Why can tick bites cause red meat allergy?
When you think about tick bites, usually infections like Lyme disease or babesiosis come to mind. But on this episode of the podcast, we explore a surprising association between tick bites, a sugar moiety called alpha-gal, and red meat allergies. The story brings together many different strands, from severe allergic reactions to red meat, geography, evolution, organ transplantation from animals into humans, and even anti-cancer antibodies.
The association between tick bites and meat allergy was first reported in 1991 at a small meeting of the Georgia Allergy Society. The presenters described ten cases of people developing hives or anaphylaxis with red meat ingestion weeks to months after tick bites. It was a small series, but it suggestion an association existed. No one immediately followed up on it.
Twent-eight years passed when in 2009, reports started to come out in journals of the emergence of meat allergies after people had been bitten by ticks. A group in Australia published a case series of 25 patients who developed allergic reactions to red meat within 6 months of having been bitten by a tick. The types of red meat included beef, pork, lamb, or game meat like venison, rabbit, and even kangaroo.
Since these initial reports, the association has been strengthened by numerous case series in different parts of the world with different types of ticks, depending on which part of the world you’re in. In the United States, the geographic distribution of red meat allergy for tick bites almost exclusively occurs in the Southeastern part of the country and overlays almost exactly with the North American lone star tick, or Amblyomma Americanum. This is the main tick implicated in the US.
The key to understanding why this association exists is a tiny sugar molecule called alpha-gal. Its full chemical name is galactose-α-1,3-galactose, as it comprises two galactose molecules attached to each other. It’s short as carbohydrate chains go, so it’s technically an oligosaccharide. And it can be found stuck onto glycoproteins and glycolipids in cells and tissues, but only in non-primate mammals. Primates, including humans, can’t make alpha-gal. While we have galactose in our bodies, we lack the enzyme (alpha 1,3-galactosyltransferase) needed to assemble alpha-gal from galactose. Without it, we cannot assemble alpha-gal from its galactose components.
The reason why humans evolved to be different than other mammals in this small but clearly very important way is a mystery. But hypotheses have been offered. There is some evidence that not being able to make alpha-gal may have been a form of defense for primates against viruses hopping from non-primate mammals. For example, a 1996 Nature paper found that anti-gal antibodies in human serum quickly inactivated animal viruses, which were coated in alpha-gal because they came from animals that make that sugar molecule. So the theory goes that our immune systems can flag viruses from animals as foreign because they have alpha-gal, thus protecting our distant primate ancestors and us from infection.
What is the role of tick bites? First, lone star tick viscera and their saliva contain alpha-gal. And what’s more, the levels of salivary alpha-gal rise when it bites a human and the tick injects it directly into a person’s skin. So that’s how a tick bite could expose you to alpha-gal. Some have now referred to this as “alpha-gal syndrome.”
Three theories have been proposed to explain why tick bites lead to explore to alpha-gal, a non-primate mammalian sugar moiety. The leading mechanistic theory supposes that ticks produce their own alpha-gal. This seems to be the most likely one. It is also possible that tick-borne alpha-gal comes from either the blood of animals that the tick previously fed on. A third possibility is that symbiont bacteria that live in tick saliva produce alpha-gal.
Exposure to alpha-gal via tick bites can lead to IgE-mediated allergic sensitization to meat, which is coated in alpha-gal. This can also occur with other animal products like milk. After sensitization, subsequent exposure to alpha-gal via ingested meat leads to cross-linking of IgE on mast cells and degranulation and systemic allergic reactions.
There are two other fascinating connections to be made. One involves cetuximab, and the other involves xenotransplantation.
