Schistosomes: beware the water

Over 700 million people worldwide are at risk from parasitic worms called schistosomes (blood flukes), which are transmitted via swimming in contaminated water. The worms are a major problem and can cause a severe debilitating disease called schistosomiasis in their hosts, which, sadly, kills nearly 200 million people each year.

This is an adult male blood fluke. Note its highly developed mouth piece on the right, which is uses to 'clamp' onto the inside of blood vessels and anchor itself against the blood flow. Once secured, it feeds on the nutrients carried in the host's blood. The fold that you can see running through the centre of the worm is called the gynacophoric canal, in which the much smaller female worm lies in permanent copulation.

Due to the large distribution of the schistosomes and their prevalence in third world countries that have very little infrastructure, they are of huge concern to the World Health Organisation, who is trying to reduce the levels of infection by educating people in endemic areas of the dangers, improving sanitation and by ensuring that the drug praziquantel is readily available to as many patients as possible.

Unfortunately, praziquantel treatment is extremely unpleasant and results in a range of negative side effects in humans, including: dizziness, somnolence, seizures, arachnoiditis and diarrhoea. To make matters worse, the parasites themselves actually worsen these side effects and patients undergoing treatment can also suffer from urticaria, rashes and pruritus. This is due to the sheer volume of dead parasitic material that is released into the blood at any one time, which can also cause eosinophilia in leukocytes.

Schistosomes are waterborne and infect human hosts when they swim in contaminated water. As the host swims, they leave a trail of fatty acids from their skin in the water behind them. The parasite is attracted to these fatty acids (L-arginine inparticular) and then attaches itself to the host's skin. Once attached, schistosomes secrete acids and enzymes from acetabular glands and literally burn through the skin until they enter the bloodstream! The distinctive and unpleasant rash that results is often called 'swimmers itch'.

Due to the problems associated with praziquantel, many health agencies are beginning to acknowledge that the best way to combat schistosomiasis is to prevent human infection in the first place. The easiest way to do this is to treat infected waters with insecticides that kill water snails – another vector that is essential to the schistosome life cycle. Without water snails, schistosomes will be completely unable to infect humans and the problem of schistosomiasis is thereby solved!

Like most parasites, schistosomes have an extremely complicated life cycle where they morph through a range of different forms and, at different stages, live in more than one host.

One of the reasons schistosomes are such a major problem is because males and females live in permanent copulation with each other inside the human body so can literally release thousands of eggs in a very short space of time. Rather than the parasites themselves, it is actually these eggs that cause the symptoms of schistosomiasis – a chronic, severely debilitating disease that is usually fatal. The exact symptoms of schistosomiasis vary (depending on the species that has infected the host and where the worms prefer to take up residence), but the most common symptoms are given below:

• Intestinal schistosomiasis is caused by the bowel-living species of blood flukes Schistoma mansoni and S. japonicum, and is associated with abdominal pain, diarrhoea and bloody faeces. Liver enlargement is frequently seen in advanced cases, which leads to gross abdominal swelling as fluid is forced into the host's peritoneal cavity as a side effect of abnormally high blood pressure
• Urogenital schistosomiasis is caused by S. haematobium, which lives in the bladder, and is commonly characterised by haematuria (blood in the urine); lesioning and scarring of bladder tissue; ureter and kidney damage; genital lesions that lead to pain during sexual intercourse; and, in advanced cases, can lead to infertility and a variety of cancers

Liver enlargement is one of the most debilitating symptoms of schistosomiasis and is fatal in almost all cases. This is due to the large-scale, irreversible damage it causes to the host's body.

What makes schistosome eggs so problematic is the large spike that protrudes from their surface. This spike is designed to slice through the walls of blood vessels so the eggs can pass into their hosts urine or faeces (and thereby be passed back into water where they hatch and infect more snails), but can become caught in the host’s tissues upon occasional. Once an egg has become lodged, the host’s immune system identifies it as 'foreign material' and a type of leukocyte called a macrophage activates in response. Macrophages quickly form a granuloma around the egg, which is essentially just a tough wall of inert proteins that prevents the egg from interacting with the body’s tissues. Ordinarily, granulomas are beneficial and are eventually removed from the body, but this cannot happen with the trapped egg. Due to this long-term presence, the surrounding tissue begins to inflame and no longer functions correctly. This problem is exacerbated as an ever increasing amount of eggs build up in the organ and are themselves enclosed by granulomas! Eventually, the organ becomes so blocked and damaged that it is unable to function correctly - leading to the symptoms of schistosomiasis!

Scientists are currently working on a waterproof cream that mask the fatty acids on our skin when we swim (which will help prevent schistosomes from invading our body), but this research is still in its early stages and doesn't look likely to have a practical application anytime soon. For now, you should simply avoid swimming in any water where schistosomiasis is prevalent (no matter how inviting it may look). If you are travelling aboard, such as to Africa (where schistosomiasis is a particular problem), I strongly recommend that you consult your doctor and travel professionals to familiarise yourself with the risks of the area before you head out.

