If Parasites Had Dating Profiles

Once upon a time, before the Internet, people actually had to venture outside to find a significant other. Popular places to find a potential mate included bars, dance clubs, dog parks, cafes, parties, and the gym. You’d have to work up the courage, and perhaps a cringe-worthy pick-up line, to ask another person out on a date. After an overpriced dinner and movie, you’d have to engage in lengthy conversation under a starry sky to learn about them.

But who has time for all that?! These days, you can simply screen dozens of candidates by reading their dating profiles on matchmaking web sites or apps like Tinder. This modern form of mate selection is unique to humans; imagine if other creatures in the natural world, like parasites, had to write dating profiles…

Toxoplasma gondii

Hanging with my BFFs in a tissue cyst.

We call ourselves "The Brady Bunch"!

Photo by David Ferguson (via EurekAlert)

Do you love cats? So do I! They’re my favorite animal, although I can weasel my way into any vertebrate animal that I want to, including weasels. That’s one of the reasons why I’m called “the most successful parasite on Earth.” I’m the clever parasite that has learned to manipulate the brains of rodents so that they become fearless morons around felines. Normally, mice and rats scurry away from the scent of a cat, but not when I’m in their head!

What turns me on? Long, romantic walks through the hollows of a cat’s innards. I like to groove under the moist sheets of their intestinal epithelium to the musical stylings of Cat Stevens. If we have kids, I promise to be a good parent and read Calvin and Hobbes to them all night long. I’ll be sure to kiss them goodbye before sending them out into the world to contaminate litter boxes, sandboxes, gardens, yards, and streams. Before long, our progeny will be inhaled or ingested by unsuspecting animals.

When I get into something that is not a cat, I get bored rather quickly and go to sleep. You can call me bradyzoite when I’m napping. Life in my intermediate host isn’t all that bad. I can pick pretty much whatever cell type I want and make it my room. The neurons in the brain are ideal because the pesky immune system tends to leave that organ alone, so I get plenty of peace and quiet. I just chill and wait for that animal to get eaten, hopefully by a cat so I can get my groove on again! What if another type of animal eats me instead? No biggie. I’m a patient parasite and will simply wait it out in another intermediate host.

Like I said before, if I landed in a rodent I know how to scramble their tiny brains to increase their chances of getting eaten by a hairball-coughing feline. The human brain is a tad more complex and taking me a little longer to figure out. While knocking around in a human head, I might have increased the risk of some people to develop schizophrenia or rage disorder. But ultimately, I’m trying to rewire the human brain so they leap into lion cages at the zoo.

In my spare time, I love to devour books instead of organ meat. My favorite books include Cat’s Cradle, The Pink Panther, The White Tiger, and of course The Cat in the Hat. I’m also writing my own book. It’s called If You Give A Mouse Toxoplasma…

Schistosoma mansoni

Come swim with Schisto!

Photo: http://schaechter.asmblog.org/.a/

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Escargot, anyone? My name is Schistosoma, but you can call me Schisto. I live in parts of South America and the Caribbean, Africa, and the Middle East. I hope you don’t think I’m being too fresh, but I’d love to start our date by skinny dipping in my favorite freshwater lake. After we’re done frolicking in the water, we’ll sneak into some snails and develop into cercariae. What? You’ve never been a cercariae before? Have no fear, my darling, I will teach you how to become one. Once we’re cercariae, we’ll break out of the snail and search for the definitive stop on our romantic adventure: an unsuspecting human swimming in our waters.

The cool thing about becoming cercariae is that we’ll look like a mermaid. We’ll gain a gorgeous forked tail that will help us swim around and find a suitable human to invade. I like to hum the theme to Jaws as I make my approach to the human creature! Do you know how many people are attacked by sharks each year? Only 75. I've infected well over 200 million people, but sharks get the scary theme song...go figure!

I think you’ll be surprised how easy it is to burrow into a human's skin – I prefer to enter through a hair follicle. They don’t feel a thing. Once we get inside a human, we can ditch our tails and I’ll give you a grand tour. After a few days gallivanting through the skin, we’ll hang out in the lungs, go through the heart, and then enjoy a bloodmeal as we take a ride in the circulatory system to the liver. This is the stop I find most arousing, and I’ll ask you to pair-bond with me. If you accept, we’ll celebrate by making our way to the veins draining the colon.