Cetuximab is a chimeric mouse and human antibody against EGFR used to treat malignancies such as head and neck and colorectal cancer. When the drug first came on the market in the US in the late 2000s, investigators noticed that many people were experiencing allergic reactions and anaphylaxis. At first, this is unsurprising as we often see allergic reactions to antibody-based therapies. But there was something odd about where these allergic reactions occurred. The vast majority of reactions were in the US Southeast. In the 2008 New England Journal of Medicine paper that described the association, the rates of allergic reactions evidence of sensitization against cetuximab were 2-3% in California and Boston and 20% in Tenessee. This matches the distribution rates of alpha-gal syndrome, with the focus in the Southeastern US.
The authors analyzed pre-treatment blood samples and found that almost everyone who had an allergic reaction to cetuximab had evidence of sensitizing IgE antibodies in their serum before exposure to the drug. Something had pre-sensitized them. That something is cetixumab, which contains an alpha-gal moiety in its heavy chain portion. What seems to have occurred is that people living in the southeast had been bitten by ticks and gotten alpha-gal sensitized, just like we’ve seen with red meat. They then got exposed to alpha-gal again with the cetuximab and had allergic reactions.
Xenotransplantation is a tough nut that modern medicine has yet to crack. And the main reason that it’s been so challenging is that the human system recognizes the xenotransplant as fundamentally foreign and rejects it. And it turns out that one of the immunological signals that an animal organ is foreign is alpha-gal. Again, recalling that humans don’t make alpha-gal at all, whereas a pig heart, say, is covered in it. Alpha-gal is one of the primary barriers to xenotransplantation.
But, what if an animal genetically lacked alpha-gal? Could organs from that animal potentially be transplanted into a human? Investigators and companies are starting to look at doing this by creating alpha-gal knockout animals that don’t make alpha-gal at all. This might mean an organ from an alpha-gal-negative animal is immunologically less visible to the human system and less likely to be whole-hog rejected. The first successful xenotransplantation of a pig heart into a human patient happened in January 2022 at the University of Maryland. The patient, David Bennet, was very open and public about his journey. Although he wasn’t considered a candidate for conventional transplantation, he was offered the first-ever cardiac xenotransplantation. The surgeons used the heart from a pig that was genetically modified to lack or be knocked out for alpha-gal, in addition to a few other genetic modifications. The company that raised the genetically modified pig, Revivicore, is a spin-off from the company that cloned Dolly the sheep in 1996. The transplant was initially successful with Bennet waking up from surgery with a pig’s heart beating inside him. He did well for the next month, but unfortunately, the xenotransplanted heart began to fail, and Bennet passed away 2 months after his transplant. It later became evident that the pig’s heart was infected with porcine cytomegalovirus, which may have contributed to the organ failing and Bennet’s overall decline and death, though this is not known for certain.
As one final wrinkle, the same company that produced the alpha-gal knockout pigs for xenotransplantation has begun to make their meat available for consumption. In December 2020, the FDA approved the sale of alpha-gal deficient pig meat, or as the company called them, GalSafe pigs. They are specifically targeting people who are alpha-gal allergic from tick bites and otherwise cannot eat meat.
No podcast episode about alpha-gal would be complete without mentioning Radiolab’s outstanding series on the topic.
Take Home Points
- Bites from the lone star tick in the American Southeast (and other types of ticks in other parts of the world) can lead to meat allergy.
- Alpha-gal in tick saliva sensitizes people to alpha-gal found in animal tissue.
- Cetuximab allergy occurs via the same mechanism as it contains alpha-gal.
- Alpha-gal knockout in pigs is a promising avenue for xenotransplantation in the future. The genetically modified animals may offer meat-allergic people a safe meat option.
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Listen to the episode
Credits & Citation
◾️Episode written by Avi Cooper
◾️Show notes written by Avi Cooper and Tony Breu
◾️Audio edited by Clair Morgan of nodderly.com
Cooper AZ, Breu AC, Abrams HR. Of ticks, alpha-gal, and red meat allergies. The Curious Clinicians Podcast. December 7, 2022.
Image credit: https://www.nbcnews.com/health/health-news/lone-star-tick-linked-heartland-virus-people-found-georgia-rcna20328