins, “the tick has already changed the repertoire.”

Ticks, of course, are noteworthy not just because they bite, but because they transmit diseases when they bite—including Lyme disease, babesiosis, Rocky Mountain spotted fever, and many, many others. And pathogens may take advantage of the fact that tick saliva suppresses a host’s immune system. Bonnet has found that ticks carrying the bacteria for cat-scratch disease (which, despite the name, is also transmitted by ticks) make more of a saliva protein called IrSPI. In a recent preprint, which has not yet been peer-reviewed, her team isolated IrSPI and found that it suppresses multiple types of white blood cells, weakening a host’s defences at the bite. The upshot is that ticks can feed undetected, and bacteria can spread into a new host undetected. Tick saliva seems to help not just ticks, but the bacteria that live inside them.

But Bonnet thinks IrSPI could also be turned into a weakness. It could be a target for vaccines. If people are inoculated against IrSPI, their bodies might immediately recognise a tick bite and mount an immune response, preventing the tick from working its saliva tricks. (That’s why people who are bitten repeatedly will sometimes find the bites starting to itch.) Scientists are also interested in components of tick saliva that could be useful in cases where doctors want to inhibit pain or prevent blood from clotting. Ribeiro notes that this could be challenging because the proteins in tick saliva tend to be large and complicated—in other words, difficult to mass produce. But molecules from tick saliva are already being used to study certain unknown pathways in the human immune system. For example, scientists have used tick saliva to study how HIV infects cells.

Using tick saliva to study the human immune system makes a kind of sense. Over millions of years of evolution, ticks have essentially reverse engineered their hosts’ immune systems to evade them.

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