Protection From Infection: Brazil Develops SM-14

Human Blood Flukes (Schistosoma sp.)

     As I finally closed in on the end of my first semester as a PhD student, I found myself being rather lazy. I missed posting last Sunday because I was preparing for finals, and then it just slipped my mind later in the week. That being said, I thought I would inform all of you that I will be taking a seminar class next semester titled: Tropical Medicine, Infectious Disease, and Global Health. Pretty cool huh? :) Anyway, for this year, the professor has decided that everyone will be given a country about which all of their weekly topic papers will be. I have a copy of the syllabus already and the topic papers due each week are pretty exciting! I was thinking to myself, "Man, I wish I knew which country I was going to have so I could get started early!". Sometimes I'm pretty sure professors can read minds...a few days later I got an email asking me to pick between India and Brazil. As my major advisor has done lots of work in Brazil and will be there three months out of the year for the next few years, I obviously picked this country!  
     As I began doing a little light research, I ran across some articles that I am surprised I haven't heard more about. Apparently back in June, scientists in Brazil successfully created a vaccine for Schistosomiasis in mice! This is the first time (to my knowledge) that a vaccine has ever successfully been created to battle helminths! Before I get too carried away, Let's talk a little about Schistosomiasis.

Schistosomiasis-a.k.a. "Bilharzia"-a.k.a. "Snail Fever" as an NTD
     This is a disease caused by a trematode (flatworm) belonging to the genus Schistosoma. There are a few that cause disease in humans and many that cause disease in other animals. Most human cases are caused by S. mansoni (Throughout Africa, Brazil, Suriname, Venezuela, and a few islands in the Caribbean), S. haematobium (Throughout Africa and in parts of the Middle East), or S. japonicum (Indonesia, parts of China, and Southeast Asia). There are a few others that infect humans, but they aren't nearly as widespread. (S. mekongi in Cambodia and Laos and S. intercalatum in Central and West Africa) None of these worms are not found in the US, but pose major threats to public health in Asia and South America. Schistosomiasis is a devastating disease that infects more than 200 million people globally. According to the CDC, it's second only to malaria in terms of impact on global health, and is considered one of the five NTDs (Neglected Tropical Diseases). The other four are Trachoma, Onchocerciasis, Lymphatic Filariasis, and Guinea Worm Disease. NTDs kill about 534,000 people worldwide every year. Sadly, the treatment cost for most NTD mass drug administration programs work out to less than $0.50/person/year, and these programs are still underfunded. The CDC also reports that 149 countries and territories are affected by at least one NTD. In fact, I'll let the CDC have the last word about NTDs:

"More than 1 billion people—one-sixth of the world's population—suffer from one or more Neglected Tropical Diseases (NTDs). NTDs are a group of infectious diseases that are the source of tremendous suffering because of their disfiguring, debilitating, and sometimes deadly impact. They are called neglected because they have been largely wiped out in the more developed parts of the world and persist only in the poorest, most marginalized communities and conflict areas. Social stigma is a major consequence of NTDs. In addition to causing physical and emotional suffering, these devastating diseases hamper a person's ability to work, keep children out of school, and prevent families and communities from thriving."

Distribution of Schistosomiasis

Biology of Schistosomes

Egg of S. mansoni
(Note the lateral spine.)

     We already talked about the worms that cause this disease a little bit. The life of a schistosome is quite a watery journey. They start off as eggs in feces or urine of an infected host. The eggs must be passed in a fresh water environment. Once in water of the right temperature, the eggs hatch and a little miracidium pops out to look for an unsuspecting intermediate host. 

Biomphalaria sp.
Intermediate Host for Schistosoma

     That host is a freshwater snail, which species of snail depends on which species of schistostome we are talking about specifically. From there, the parasite undergoes a series of changes before morphing into little cercariae that eventually leave the snail. This is the infective stage of the parasite's life cycle. The cercariae find and penetrate a human's skin before shedding their tails and swimming through tissues in search of the perfect place to settle down with a nice member of the opposite sex. Some settle near the bladder, some in the veins around the liver, some move towards the intestinal lumen. Many animals serve as reservoirs for this disease. It seems to be carried by dogs and cats, rodents, and several types of livestock, such as pigs, horses, and goats.

