Why do ticks make people allergic to meat?

Written by Joe Ballenger

This question was very unique. We had a person in the AaE Facebook inbox reach out to us after she had been diagnosed with a meat allergy, most likely from a tick. After a conversation with her physician, she had wanted to know more about how ticks work. The physician wasn’t able to answer her questions about bugs, so she reached out to us.

Lone Star Tick

The start of this week’s post: the Lone Star Tick, Amblyomma americanum. The females can be easily ID’d by the white spot on its back.

Unfortunately, since her query contains medical information, I’m not really comfortable posting it here. However, it’s important because tick-associated meat allergies allergies appear to be on the rise, and it’s a good idea for people to have a resource to understand what’s going on from the entomological side.

Researching for this post was an unexpected treat, as well. Normally, when I do a post, I have a pretty good idea of what I’m going to find. This was a rare post where, even though I knew the subject was interesting, the story ended up being a lot more interesting than I thought it would be.

What I feel makes this story really unique is how it bounces around a lot of disciplines. It starts with the first organ transplants, involves a lot of cancer biology, and then ends up talking about conservation practices in the Southern US.

Organ Transplantations

Sergei Voronoff

Serge Voronoff, image courtesty of the Library of Congress. The history of organ transplantation is one of the most bizarre endeavors humans have undertaken. Sawbones has a great episode on this guy.

The history of organ transplantations takes some truly bizarre twists and turns. During the 1920s, we figured out pretty quickly that organs transplanted from non-primate animals to humans would fail pretty quickly. These organs would be rejected by the recipient, because the immune system would attack them. The reason for a lot of these organ rejections is because of a sugar called Galactose a(1,3) galactose, or alpha-gal for short.

Most proteins have sugars tacked onto them, a modification called glycosylation. These sugars can have a number of functions. Sometimes they make the protein more able to dissolve in the body fluids, other times they’re used to help the protein fold into the proper shape. The exact sugars on the outside of the protein differ based on the animal making it, and this makes it really useful for animals to determine whether a hunk of tissues belongs to that animal.

See, all mammals make alpha-gal. All mammals except for old-world primates, and humans are old world primates. All other mammals make alpha-gal, we don’t, so we’re flooded with antibodies to the sugar.

How did we even find this allergy?

EGF Biology

Greatly simplified diagram of the EGF pathway

The first step to figuring out the association between ticks and red meat allergies actually came from problems revolving around a colon cancer drug called Cetuximab.

There’s a protein called Epidermal Growth Factor (EGF) which tells cells to divide and grow when it binds to its receptor, the EGF receptor (EGFR). A lot of cancers form when specific mutations accumulate in EGFR in such a way that the growth process is constantly turned on. Cetuximab is an antibody which binds to EGFR, shuts down the receptor, and shuts down the out of control growth.

Cetuximab is produced in a mouse cell line, which isn’t normally a problem for most drugs of this type. However, these cell lines slap alpha-gal molecules on the antibody which means that there’s a potential for allergic reactions in some people.

Cetuximab

Greatly simplified diagram explaining how antibodies like Cetuximab work. In reality, some bend the protein to keep it from working. Others block receptor binding. Anti-cancer antibodies can work in a lot of different ways.

Soon after release, post-implementation monitoring discovered that people from four states in the Southern US had allergic reactions to the drug. Furthermore, it was noted early on that the places where this allergy occurred were strongly correlated with cases of the tick-bourne illness Rocky Mountian Spotted Fever as well as the Lone-Star tick Amblyomma americanum. The allergy to the medicine also happened to be correlated with the incidents of meat allergies.

At about the same time, there was a paper which came out from Australian researchers who discovered that one of their tick species was associated with meat allergies. Suddenly the correlation made sense.

Alpha Gal

Alpha gal, the molecule which causes a lot of meat allergies including the Amblyomma induced type. Image credit: Edgar181, via Wikimedia commons. License info: Public domain

This spurred a lot of research into this topic on both sides of the pond. Here in America, allergists started interviewing people who had been recently diagnosed with meat allergies and found that many reported they had been bitten by ticks. There was even a paper, where doctors were monitoring the bloodwork of patients and were able to watch these allergies form in real time. Across the pond, other workers found similar correlations in time and space between tick bites and the onset of meat allergies.

This was all solid work, corroborated by several different methods and using several different teams working independently which all came to the same conclusion.

Why do ticks make people allergic to meat?

To understand why ticks could make people allergic to something, you need to understand how they eat. There’s a (slightly gross, I’ll admit) video below which shows how the tick’s mouthparts enter the skin, but that’s only where this process begins. The tick below will feed for more than a week in it’s host. To do that, it needs a whole suite of adaptations to keep it there.