Why the veins of the colon? I’m glad you asked, my pet! You see, the colon is where the human stores his waste until he can’t hold it in any longer. We can easily send our eggs into his colon, giving our kids a free ride back out into the water so they can find snails of their own one day. It’s a strategy not unlike the one used by Han Solo in The Empire Strikes Back when he evaded the Star Destroyer by making it appear his ship was just a part of the Imperial garbage.

I think you’ll find that the chemistry between us is no fluke, but rather truly meant to be.

Trypanosoma cruzi

Come cruzi with me! I'm the cute wavy purple things!

Photo: Wikipedia Commons

What could be more romantic than a date that involves a “kissing” bug? That is where our enchanting evening shall begin. From inside the so-called kissing bug, we will watch it latch onto human flesh and suck its blood – cool, huh? After the kissing bug has its fill, it gets the urge to go to the bathroom, using the tiny wound it made as a toilet. That will be our cue to exit: out of the kissing bug, into the human – right through that convenient little hole the bug made in its flesh.

Once under the human’s skin, we’ll transform from trypomastigotes into amastigotes while inside the host’s cells. I hope you don’t think I’m being too prudish, but I’m really not all that into sex. I’d prefer that we multiply on our own, but how about this…we can watch each other divide!

After we make clones of ourselves, there will be too many for the host cell to hold. I just love it when a host cell pops, don’t you? As trypomastigotes again, we’ll be free floating in the blood, where we will hitch a ride when the next hungry bug comes along to “kiss” our human host.

I just hope the kids we leave behind don’t cause trouble. Most of the time when I go through a human, my kids get all rowdy and start having a bunch of kids of their own. The extensive damage they leave in their wake can cause serious problems for the human host, which they call Chagas disease.

While waiting for a kissing bug to pick me up, I enjoy listening to music. Some of my favorite songs include Kiss Me Deadly, Love Bites, and Blow Me (One Last Kiss).

Plasmodium falciparum

I'm a little camera shy, but I like these plushies of me

as they show my softer side!

Photo: Giant Microbes

If you have a fetish for vampires or other blood-sucking creatures, I am the parasite for you! My name is Plasmodium, but most people know me as malaria, which means “bad air.” I hasten to clarify: I do not suffer from flatulence or rancid breath. Before people realized I was a parasite, they attributed the cause of malaria to breathing in “bad air.”

Two of my favorite things in life are blood and sex. I use humans for blood and Anopheles mosquitoes for sex. You might not think that there is enough room in the gut of a mosquito to have a lot of great sex, but give me a chance and I’ll show you that size isn’t everything. After the love making, we’ll take a lovely stroll up to the mosquito’s salivary glands and take a little nap before dinner. While we’re in the salivary glands, you can call me sporozoite.

The mosquito will be our limo to a fine human restaurant where the blood flows like wine. We will get our wake-up call when the mosquito bites a person; then hang tight while we take an exhilarating slide down her proboscis and into a red river. After a quick pit stop in the liver to transform into merozoites and put on our bibs, we’ll jump back into the red river and take our pick at which blood cell we’d like to dine at first. All the hemoglobin you can eat! We will be the envy of Count Dracula!

In humans, red blood cells carry oxygen around the body, so as we destroy them, our human host will soon feel woozy, suffering from anemia, chills, and fever. But have no fear, as I’ll send out an SOS that changes our victim’s scent to be more attractive to mosquitoes. Before you know it, we’ll be pulled up into a fresh mosquito for some more amore.

I’m also a huge movie buff. My favorite movies are The Mosquito Coast, There Will Be Blood, Jungle Fever, and Red River.

Contributed by: Bill Sullivan

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From Herb Garden To Medicine Cabinet: Developing A New Drug for Malaria

We live on a lush planet filled with over 290,000 species of plants. Herbs are a particular type of plant that lack a wooden stem, and humans have often sampled them with hopes of finding a new food or flavoring. Sometimes ingestion of an herb produces unwanted effects, such as death. But other herbs have medicinal qualities, such as the alleviation of fever.

Dichroa febrifuga, a medicinal herb that has been historically used to treat fever, is named for its active ingredient, febrifugine.