Generalized Life Cycle of Schistosomes

Pathology and Detection of Schistosomiasis

Brazilian children suffering from Schistosomiasis.

     Most people don't have any symptoms when first infected, but after a few days there is often a rash or itchy skin sensation. If gone unchecked for a few months, people experience chills, caughing fever, and muscle aches. If not treated, the disease can last for years and cause enlarged liver, bloody urine or stools, abdominal pain, and even bladder cancer. These symptoms are not caused by the worm itself for the most part, they are caused by the body's reaction to these little invaders. They symptoms lead to other problems, especially if the disease progresses to a chronic stage. Distended abdomens and dis-figuration are often observed.

Tortuous varicosities in a 24-year-old man
suffering from chronic schistosomiasis.

     To diagnose schistosomiasis, one must demonstrate the presence of the eggs from sample's of a patient's urine or feces. A blood serologic test is often useful in detecting presence when eggs were not found in urine/stool samples, as the eggs are shed intermittently rather than continuously.

The Whole Point of this Post
     An antihelminthic drug, Praziquantel, is an effective treatment for this disease. However, after treatment, many people become reinfected because they return to conditions that are conducive  to parasite proliferation. Efforts to prevent the disease have focused on killing off the intermediate host snails and telling people to stay out of the water. Neither of these "preventative" measures has been entirely successful. Snail-killing chemicals often harm other important species in freshwater ecosystems and must be administered fairly often to keep snails from returning. And let's face it, people need water. People in third world countries don't always have sources of clean water, and often people defecate in or near water sources from which they drink, or use for bathing or for livestock. Domesticated animals need water too. Just like humans, these animals can carry the parasites and pass eggs in their waste products. These products often find their way into freshwater sources.

Researcher holds a vial of SM-14.

     Since preventative measures are ineffective and impractical, researchers began work in the 70s to develop a vaccine. Vaccines are wonderful because they aren't temporary solutions to long-term problems. Vaccines are less costly in the long run because prevention can be delivered in a short series or even a single dose, rather than treating something that may reoccur later in a patient's life only to have to be treated again. Vaccines teach our immune systems how to fight off infections rather than requiring medication aimed at suppressing isolated infections. I love vaccines, and you should too. However, creating a vaccine for parasites is more difficult than creating vaccines against viruses or bacteria. Parasites are more complicated organisms...especially when we start talking about worms such as Schistosoma.
     After years of progress, Brazilian researchers have developed a vaccine for this disease! The vaccine is called Sm-14, and may be the first antihelminthic vaccine ever created.  It's also extremely safe. From what I understand, they found proteins on the worms that could be manipulated with enzymes to induce immunological protection. The proteins were located on the tegument (skin) of the worms. Research has shown that using these proteins in a vaccine tested on mice either eliminated or at the very least greatly reduced the infective capability of the parasites. Immunization combined with drug treatment and sanitation efforts offer the best solution to protecting those affected by the devastation of this disease. Brazilian researchers believe that immunization of populations in areas of endemic schistosomiasis can be completed in five years, eradicating the disease from such places.

An awesome poster showing the lead SM-14 researchers: (from left to right) Peter Hotez, David Dunne, and Alan Fenwick.