Ticks are parasites, which means they’re exceptionally adapted to taking over the host. Those mouthparts are going to work at the skin, and create a small pool of blood just beneath the surface. It will keep that pool there for the entire week, while it grows to 500 times it’s original size. This pool of blood isn’t big, but wounds heal pretty quickly. To keep feeding, it needs to inject a whole suite of host-manipulating proteins in it’s saliva.

Tick allergy

A.) Areas where Cetuximab allergies were common. B.) Range of meat allergies (known at the time) C.) Incidence of Rocky Mountian Spotted Fever. D.) Range of Ambylomma americanum. Image Credit: Commins et. al 2011

In general, we know what the saliva in ticks does. We also know what some of the proteins do. We know, for example, that some ticks increase bloodflow to the bite site by injecting proteins which force cells to release histamine. Other salivary proteins knock out the proteins which cause blood to clot. In addition, ticks also take the direct route of straight-up dissolving clots that form by injecting proteases that degrade blood clots.

So…here’s the problem, though. We know that ticks inject salivary proteins, and occasionally barf back up into their hosts. However, sorting out whether alpha-gal allergies come from a salivary protein or proteins from a previous non-human blood meal might take awhile.

Allergy development

Development of allergies to meat after tick bites (red arrows). Image Credit: Commins et. al 2011

See, when we study proteins, we need large amounts of pure proteins. The easiest way to get these proteins is to put them into bacteria, and let the bacteria make the proteins for us. This is a great way to study what function these proteins have, but we can’t use this method to study alpha-gal allergy.

When ticks make these proteins, they’re putting sugars on the outside. However, when we make these proteins in bacterial culture, those bacteria are putting their own sugars on the outside. As a result, we know what the proteins do but we can’t quite figure out how the tick accessorizes the proteins. We need large amounts of proteins purified from tick saliva to see if the ticks are putting lots of alpha-gal sugars on their proteins.

Alternatively, it may not even be a salivary protein. Ticks also inject a lot of small molecules, one of which is called prostaglandin E2 (PGE2). PGE2 keeps the body from releasing signaling molecules which cause immune reactions, which could cause the host to push the tick out. One hypothesis researchers have put forward is that PGE2 injected by ticks could cause cells which produce antibodies that don’t cause allergic reactions into antibodies that produce antibodies that do cause allergic reactions.

So we’re stuck in this situation where we know that ticks cause meat allergies, but we don’t know how they do it…and figuring out how they do this really isn’t an easy task.

Conservation Matters

This is the part of the story which really fascinated me.

I’ve grown used to living in rural areas, where deer hunting is a popular past time. In fact, it’s so popular that it’s essentially an unofficial holiday in many areas because so many people plan their vacations around deer season. It’s not uncommon for work to shut down. Furthermore, when I was living in Iowa, deer were pretty much a fact of life in suburban areas.

Deer in the city.png

White-tailed deer, picture taken in suburban Houston

So it was kind of surprising to me to learn that the white tailed deer, which is a really important host for ticks, had once been hunted nearly to extinction.

Early in US history, we had a lot of forests. These were cleared for a variety of purposes; a country growing as quickly as the US needs wood so it can build a lot of things countries need to run. These forests were also replaced with farmland, which meant that the habitats these deer depended on were destroyed. Additionally, the predators which kept deer populations in check were eliminated.

At the beginning of the 1900s, there were 500,000 deer left in the US which mostly hung out in areas away from people. Thanks to a number of conservation and reintroduction programs, the deer population increased massively to 18 million in the 1990s. The population is around 30 million today. As the deer population increases, and as deer more frequently move into cities, they bring their ticks with them. Because deer, and their ticks, are more commonly hanging out in areas where people are, the incidence of tick-borne diseases is increasing.

Ambylomma americanum also has a similar story. It was thought to be the most common tick species in New England in the 1700s, but was nearly extinct by 1870 in areas where it had once been common. However, as time went on, there’s evidence of a rebound especially in the Southeastern US. Although records are spotty, Amblyomma americanum is considered the most common biting tick species in the Southeastern US.

The Bottom Line

This topic is really important, because these allergies are increasing for reasons we don’t quite understand. When trying to answer this question, I tried looking for resources which explained the whole history-medical and ecological-but couldn’t really find a whole lot which approached the topic from a multifaceted standpoint.

It’s also important to mention in this space that I’m not a doctor, but I’m also writing about a decidedly medical topic. Although I’ve got a good handle on the insect immune system (my MSc was in insect immunology), human immune systems are very different because insects don’t actually make antibodies.

As time goes on, expect this story to get more complicated. We know, for example, that red meat allergy occurs all over the US. It’s even found in places where Amblyomma isn’t present. However, people also move around a lot, and it’s not really known whether these people had visited the Southeastern US…or if there’s other ways this allergy can develop.