Skinchangers: fact or fiction?

Throughout much of sub-Saharan Africa a disease called African trypanosomiasis (or sleeping sickness) is rife that affects both humans and animals alike. The main characteristic of the disease is the disruption of sleeping patterns that causes suffers to be awake at night and asleep during the day. Other symptoms of sleeping sickness include fever, sweating, headaches and the tendency to experience rapid mood swings. If the disease is left untreated, those infected with sleeping sickness could die from heart failure within 6 months of infection and, even if they get medical help in time, are likely to suffer from permanent damage to their nervous system so that their ability to live a normal life is impinged. Over 60 million people are at risk from African trypanosomiasis, which affects 50% of people in endemic areas. Furthermore, the loss of domestic cattle has had significant socio-economic consequences and the reduced ability for cattle farming has cost a staggering US$12, 000 million!

African trypanosomes are extracellular parasites, which means that they live freely in their hosts blood rather than inside of cells. Humans can be infected by two types of African trypanosome: Trypanosoma brucei gambiense and Trypanosoma brucei rhodiense, which is the most common and most deadly type, and is featured in this photo.

Sleeping sickness is spread by blood-sucking tsetse flies, which inject parasites called African trypanosomes* into their host's bloodstream along with the anticoagulants in their saliva. Once inside their host's bloodstream the parasites rapidly divide by binary fission and spread through various fluids throughout their body. What is interesting about African trypanosomes is the fact that they remain free-living in their host's body throughout their entire life cycle. This is highly unusual and most parasites (with the exception of worms), are intracellular and invade a specific type of cell to live and divide in as soon as they enter their host. The main reason many parasites do this, to put it simply, is to avoid their host's immunodefences. It is quite remarkable that African trypanosomes can manage to survive in the bloodstream,  which is a very hostile environment that is full of leukocytes (white blood cells)!

How they survive here is amazing and African trypanosomes are quite literally skinchangers! The parasites have special proteins on the surface of their 'skin' called variable surface glycoproteins (VSGs), which are encoded for by over 1, 000 different genes. The many proteins produced by these genes can be spliced together at random so that an infinite number of unique VSGs can be produced. This plays havoc for the host's defences and effectively renders the infection unclearable. This is because our immune system relies on shape: foreign invaders (or pathogens) have very specifically shaped antigens on their surfaces to which our bodies produce antibodies against in order to kill them. So, by changing the VSGs that they are displaying, African trypanosomes prevent their host's immune system from killing them off.

To explain this further, most of the parasites display the same unique VSG on their surface that their host's body cannot fight against so that they can divide unchecked. Eventually, and after a delay, the host's immune system produces new antibodies against this VSG and all of the parasites expressing that particular phenotype are killed. However a small number of the parasite population have already changed their skins by then and survive. These parasites then divide very rapidly (as they have less competition with other parasites), until the body 'learns' how to kill them and the whole cycle starts again. Eventually the parasites have done so much damage to the host, that it dies. Thus, outside medical treatment is required to kill all of the parasites at once that entails using powerful drugs such as Pentamidine or Melarsoprol.

The population of African trypanosomes in their host's bloodstream cycles depending on whether their host can kill them off or whether it is trying to produce new antibodies against them. The peaks in their population, which coincide with peaks in the symptoms of the disease, are called trypanolytic crises and were first discovered in 1910 by an Italian doctor.

So there you have it! African trypanosomes quite literally change their skin to avoid being detected and killed by their host's immune system, which allows them to persist in their host's body nearly indefinitely. 

* note that African trypanosomes are fundamentally very different to their cousins, South American trypanosomes, which cause Chagas Disease and have very different life cycles.

Parasites can cause schizophrenia?!

Everyone's heard of parasites, how can you not have? They are everywhere - infecting billions of animals, plants and bacteria worldwide and are found in almost every ecosystem imaginable. In fact, parasitism is the most successful form of life on the planet and countless species choose to live in this manner; having evolved over millions of years to take advantage of their hosts and to avoid their defensive capabilities.

Unfortunately parasites also exploit humans and tens of millions of individuals die each year as a result of parasites, with countless more suffering from chronic and debilitating diseases. Probably the most well-known deadly parasites of  man are those from the genus Plasmodium, which affect over half the world's population and are responsible for causing malaria - a disease that kills a person every 12 seconds and has killed more humans throughout our history than all of our wars combined! Of course many other parasites prey on man as well, with other fairly well-known examples including African sleeping sickness (which is caused by African trypanosomes) and the debilitating disease leishmaniasis (which is caused by Leishmania parasites).