Moral of the Story
     This. Is. HUGE. Seriously, this is history in the making. The development of Sm-14 was publicly announced on December 6th, 2012. For those of you counting, yes, that was a mere 10 DAYS AGO! Just over a week ago, the results of clinical trials were released giving hope to the 200 million+ people who suffer from the second most-devastating tropical disease (just behind malaria). Be excited that you are living at a time when this medical breakthrough occurred. Then be sad that many people have never heard of schistosomiasis despite how many lives it's claimed. Then be excited again that the people who HAVE heard of it...the people who SUFFER from it or have friends or family members suffering from it at this very moment...have something to look forward to when vaccine administration programs begin distributing these little bottles of hope. This could very well be the beginning of the end for schistosomes. Maybe the Mayans were talking about them rather than about us....we will see what happens on Dec. 21st! :p

P.S. In looking for photos, I stumbled onto a website for an organization called United Against Infectious Diseases (UAID). Below is their mission statement and one of the posters they've created relating to this post.

"To empower students in making our world a better,
healthier place through awareness, prevention,
and treatment of infectious diseases."

Küchenmeister's Tasty Tapeworm Soup and Sausage

It is important for us to learn not just about the organisms we like to study as parasitologists, but also about the history of our chosen profession. The field of parasitology has a rich and colorful history full of people who make it such. Today, I’ve decided to post not about a parasite, but about one of the many parasitophiliacs who contributed to what we know about parasites today.

Gottlieb Heinrich Friedrich Küchenmeister

 Today’s parasitophiliac of interest: Gottlieb Heinrich Friedrich Küchenmeister (No, not the alcoholic cake, silly pants! The person!)

 

Can you guess where Dr. Küchenmeister hailed from? That’s right! He was born in Germany in 1821. After studying medicine in Leipzig and Prague he became a general practitioner in Zittau. In 1856, he and his wife moved to Dresden where he began his research on parasites such as Trichinella spiralis and various tapeworms. In 1852, he came up with a theory that would lead him down a controversial path as a parasitologist.

Parasitology After Steenstrup

To tell his story, let’s back up just a tad. A Danish zoologist named Johann Steenstrup made some great contributions to the field of parasitology in the 1830s by discovering that flukes had various life cycle stages that were morphologically different. This researcher proved that the eggs, rediae, cercariae, and adults were all different parts of the life cycle for a single species rather than being four distinct species as had been believed previously by science. These were the days when people believed that parasites were spontaneously generated by the body because they didn’t understand how parasites worked. 

After his ground-breaking work, Steenstrup decided to do some work with “bladder worms”, which lived in mammalian muscles. He thought these worms might actually be juvenile stages of some other unknown worm. Other scientists began postulating that these little worms that ended up in the tongues of sheep and pigs were baby tapeworms that somehow screwed up their life cycle and were malformed pockets of babies that would eventually die because they were in the wrong host.

Enter Küchenmeister

When Küchenmeister heard about this in the 1840s, he was more than a little upset. Küchenmeister was a very religious man, and he refused to accept the idea that God could screw up so badly and sentence his own creations to such an awful, and frequently occurring, dead end. So, in the interest of biological science as well as proving that ALL of God’s creatures had a purpose, this man set out to unlock the mystery of the “bladder worms”. Küchenmeister believed that the “bladder worm” stage was a very much natural and integral part of the tapeworm life cycle.

By 1851, Küchenmeister was busy conducting experiments to prove his theory. He harvested bladder worms from rabbits and fed them to foxes. A few weeks later he would cut open the foxes to find adult tapeworms. He did the same thing with mice and cats using a different species of tapeworm. He eventually moved on to harvesting from a sheep and infecting a dog. This time, when the dog began to pass proglottids in its feces, Küchenmeister fed the proglottids back to a healthy sheep. After 16 days the sheep became ill, and after it died Küchenmeister gazed inside its skull. He found little bladder worms resting atop the brain of the recently deceased sheep.

 

When he reported his findings, an uproar ensued amongst the biological community. This guy was a general physician who played with parasites for fun and was uber-pro-cremation. He wasn’t a serious researcher like so many others who had not been able to unlock such mysteries on their own. He couldn’t possibly be taken seriously. Established scientists worked hard to poke holes in the good doctor’s theories, but none of them managed to do so. Why? Because he was RIGHT!