Dichroa febrifuga is one of the most important herbs in traditional Chinese medicine, used for millennia to treat ailments such as malaria. Malaria is caused by a unicellular parasite called Plasmodium that is transmitted by mosquitoes, and a high fever is one of the trademark symptoms.

 

Malaria has a complex life cycle. After the parasites (sporozoites) are injected via mosquitoes, they travel to the liver (merozoites) and then infect red blood cells. In blood cells, they gobble up the hemoglobin as a nutrient source for replication and development into sexual stages (gametocytes) that can be taken up by another mosquito, thereby spreading the parasite to a new victim.

Malaria continues to be a devastating disease, killing up to 1 million people each year, most of whom are children under the age of five in sub-Saharan Africa. There is an urgent need for new treatments since the parasite has developed resistance to most of our anti-malaria drugs.

While effective against malaria, febrifugine is not tolerated well. What is needed is a better understanding of how febrifugine works:  how does it kill the malaria parasite? If the natural product’s mechanism of action against malaria could be identified, it would pave the way for the development of refined derivatives that are more specific against the parasite and less detrimental to patients. Alas, this is not an easy task. Over 2000 years in the making, scientists have now identified an enzyme in the parasite that is inhibited by febrifugine. That enzyme is called prolyl-tRNA synthetase.

Prolyl-tRNA synthetase is critical for the production of proteins in a cell, a process known as translation. As shown in the figure below, messenger RNA (mRNA), which serves as the “middle man” conveying the information in genes to build proteins, is read by molecular machines called ribosomes. Another type of RNA molecule called transfer RNA (tRNA) recognizes specific nucleotide sequences in the mRNA, bringing the corresponding amino acid to the ribosome so it can be added to a growing protein sequence.

The production of proteins in the cell. Proteins are composed of amino acids (the colored balls) that are connected together in a specific order, as directed by the gene coding for it. The chain of amino acids then typically folds into a three-dimensional shape so that the protein can do its job in the cell.

Aminoacyl-tRNA synthetase enzymes are needed to “charge” the tRNA; in other words, they attach the correct amino acid to the correct tRNA. When prolyl-tRNA synthetase is blocked by febrifugine, the amino acid proline does not get attached to tRNA. This leads to a buildup of “uncharged” tRNA, which is interpreted as a sign of starvation by the cell (or by the single-celled malaria parasite in this case). Proline is a common amino acid needed to build many proteins, and when prolyl-tRNA synthetase isn’t able to do its job, protein production grinds to a halt.

Even better, this enzyme is required in multiple stages of the parasite’s life cycle, knocking out both the liver and the blood forms. But as mentioned above, humans do not tolerate febrifugine very well, probably because we also have a version of prolyl-tRNA synthetase and perhaps other proteins that febrifugine poisons. Having identified this drug target is helping researchers develop derivatives of febrifugine, such as halofuginol, that act more strongly against the parasite’s prolyl-tRNA synthetase with less toxicity in humans.

Halofuginol is chemically similar to febrifugine (see above), having potent activity against malaria but less adverse effects on the host.

So how did scientists figure out that febrifugine targets prolyl-tRNA synthetase? There are several ways to identify the molecular mechanism of drug activity. In this case, the group cultured malaria in the presence of drug, forcing the parasites to evolve or die. Those that lived were less sensitive to febrifugine, meaning that they accrued a genetic change (one or more mutations in their DNA) that allowed them to persist despite the presence of the drug. This process is very analogous to the development of penicillin-resistant bacteria.

Parasites that were able to grow better in febrifugine had their genomes sequenced. Such a feat would have taken years and millions of dollars not long ago, but today it has become routine. The genome sequence of the febrifugine-resistant parasites contained a common mutation in the gene encoding prolyl-tRNA synthetase, which signaled that this enzyme plays a critical role in the drug’s action. Understanding how the parasite develops resistance also helps scientists design compounds that act on the target differently. As you may surmise, we are in a constant “arms race” with these insidious microbes, but this discovery is a step towards a victory for us.

 

Two independent parasite lines that were resistant to febrifugine, HFGR I and II, contained mutations in their prolyl-tRNA synthetase gene. In drug-sensitive parasites (Dd2), an amino acid called leucine (leu) is present at position 1444, but in the mutant parasites, a DNA change led to a different amino acid that conferred resistance to the drug.

 

Contributed by:  Bill Sullivan
Follow Bill on Twitter.