A child suffering from leishmaniasis, a protozoan parasite that inhabits macrophages - the same type of white blood cell that the AIDS virus (HIV) lives in. Depending on the strain of the parasite this lesion will either disappear by itself or, without medical intervention, could continue to grow until the child's death.

However many of these diseases occur in hot and distant countries, such as Africa which is plagued by the examples mentioned above, and it is easy to forget that parasites regularly effect us here in Europe, the United Kingdom and the USA as well. In fact, anyone who's ever had an itch in a rather private place knows that we can catch 'worms' - intestinal nematode parasites that latch onto the walls of our gut and shed their eggs through our faeces. However, although unpleasant, catching 'worms' is rarely life threatening and can even help to alleviate the symptoms of asthma and other inflammatory diseases as the body shifts the dominance of its immune response away from the inflammatory causing Th1 response to a Th2 response, which is more suitable for killing worms in the gut! Cases such as this, where parasites can to help reduce the symptoms of 'modern diseases' that have only recently appeared in the civilised world, have led many scientists to believe that our hygiene and healthcare is now so good it it actually harming us in some ways as with less infection our leucocyctes (white blood cells) have nothing to fight and actually begin to harm our own bodies!

However, many of the parasites that can effect us in Europe are much more sinister and do not have such helpful side effects. One such parasite is Toxoplasma gondii, an intracellular protozoan that is arguably the most successful parasite in the world as it can effect almost any warm blooded animal (most parasites can only inhabit one or a very small number of specific species) and is found on every continent of the globe. The parasite is spread through cat  faeces, by ingesting under-cooked meat or across a mother's placenta to her unborn baby (which is known as congenital or 'vertical' transmission) and can affect up to 80% of human populations depending on where you live. For example, the incidence of T. gondii is about 16% in the UK where eating rare meat is unpopular; yet in France, where rare meat and blue meats are in high demand, 8 in every 10 people are infected by the parasite!

While all felids can contract T. gondii and pass sporolating oocysts (which are essentially just 'bags' of membrane that contains multiple parasites) with their faeces, is the domestic cat (Felis catus) that mainly transmits them to humans. This is usually when their owner has changed their litter or stroked them near to their tail and then prepared food without first washing their hands.

It may be confusing then, why so few people have heard of T. gondii or about toxoplasmosis (the disease that it causes) and even more so, why we do not have a vaccine against the parasite. The answer however, is fairly mundane - it is because the parasite does not cause any symptoms in individuals with a normally functioning immune system meaning that healthcare organisations around the world largely ignore the parasite. In fact, healthcare institutions only bother worrying about the parasites in patients in a state of  immunodeficiency, such as AIDS or chemotherapy patients; and during pregnancy, as congenital infection can result in the baby being born  blind, deformed or even in a miscarriage (don't worry - the parasite is checked for during routine baby checks throughout pregnancy and can be killed safely by the antibiotic Spiramycin, which builds up and persists for long periods of time in placental tissue).

The lack of symptoms that T. gondii parasites cause has led many scientists to believe for years that the parasite is safe and doesn't merit further study, despite the parasite forming life-long cysts in our brains that contain bradyzoites (parasites that become active by turning into tachyzoites when the cyst is eaten by another organism. Obviously, this is a 'dead end' for the parasites in humans since we are only rarely eaten). However, recent research suggests that the parasites are in fact harmful to us - slowing down our reaction times, altering our behaviour and inducing many psychotic diseases like the infamous schizophrenia (which despite popular belief, is NOT a split-personality disorder!).

Toxoplasma gondii tachyzoites can be seen here, after absorbing an intracellular blue/purple dye. The parasites can enter almost any nucleated cell and illicit a strong Th1 immune response. Oddly, they want this response from their host and even promote it by secreting their own chemicals! These chemicals can also be beneficial for their host in other ways, helping them to overcome long-established intestinal worm infections and even develop immunity to Leishmania parasites!

It is still not clear exactly how the parasites alter our behaviour, with the outcome appearing to be dependent on gender and personality-type in humans but the changes are believed to be similar to those altered in rodents, where the animals become more likely to take risks; have delayed reaction times; become less able to learn; spend more time in open spaces; and lose their fear of cats - one of their major natural predators! Amazingly, the behavioural changes are so profound that infected mice have been seen to start running in circles with their eyes closed whenever they see a cat! It is believed that these changes are induced in rodent behaviour to increase the changes of them being eaten by a felid - a fact that is highly beneficial to the parasite as T. gondii can only enter the sexual stage of its life cycle inside a cat! Thus, cats are its definitive host and the parasites effectively spend their entire lives trying to get inside a cat. The changes in human behaviour are not believed to be aimed at us directly, but are thought to take place due to the similarities that our brains have to those of rodents.