Dr. Küchenmeister did manage a few little slip ups with his research. Apparently he sometimes lost parasites because he fed them to the wrong hosts and failed to get the next life-cycle stage. But this negative data wasn’t really wrong…it just proved that tapeworms were species-specific. So his theory still stood.

Bladder Worm Soup with a Side of Blood Sausage

So what’s the big deal? They guy fed some tapeworms to some animals and figured some stuff out? What should we care? Küchenmeister wasn’t done with his research yet. Hang in there people, this is where it gets interesting!

To further prove his theory, the good doctor began experimentally infecting humans with tapeworms. That’s right, HUMANS! He started feeding bladder worms to prisoners with the permission of the prisons, but not with the knowledge of the prisoners themselves. He found prisoners nearing their execution dates and fed them delicious meals full of little parasites. After the prisoners were executed, he would cut them open like one of his foxes to find fully-grown adult tapeworms in their intestines.

Interesting sidenote: He cooled a noodle soup to body temperature and added some bladder worms for his first prisoner, who liked the soup so much that he asked for seconds. Küchenmeister, being the nice guy he was, gave the prisoner seconds AND gave him a nice bladder worm-spiked blood sausage to go with it.

The first prisoner was executed three days after eating Küchenmeister’s special meal and upon dissection, Küchenmeister found tapeworms belonging to the genus Taenia. His second prisoner was fed four months before his execution and his corpse revealed a nice five-foot tapeworm.

Küchenmeister’s experiments were looked on as barbaric by most of his colleagues. However barbaric it was, his work helped to establish the life cycle of these tapeworms. His work was also very important because he was the first person to demonstrate that not all parasites had to spend part of their lives out in the environment. Küchenmeister proved that some parasites could be transmitted from host to host simply by being eaten.

Life Cycle of Taenia from the CDC

Moral of the Story

Taenia solium scolex

Sometimes it takes someone who isn’t an “expert” to make remarkable discoveries. Sometimes we need to look at a problem with fresh eyes and open minds if we want to figure out how things work. The beauty of biology is that what we KNOW today may or may not be the great truth of tomorrow. There is constant change and adaptation in the field just as there is constant change and adaptation in nature. It’s amazing how even the history of our field reflects the very essence of life as we understand it! So remember to always question even the most well-established principles for yourself. And if you can develop an experiment to test your hypothesis, it’s always nice to be able to test it out on prisoners lab rats.

Who Ate the Dinosaurs? Part IV: Helminthic Parasites

            At the recommendation of a well-known parasitologist, I began reading about the parasites that plagued everyone’s favorite prehistoric animals: the dinosaurs. I found lots of information on various forms of dino-parasites…everything from protists, to helminths, to insects. Today, we’ll be talking about some of the worms that burdened our giant lizard buddies. One of the earliest records of fossilized helmithic parasites in terrestrial vertebrates was reported by Poinar and Boucot in 2006. This report described a trematodes and two species of nematodes found in a dinosaur coprolite that dated back to the Early Cretaceous.

Dino-Flukes

Digenites proterus egg with arrow indicating the operculum.

            The aforementioned paper did not report an adult trematode (a.k.a. a “fluke”) but rather reported a trematode egg. The egg was described as a new species and dubbed Digenites proterus. It seems that there are many types of digenetic trematodes that parasitize modern reptiles. There are over 400 species that parasitize turtles, 75 that parasitize lizards, and 250 that parasitize snakes. These little guys find their way into many different organs…the pancreas, the gall bladder, the kidneys…and their eggs are passed out in the feces, urine, or even in oral mucus. Despite their diversity, these parasites tend to be asymptomatic (causing no clinical symptoms) in our modern day reptile friends, and were probably asymptomatic for our prehistoric buddies as well. The study mentioned only had one coprolite to work with, but the coprolite only yielded one such egg, so at the very least the dinosaur who left behind those remains was not heavily infected and probably wasn’t too bothered by the trematode(s) within him or her.