Herman JD, Pepper LR, Cortese JF, Estiu G, Galinsky K, Zuzarte-Luis V, Derbyshire ER, Ribacke U, Lukens AK, Santos SA, Patel V, Clish CB, Sullivan WJ Jr, Zhou H, Bopp SE, Schimmel P, Lindquist S, Clardy J, Mota MM, Keller TL, Whitman M, Wiest O, Wirth DF, & Mazitschek R (2015). The cytoplasmic prolyl-tRNA synthetase of the malaria parasite is a dual-stage target of febrifugine and its analogs. Science translational medicine, 7 (288) PMID: 25995223

Blood. It’s What’s For Dinner.

Halloween will soon be upon us, and our streets will once again be filled with ghosts, zombies, Lady Gagas, and other terrifying creatures of the night. And you can “count” on seeing a few vampires as well, lurking through the shadows in search of blood.

Okay, so maybe not all vampires are scary. If you have trouble sleeping Halloween night, check out this movie and “howl” with laughter.

The practice of feeding on blood, known as hematophagy, is actually a lot more common than you might realize. A wide variety of creatures suck blood, including bats, ticks, leeches, vampire finches, politicians, and so on. Similar to milk, blood is an easily accessable liquid meal containing many proteins and lipids – it does a body good. Many people who are not undead also consume blood, either directly or cooked in foods like sausages, pancakes, and soups. As seen on an episode of the hit reality TV show, Survivor (Africa), the Maasai of Tanzania get their blood straight out of the tap. They cut the neck of cattle just enough to collect blood to make a milk-blood cocktail, and then allow the wound to heal for another drink in the future.  

But not all creatures can easily digest blood. Plasmodium, the single-celled parasite that causes malaria, had to evolve some clever strategies to deal with the toxic byproducts that accumulate during the breakdown of hemoglobin, the oxygen-carrying molecule that comprises approximately 96% of the red blood cells’ dry content by weight in mammals.

(a) The malaria parasite is injected into the host’s bloodstream by another bloodsucker, the mosquito. (b) Sporozoites migrate to the liver and develop into merozoites that invade red blood cells (c). (d) Gametocytes then develop in red blood cells that can be taken up by another mosquito, which will bite a new host to continue the cycle. Life cycle image from: http://www.nature.com/nature/journal/v462/n7271/full/462298a.html   

While in the red blood cell, the parasite replicates like mad. That feverish replication requires a lot of raw materials, like amino acids to build new parasite proteins. Fortunately for the parasite, those red blood cells are rich in hemoglobin, which can be broken down into amino acids the parasite can use. However, as any malarial parasite (or Dr. Dan Goldberg) will tell you, the digestion of hemoglobin is not trivial. As the parasite’s enzymes break it down, the free heme molecules that are released as by-products within the parasite’s food vacuole are highly toxic. If these heme molecules are not disposed of properly, the parasites would die in their own waste.

Bloodsucking humans have an enzyme called heme oxygenase, which can degrade toxic heme; so unlike the malaria parasite, vampires do not need to worry about heme toxicity. But they do have trouble keeping their teeth clean!

So how does Plasmodium solve this problem? If heme were lemons, hemozoin would be the lemonade. The parasite neutralizes the toxic heme subunits by sticking them together into an inert crystal structure called hemozoin. Hemozoin crystals are non-toxic and provide decorative conversation pieces to dress up the parasite’s food vacuole. Probably looks a lot like Shirley MacLaine’s house.

Hemozoin crystals formed within the food vacuole of the malarial parasite.

Incidentally, the process of building hemozoin turns out to be an Achilles’ heel for malaria, as a number of antimalarial drugs work by interfering with hemozoin formation. Unfortunately, the malarial parasite is remarkably adaptive and has evolved multiple ways to become resistant to several drugs in this family.

Contributed by:  Bill Sullivan

Follow Bill on Twitter.


Goldberg, D. (2013). Complex nature of malaria parasite hemoglobin degradation Proceedings of the National Academy of Sciences, 110 (14), 5283-5284 DOI: 10.1073/pnas.1303299110

Gorka AP, de Dios A, & Roepe PD (2013). Quinoline drug-heme interactions and implications for antimalarial cytostatic versus cytocidal activities. Journal of medicinal chemistry, 56 (13), 5231-46 PMID: 23586757