Research has found that individuals infected with T. gondii are 2.65 times more likely to be involved in a car crash. This is not surprising really, given that the parasites slow down our reaction times and make us more likely to take risks.

Although inducing changes in our behaviour is undesirable and no-one wants to think that they are being manipulated by a parasite so that they get eaten by a cat, it may not really matter in the grand scheme of things - are most of us ever going to be in a position where a cat could eat us? The most worrying problem that is caused by T. gondii then, is the fact that they alter our brain chemistry. Studies have found that the parasite increases the production of the neurotransmitter dopamine in our brains and that this in turn, can lead to schizophrenia - a debilitating disease that is characterised by a range of symptoms including social withdrawal, delusions, self neglect, hallucinations and altered perception and thinking patterns. Schizophrenia is the ninth most prevalent cause of disability worldwide and frequently leaves its sufferers unable to function normally in society. Furthermore, the parasites have been found to be positively correlated with the risk of having a stroke, developing Alzheimer's disease, epilepsy and depression!

Thus, catching and living with T. gondii may not be as unproblematic as previously thought, especially because once you've been infected with the parasites, you will unfortunately have them for the rest of your life. To further complicate matters, it is unlikely that a drug can be developed against T. gondii parasites because once they switch to bradyzoites and form cysts throughout brain and muscle tissue, killing them becomes more trouble than its worth - killing that many parasites at once could release huge amounts of toxins into the host's bloodstream, causing them to die very rapidly from anaphylactic shock. Therefore, the only real protection against T. gondii is to prevent yourself from catching it in the first place. The easiest way you can do this is to ensure that you cook all meat thoroughly at temperatures above 65C for a least 10 minutes, even if the meat has been frozen as the parasites can survive for very long periods of time in temperatures as low as -12C!

Irradiated parasites? Good for your health?

Malaria is one of the biggest killers of man, with 300 - 500 million cases of the disease each year, causing 2 - 3 million deaths worldwide. Sadly, the majority of these deaths are children younger than 5 in sub-Saharan Africa. The disease is caused by small, protozoan parasites from the Plasmodium family, which predominately live in their host's erythrocytes (red blood cells) as merozoites, where they replicate by dividing over and over again. Eventually, an erythrocyte becomes so full of parasites that it ruptures and they burst out into the bloodstream and invade the surrounding red blood cells. And, once inside, they begin to divide all over again. It is this bursting of red blood cells that causes the symptoms of malaria, which include fever, headaches, sweating, coughing and muscle pains.

Red blood cells that have been infected with malaria and have ruptured. Small merozoites can be seen in the surrounding plasma that will enter and infect the nearby red blood cells.

Despite scientists having a good understanding of the complex life cycle of malaria and knowing that it is spread by female Anopheles mosquitoes (male mosquitoes drink plant fluids and not blood, so cannot spread the disease), no effective vaccine has yet been developed - the best we have at the moment is drugs that can prevent malarial infection in the short term by regularly taking a drug. Chloroquine is probably the most well known example of an anti-malaria drug. However, whereas this method of prevention is useful to those living in rich, developed countries as they can afford to buy the often expensive drugs, it is not much use in the poorer countries where malaria is actually endemic. This is mainly because the people there can't afford the drugs in the first place and there is often no way of getting drugs to people in isolated villages, as many of the countries lack a proper road network. This however, may be about to change.

New research by Sanaria, supported by the Bill & Melinda Gates Foundation, has identified a possible and highly promising vaccine for malaria called PfSPZ that protected 6 out of 7 participants in a clinical trial, providing them with lasting protection for about two months. The vaccine is made by irradiating mosquitoes that have been infected with malaria and then by harvesting sporozoites (the infectious form of its life cycle) from their salivary glands. These weakened, or attenuated, parasites are then used as the basis of the vaccine. When a weakened parasite such as this, is injected into an individual it is unable to make them as sick as it could have normally, meaning that the individual's body 'learns' how to kill malaria without the usual dangers from the disease. Once their body has 'learnt' how to kill malaria parasites, it remembers for a long period of time. This means that if the vaccinated person is bitten by an infected mosquito, their body will be able to mount a much more effective immune response in a shorter period of time and they will not become as ill as they otherwise would have, meaning that they are much more likely to survive the disease.

A researcher harvesting sporozoites from an irradiated mosquito's salivary glands.

Despite showing great promise at clinical trials, this vaccine has one major and unfortunate limitation. Sporozoites are tiny and an infected mosquito usually only carries around 1, 000 of them. Therefore, unless a more efficient method of producing irradiated sporozoites is developed, it is unlikely that the drug will ever become commercially viable as a vaccine for malaria, simply due to the sheer number of mosquitoes that would need to be harvested and the amount of time and effort that this would take. So, despite its potential, PfSPZ may never make it into mass production. Still, the vaccine holds great promise and in a number of years, it may potentially save millions of lives every year.