Highlights

• Explore the life cycle of Entamoeba histolytica
• Research has uncovered an entirely different mechanism of cell killing by E. histolytica known as trogocytosis.
• E. histolytica cleverly disguises itself to evade the human immune response.

When food bites back: the intestinal parasite that nibbles

When contaminated food or water gives you stomach trouble, you’ve probably unintentionally invited a foreign microbe into your gut. If stomach trouble turns into something worse, Entamoeba histolytica might be snacking on your intestines. This parasitic amoeba doesn’t just take bites of your cells – it cleverly uses those bites to escape detection by your immune system.

Sometimes travel has a price

Imagine that you’ve just arrived in a foreign country. Eager to begin experiencing a new culture, you devour whatever local delicacy is being sold on the street. Several hours later you’re hit with stomach illness and regret all of your life choices. After a day or two of misery, you are well enough to begin enjoying your visit – with some hard-earned caution about what you eat or drink.

Intestinal issues are so common for travelers to experience that the condition has a name: traveler’s diarrhea. But have you ever wondered what’s actually causing your gut so much trauma during a bout of food-borne illness? There are so many microorganisms willing and able to flourish at our expense that you may never know which bug is responsible for a particular episode of stomach upset.

These microbes come in all shapes and sizes and employ an astounding array of strategies to grow and spread to other human hosts. Bacteria like E. coli and Salmonella and viruses like rotavirus and norovirus are the most common sources of intestinal disease, secreting toxins that elicit an immune response in the gut resulting in diarrhea and spread to new hosts. Disease caused by protozoan parasites like Giardia and Cryptosporidium is less common and not as well understood.

From cyst to amoeba to cyst again

Entamoeba histolytica is one of those lesser-known parasites responsible for global diarrheal disease. Its lifecycle is relatively simple. Spread through the fecal oral route, it enters the body through ingestion of food or water that has been handled without proper sanitation or cleanliness. Initially in a cyst form when consumed, E. histolytica is in protected hibernation and can easily pass through the low pH of the stomach until it reaches the large intestine. At that point the cyst hatches into four amoebae (the plural of amoeba) that multiply like crazy and create chaos in your gut. Cysts are formed again and leave the body to infect the next unsuspecting consumer of tainted food or water.

How an individual responds to E. histolytica infection is unique – because every person is unique! Only about 10-20% of people exposed actually experience symptoms. Of the folks who do get sick, they often have a noninvasive infection with diarrhea and stomach pain. An unlucky few will experience a severe form of the disease, in which amoebae breach the intestinal wall and cause massive tissue damage, resulting in bloody diarrhea and intestinal ulcer. In some cases E. histolytica will disseminate to other parts of the body like the liver and cause abscess formation. The level of destruction this parasite causes is so dramatic that it is named for it: histolytica directly translates to “tissue dissolving”.

Nibbled to death

So how does E. histolytica wreak so much havoc on the digestive system? Initially, researchers thought that amoebae released toxins called amoebapores that poke holes in human cells.¹ After the human cells deflate to their death, E. histolytica would lengthen its membrane into makeshift arms (pseudopods) and swallow the cell remains whole – a general process called phagocytosis.²

About a decade ago, new research uncovered an entirely different mechanism of cell killing by E. histolytica. Instead of killing and then swallowing human cells whole, amoebae actually take discrete bites of living cells.³ This process of cell nibbling is called trogocytosis. Nibbling continues until the human cell dies, at which point the amoeba abandons the dead cell and starts snacking on other live cells nearby. The resulting tissue damage is likely what allows amoebae to invade the intestine so thoroughly.

Amoebae are what they eat

At this point you might be wondering what the immune system is doing while E. histolytica ravages the tissue in your gut. There are several layers of defense that would prevent pathogens like E. histolytica from spreading further into the body. White blood cells patrol blood and neighboring tissue and sense foreign microbes, and either attack immediately or initiate a long-term response via antibody formation. Soluble proteins in the blood called complement deposit on pathogen surfaces and form pores in their membranes.

So how does E. histolytica evade the immune response? To prevent the immune system from attacking itself, all human cells have a combination of “self” markers and complement regulatory proteins on their surface. When amoebae take bites of human cells, they are ingesting these “self” markers and displaying them on their own surface.⁴ This camouflages amoebae from the harmful actions of complement and allows safe passage in the blood to other areas of the body.

We all love a good snack

If this is the first time you’ve ever heard about cell nibbling, you’ll be surprised to hear that this process is used by many other organisms besides E. histolytica. The infamous brain-eating amoeba Naegleria fowleri takes bites out of human cells to kill them⁵. Francisella tularensis bacteria evade the immune system by traveling between macrophages within bites.⁶ In a role reversal, immune cells have been observed using trogocytosis to fight foreign invaders. Neutrophils nibble Trichomonas vaginalis parasites to kill them, and macrophages gnaw on cancer cells to destroy them.^7,8 Immune cells can also use nibbling as a form of communication.⁹ By munching on infected cells, T cells can display pathogenic proteins to further alert the immune system to invasion.¹⁰

Despite how widespread trogocytosis is, our understanding of it is far from complete. The genes and corresponding proteins that drive cell nibbling are still mostly unknown, and it isn’t clear why some cells nibble and others don’t.¹¹ Scientists are hard at work trying to answer these questions. Their findings could potentially lead to more effective therapeutics for combating serious E. histolytica infection. But until then, exercise caution with what you eat!

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References

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2. Sateriale A, Huston CD. A sequential model of host cell killing and phagocytosis by Entamoeba histolytica. Journal of parasitology research. 2011;2011.
3. Ralston KS, Solga MD, Mackey-Lawrence NM, Bhattacharya A, Petri Jr WA. Trogocytosis by Entamoeba histolytica contributes to cell killing and tissue invasion. Nature. 2014;508(7497):526.
4. Miller HW, Suleiman RL, Ralston KS. Trogocytosis by Entamoeba histolytica mediates acquisition and display of human cell membrane proteins and evasion of lysis by human serum. mBio. 2019;10(2):e00068-19.
5. Brown T. Observations by immunofluorescence microscopy and electron microscopy on the cytopathogenicity of Naegleria fowleri in mouse embryo-cell cultures. Journal of medical microbiology. 1979;12(3):363-371.
6. Steele SP, Chamberlain Z, Park J, Kawula TH. Francisella tularensis enters a double membraned compartment following cell-cell transfer. Elife. 2019;8:e45252.
7. Mercer F, Ng SH, Brown TM, Boatman G, Johnson PJ. Neutrophils kill the parasite Trichomonas vaginalis using trogocytosis. PLoS biology. 2018;16(2):e2003885.
8. Velmurugan R, Challa DK, Ram S, Ober RJ, Ward ES. Macrophage-mediated trogocytosis leads to death of antibody-opsonized tumor cells. Molecular cancer therapeutics. 2016;15(8):1879-1889.
9. Joly E, Hudrisier D. What is trogocytosis and what is its purpose? Nat Immunol. 2003;4(9):815-815. doi:10.1038/ni0903-815
10. Huang JF, Yang Y, Sepulveda H, et al. TCR-Mediated Internalization of Peptide-MHC Complexes Acquired by T Cells. Science. 1999;286(5441):952-954. doi:10.1126/science.286.5441.952
11. Bettadapur A, Miller HW, Ralston KS. Biting Off What Can Be Chewed: Trogocytosis in Health, Infection, and Disease. Ottemann KM, ed. Infect Immun. 2020;88(7):e00930-19, /iai/88/7/IAI.00930-19.atom. doi:10.1128/IAI.00930-19