Dino-Nematodes

A. priscus (right) and A. gerus (left) eggs
with arrows showing developing nematode larvae.

            Much like the trematodes that Poinar and Boucot described, there were three nematode eggs that represented two new species of prehistoric nematodes,  Ascarites priscus (two eggs found) and Ascarites gerus (one egg found). Unlike the trematodes egg, these eggs had visible juveniles that had been frozen in time within the egg casings!  There are close to 100 species of ascarids in modern day reptiles. These worms typically lay lots of eggs that get passed out in the feces of their hosts. Just as before, the low parasite load from this sample indicates that this particular dinosaur probably had no clinical symptoms of being parasitized by these worms.

 

Everyday They’re Burrowin’ Burrowin’

            I ran across an article about another interesting find relating to helminthic parasites of dinosaurs. In this article, researchers led by the University of Colorado, Boulder’s Karen Chin analyzed the gut from a duck-billed dinosaur that they affectionately called “Leonardo”. “Leonardo” was excavated from a river formation in Montana in 2000 and 2001 before its intestinal materials were given to Chin’s team in 2006. The team found over 200 burrows from parasitic worms that were similar to either modern day annelids or nematodes. As far as I know, they couldn’t tell which specific parasites caused the tunnels, but they could tell that it was a parasite and not something that invaded the dinosaur’s body after it died. The question on my mind, and probably yours too: How exactly does one land the job looking at the intestinal materials from a dinosaur anyway?

An artist's depiction of how "Leonardo" might have appeared.

Waiter! There’s a Snail in My Dinosaur’s Dung!

            So this part isn’t COMPLETELY relevant…but it is somewhat, so I’m going to bring it up anyway. I ran across a nifty little paper describing the recovery over snail fossils in dinosaur dung. The fossilized snails were incredibly well-preserved with some 46% of the snails being whole fossils! Due to the extent of preservation, it is believed that the snails found their way into the dung after it was deposited rather than the snails being something that the dinosaurs ingested and then passed themselves. 

Lioplacodes (a fossilized snail) embedded in a
coprolite from an herbivorous dinosaur.

For those who aren’t parasitologists, allow me to enlighten you as to the significance this has for this blog. There are many different snails that play integral roles in the life cycles of helminthic parasites. Various species of snails serve as intermediate hosts for many different types of trematodes and also for some nematodes. There have been seven different genera of fossilized snails recovered from dino-dung pats, some of them terrestrial and some of them aquatic types of snails.  In my humble, personal opinion (understand that I have absolutely no literature to back this up), I believe that there very easily could have been parasites that were passed in the dung by dinosaurs and picked up by some of these snails as part of those parasite life cycles. It would be interesting to find fecal remains from animals that may have been dinosaur prey and examine them for the presence of these snails and, if possible, whatever parasites they may or may not be carrying. Hopefully someone will have the answer to that question in the future, if they don’t already. Escargot for thought?!

Moral of the Story

            When a conversation turns to dinosaurs, we don’t often think about how these majestic creatures may have hosted intestinal worms in the same way that so many creatures, including ourselves, do today. It is all too easy for us to think of dinosaurs as animals that ruled the earth as giants rather than as animals that existed as part of a vibrant and evolving ecosystem. It’s all too easy to forget that parasitism is an important part of any ecosystem, with the world on and inside of ancient reptiles being no different. If there exists some cosmic thread that connects today’s world to the world of the past, parasitism certainly makes up many of the fibers. So, the next time you are at a party, you should throw around the idea that we aren’t so different from dinosaurs because we all have played host to parasites. When you lock eyes (Personal Communication, Grant Shulman, 2012) with another person who finishes your sentence and lovingly whispers, “Psuedopulex jurrassicus” and then the two of you exchange numbers, go out for coffee, start dating, get married, and start making your own little parasites, you can come back here and comment on my blog! :p Ahh young love…sprung from parasitophilia…I’m not gonna cry…I’m not gonna cry…

Who Ate the Dinosaurs? Part III-Protozoan Parasites

           At the recommendation of a well-known parasitologist, I began reading about the parasites that plagued everyone’s favorite prehistoric animals: the dinosaurs. I found lots of information on various forms of dino-parasites…everything from protists, to helminths, to insects. I’ve decided to break up this topic into a series of posts over the next few weeks.

