Ticks may hold the key to treating tick-borne disease

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You may have more in common with ticks than you think-at least when it comes to immunobiology.

According to Utpal Pal, PhD, a professor of veterinary medicine at the University of Maryland, ticks don't want to be infected with pathogens any more than you or I do. In fact, their immune systems have developed sophisticated ways of both sensing and suppressing pathogens that may hold the key to developing vaccinations and treatments for tick-borne illnesses one day.

It's these aspects of tick-borne illness that Dr. Pal will be researching for the next five years, leading a multi-institutional team from the University of Maryland School of Medicine, Yale University and the University of Minnesota, and funded by a $7.7 million grant from the National Institute of Allergy and Infectious Diseases.

I recently got the opportunity to talk to Dr. Pal and Samantha Watters, assistant director of communication at the College of Agriculture and Natural Resources at the University of Maryland, about this first-of-its-kind research.

dvm360: What does studying the indirect immune response entail?

Dr. Pal: When a pathogen infects a host, the host recognizes it by the microbial signature molecules present on that pathogen-sort of a direct recognition: “You're here. I can see you.” Now, for the first time, we've discovered that ticks, in addition to having direct detection capability, can also understand that something is coming along with the pathogen.

When a tick takes a bloodmeal from the host, that may be the first time it acquires the infection. Tick-borne diseases aren't transmitted tick to tick. The tick has to get the infection from the infected host and transmit it to another host. So the disease-causing pathogen is always cycling from a mammalian host (typically a white rodent) to ticks. When taking the bloodmeal, the tick can sense the immune molecule produced by the infected host. It's like they're testing the quality of the bloodmeal-whether it's coming from an uninfected host or an infected host.

We discovered that when a mammal is infected with Borrelia burgdorferi, the pathogen that causes Lyme disease, it produces many immune molecules to fight off the bacteria. One of those immune molecules is a cytokine, and that cytokine is present in the blood when a mammal is infected with Borrelia. Now, if a tick feeds off an infected host, it will ingest blood as well as the cytokines in the blood, and it's developed a sensor to recognize that cytokine molecule-a more indirect way of recognizing the infection. This is the first time we've discovered this.

dvm360: What ticks are being  studied and why?

Dr. Pal: There are many, many species of ticks. In Maryland, we have five different ticks that transmit zoological diseases. The black-legged tick, or deer tick (Ixodes scapularis), transmits the most prevalent and serious infections-bacterial diseases such as Lyme disease and anaplasmosis, viral diseases such as the Powassan virus, and protozoan diseases like babesiosis. This is the most widely distributed tick geographically, and it transmits more disease than any other tick.

Watters: The tick carries the infection, but it doesn't want to be infected any more than you do. So Dr. Pal and his team are looking at the ways the tick is trying to sense and kill that bacteria-it tells you how incredibly persistent these Borrelia bacteria are for this whole process to occur wherein, at the end of the day, a mammal becomes infected by a tick.

The tick can use either direct sensing to tell that the bloodmeal contains Borrelia (usually based on a protein it recognizes that's related to this specific pathogen), or it can indirectly sense it, which is the phenomenon that Dr. Pal's lab discovered-“This bloodmeal I just took; something's not quite right with it. This is not a healthy bloodmeal because I'm seeing signs of infection (cytokines) that I've picked up in the blood itself.” Based on this sensing, the tick is able to send out a less specific but immediate immune response to try to combat whatever is in the blood before it directly figures out exactly what it is and sends a direct response.

The tick has multiple pathways to control invading pathogens like Borrelia, and Dr. Pal's lab will be studying this indirect pathway and its interaction with other pathways and the microbiome in more detail over the coming five years.

dvm360: How will this information contribute to the larger picture-i.e., prevention and treatment of tick-borne illness?

Watters: Dr. Pal's work tells us things about ticks but also about bacteria-how pathogens combat these different waves of immune response and sensing-and these findings are very important in figuring out how to fight bacteria through either vaccinations or treatments.

Dr. Pal: The depth of the damage, the seriousness of what ticks can do, has not been appreciated as it should. Mosquitoes get most of the attention. But the genetic difference between ticks and mosquitoes is like the difference between humans and-not even mice, but fish. They are widely different. So the knowledge we have from studying mosquitoes isn't applicable to ticks. It's important that we focus more on using ticks and tick-borne diseases in experimental research. And I think this will help us understand how the infection functions and is transmitted by ticks. Our research will look at how ticks kill the pathogens, because if you disable a tick's immune system, Borrelia skyrockets. So ticks actually suppress infection. If we know how they do this, we can turn the tables and use that information to develop vaccines.

dvm360: Why hasn't this been studied before? Why is there interest now?

Watters: It's similar to the trajectory taken with the rabies virus. If you think about how rabies has been curtailed, it's remarkable. Knowledge around tick-borne disease just hasn't been gathered yet on a large scale of any kind, really.

Dr. Pal: Tick-borne diseases have been underreported for a lot of reasons. First of all, a lot of these illnesses, such as Lyme disease, carry symptoms that are common in many bacterial and viral infections. So the disease is often misdiagnosed. Only 60 to 70 percent of people who get bitten and infected by a tick with Lyme disease get the characteristic rash-a big red circle like a target that goes around the bite center. In many cases the exact appearance of the rash varies. So most people have a hard time connecting their symptoms to a tick bite. And it's not top-of-mind for human medical professionals.

There's also a weakness with the current diagnostic tests that are being used to find early infection or presence of Borrelia in the bloodstream. There's a window of time when the bacteria is more detectable, and if you miss that window, you will end up with a negative blood test even if the subject is infected.

Tick-borne diseases cause low quality of life and a substantial burden on the human healthcare system overall because these conditions often become chronic. But because they're not killing people at the same rate as malaria, they don't get the same level of attention. It's morbidity vs. mortality.

Reporting Lyme disease is a long and difficult process that can be confusing and difficult for doctors. And because scientists have discovered five new tick-borne diseases during the past two decades, research into these conditions is even more urgent.

Fortunately, things are happening on a federal level. Legislation has been introduced in Congress emphasizing more research and more investment on tick-borne diseases. In addition to the work we are doing now, we want to encourage next-generation scientists to study this neglected but important field of tick-borne infections.