So there’s a lot of mysteries surrounding this illness. We know one way in which it develops, but ticks may not be the only factor even if they’re a major one. We know that ticks can cause this allergy, but we’re not quite sure how. It’s still a very new discovery, and there’s still a lot of work that needs to be done.

Author’s Note:

As an aside…although we’re writing about an allergy, please don’t email us to ask questions about how you can live around this condition. We’re sympathetic, but we should also mention that none of us are medical doctors. The person who messaged us had spoken to their doctor, who gave them some very specific dietary advice based on their medical history.

Any discussion about living with allergies is best had with your family doctor.

Works Cited

  1. Cabezas-Cruz, A., Mateos-Hernández, L., Chmelař, J., Villar, M., & de la Fuente, J. (2017). Salivary Prostaglandin E2: Role in Tick-Induced Allergy to Red Meat. Trends in parasitology, 33(7), 495-498.
  2. Chmelar, J., Oliveira, C. J., Rezacova, P., Francischetti, I. M., Kovarova, Z., Pejler, G., … & Kotsyfakis, M. (2011). A tick salivary protein targets cathepsin G and chymase and inhibits host inflammation and platelet aggregation. Blood, 117(2), 736-744.
  3. Commins, S. P., James, H. R., Kelly, L. A., Pochan, S. L., Workman, L. J., Perzanowski, M. S., … & Cooper, P. J. (2011). The relevance of tick bites to the production of IgE antibodies to the mammalian oligosaccharide galactose-α-1, 3-galactose. Journal of Allergy and Clinical Immunology, 127(5), 1286-1293.
  4. Commins, S. P., James, H. R., Stevens, W., Pochan, S. L., Land, M. H., King, C., … & Platts-Mills, T. A. (2014). Delayed clinical and ex vivo response to mammalian meat in patients with IgE to galactose-alpha-1, 3-galactose. Journal of Allergy and Clinical Immunology, 134(1), 108-115.
  5. Dai, J., Narasimhan, S., Zhang, L., Liu, L., Wang, P., & Fikrig, E. (2010). Tick histamine release factor is critical for Ixodes scapularis engorgement and transmission of the lyme disease agent. PLoS pathogens, 6(11), e1001205.
  6. Francischetti, I. M., Mather, T. N., & Ribeiro, J. M. (2003). Cloning of a salivary gland metalloprotease and characterization of gelatinase and fibrin (ogen) lytic activities in the saliva of the Lyme disease tick vector Ixodes scapularis. Biochemical and biophysical research communications, 305(4), 869-875.
  7. Richter, D., Matuschka, F. R., Spielman, A., & Mahadevan, L. (2013, December). How ticks get under your skin: insertion mechanics of the feeding apparatus of Ixodes ricinus ticks. In Proc. R. Soc. B (Vol. 280, No. 1773, p. 20131758). The Royal Society.
  8. Saleh, H., Embry, S., Nauli, A., Atyia, S., & Krishnaswamy, G. (2012). Anaphylactic reactions to oligosaccharides in red meat: a syndrome in evolution. Clinical and Molecular Allergy, 10(1), 5.
  9. Šimo, L., Kazimirova, M., Richardson, J., & Bonnet, S. I. (2017). The essential role of tick salivary glands and saliva in tick feeding and pathogen transmission. Frontiers in cellular and infection microbiology, 7, 281.
  10. Sonenshine, D. E., & Roe, R. M. (Eds.). (2013). Biology of ticks (Vol. 2). Oxford University Press.
  11. Springer, Y. P., Jarnevich, C. S., Barnett, D. T., Monaghan, A. J., & Eisen, R. J. (2015). Modeling the present and future geographic distribution of the Lone Star Tick, Amblyomma americanum (Ixodida: Ixodidae), in the continental United States. The American journal of tropical medicine and hygiene, 93(4), 875-890.
  12. Steinke, J. W., Platts-Mills, T. A., & Commins, S. P. (2015). The alpha-gal story: lessons learned from connecting the dots. Journal of Allergy and Clinical Immunology, 135(3), 589-596.
  13. Stromdahl, E. Y., & Hickling, G. J. (2012). Beyond Lyme: Aetiology of tick‐borne human diseases with emphasis on the South‐Eastern United States. Zoonoses and public health, 59(s2), 48-64.

About Polistes fuscatus

Hello, I'm the friendly admin for the Ask an Entomologist blog
This entry was posted in Uncategorized. Bookmark the permalink.

2 Responses to Why do ticks make people allergic to meat?

  1. Lee Rowan says:

    Interesting! I don’t think you’d need to share any identifiable info to cite specific details about the medical case. If you had cited specific details, other people who have similar problems might have recognized the situation as relating to their own health issues. I have two cats who seem to have many meat allergies and now I wonder if they had tick bites before we adopted them.

    Like

Discuss with Us

Please log in using one of these methods to post your comment:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google+ photo

You are commenting using your Google+ account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

w

Connecting to %s