           Today, let’s talk about some insidious little creatures that may have infected dinosaurs…protozoan parasites! These parasites are single-celled and not something that preserves well in fossils or in amber as our ectoparasites did. However, they can still be detected in coprolites (fossilized feces) and by the pathological problems they left evidence of in the bones of ancient beasts.

Confirmation from Coprolites

Entamoebites antiquus

            In 2006, Dr. Poinar and his college Dr. Boucot reported the earliest evidence of protozoans from a Belgian coprolite. This coprolite dated back to the Early Cretaceous, making this paper the first paper to report intestinal protozoan parasites from a dinosaur. This protozoan was identified as the cyst from of Entamoebites antiquus, and is more similar to our modern day genus Entamoeba than to our modern day genus Endolimax.

Always Check the Amber

            As we talked about last week, there is also a lot of evidence regarding parasitism that can be found encased in amber. Specifically, we talked about the face that insects that are known vectors for modern diseases have been found in these little time capsules. This leads us to believe that they may have been transmitting diseases back in the days of the dinosaurs as well. Some scientists, such as Dr. Poinar (co-author or What Bugged the Dinosaurs?) have claimed to find evidence of protozoans that are similar to modern-day Leishmania and Haemoproteus parasitic protists.

An adorable stuffed-protist
version of Leishmania

            However, some people, such as Dr. David Grimaldi, (with the Division of Invertebrate Zoology at the American Museum of Natural History) is skeptical of such claims. In his review of Dr. Poinar’s book he states, “Unfortunately, the vague, dark forms in their light micrographs fail to convince. Since cells within amber-fossilized insects are well known to have preserved organelles, identification of the putative pathogens should have been made with electron microscopy.”

            Either way, finding protozoans in insects that have been preserved in amber can’t be an easy task. I suppose we will have to wait and see what science and technology can do in the coming years to either support or debunk claims about the presence of the tiny, unicellular menaces.

Detection of Protists Via Paleopathology

Depicting the lesions found on "Sue"
a T. rex who suffered from parasitic
protozoan infections.

            In 2009, another article came out about ancient protozoan parasites that plagued dinosaurs. By examining lesions in the jaw bones of Tyrannosaurus rex skulls, these researchers determined that the lesions were a pathological result of a transmissible parasitic disease that bears striking resemblance to a disease that plagues modern-day birds. Because they found the effects of such disease, and not the actual causative agent, scientist can’t pinpoint the species to blame. However, there is strong evidence that the parasite to blame was similar to Trichomonas gallinae. Paleopathological evidence of this disease has only been found in the bones of tyrannosaurs, so far. It seems to have been fairly common among species in some populations and was probably spread through either consuming infected prey (or cannibalism) or through nasty bloody battles over T. rex turf. Some of the specimens in this study were so heavily infested, that paleopathologists determined that those specimens most likely died as a direct result of having that infection. The idea is that these mighty beasts starved to death because it was too painful too eat when you’ve got your jaws packed full of protists.

Moral of the Story

            When a conversation turns to dinosaurs, we don’t often think about how these massive creatures may have played host to unicellular demons. It still astonishes me that something so small and seemingly insignificant can cause such pathology in animals as massive and seemingly invincible as a Tyrannosaurus rex. And those poor guys couldn’t even scratch a jaw being systematically riddled with holes. Anyway, the next time you are at a party, you should definitely throw around the name ­­­­­­­­­­­­­­ Entamoebites antiquus. If a dude introduces himself after hearing you utter such a phrase, you should let him take you out for coffee. I urge you to accept this offer because he’s either really awesome for knowing something about ancient parasites, or he reads my blog…which makes him even more awesome. ;)