The Hygiene Hypothesis, Part 3. Are Parasitic Worms Friend or Foe?
Previously we saw that the
hygiene hypothesis suggests that a lack of exposure to certain infectious organisms, notably parasitic worms or 'helminths', is causing a rise in immunological diseases in the developed world. These include allergy and autoimmunity, where the immune system initiates excessively aggressive or inappropriate responses and damages our own tissues in the process. We also learned how helminths like pig whipworm might constitute
an exciting new treatment for certain autoimmune diseases. The question we're now looking at is: why?
'Why' questions in biology require evolutionary explanations; it is a matter of understanding the history of how species' evolved through time, and what mechanisms drove their evolutionary change.
The co-evolution of humans and our parasites goes back a very, very long way. In fact, it pre-dates our species.
Eggs belonging to helminths such as Trichuris trichiura (whipworm) and hookworms in the Ancylostoma group have been found in a Brazilian mummy dating back over 3.4 thousand years. The superbly well-preserved body of a 5,300 year-old human, nick-named 'Ötzi the Iceman' (Figure 1), has been confirmed as also being infected with Trichuris trichiura.
Fossilized dinosaur faeces, known as coprolites, dating to over 100 million years ago have been found in Belgium that contain recognizable parasite eggs. These included eggs from a single-celled parasite, probably in the Entamoeba group (which causes amoebiasis in humans today), and at least three types of intestinal helminth, including both tapeworms and nematodes. And a study published in 2009 concluded that the iconic dinosaur Tyrannosaurus rex probably suffered from a relative of Trichomonas gallinae, a single-celled parasite that causes avian trichomoniasis in modern birds (Figure 2).
So there is every reason to believe that humans and our evolutionary ancestors going back hundreds of millions of years have suffered from a veritable smorgasbord of infectious organisms such as helminths. What effect could this have had on ours and the parasite's evolution?
An arms race in deep time
An 'evolutionary arms race' occurs when two lineages enter a struggle of adaptation and counter-adaptation to try and surpass one-another. For example, cheetahs impose a selective pressure on gazelles for faster running; slower gazelles tend to get eaten more so the faster runners enjoy relative reproductive success and pass those fast-running genes on to the next generation. But gazelles in turn impart a selective pressure on cheetahs for them to run faster, because a slow cheetah is a hungry cheetah that can't parent as many offspring. Thus, the two species propel each-other to ever greater sprinting speeds (Figure 3).
Parasites and their hosts are also locked in an evolutionary arms race, whereby any adaptation from the host to reduce its parasite burden drives the evolution of a counter-adaptation in the parasite to evade this new mechanism.
A parasite is an organism that lives in or on its host and derives benefit from the arrangement at the host's expense. More specifically, parasites reduce the Darwinian fitness of the host, which basically means that infected hosts produce fewer offspring than their uninfected rivals.
The host is therefore under a selective pressure to reduce its parasite burden (because hosts with fewer parasites produce more offspring). This could be achieved by limiting parasite exposure, for example with barriers like skin and mucus-lined airway passages, or by actively expelling parasites from the body, for example by shedding the outer layers of the gut lining when infected with intestinal worms. Another strategy is to employ a 'seek and destroy' service to target parasites and eliminate them. We call this our immune system.
As we saw in the first article, our immune system targets parasites via a special system called TH2 immunity. This is based mainly on the production of a type of antibody called IgE, various parasite-killing cells including 'eosinophils', and a variety of immune signaling molecules called cytokines.
The immune system has also evolved an elaborate control system to stop it from getting out of hand and causing excessive damage to our own tissues. Mechanisms for this 'immune regulation' include the production of certain cytokines that dampen down the immune response, such as IL-10 and Transforming Growth Factor beta (TGF-β), and a special band of cells that suppress the activity of other immunological cells, called regulatory T cells, or Tregs.
Ideally, the immune system should first detect invading parasites, then develop a predominantly aggressive attack strategy to eliminate them, with toxic cells and other damaging processes. Finally, the prevailing atmosphere should switch to a regulatory one, so that once the parasite is cleared the immune response is shut down and any collateral damage minimized.
But these various host mechanisms in turn impose a selection pressure on parasites to circumnavigate the barriers to infection and evade our immune system for long-term colonization. It's part of the ongoing evolutionary tug-of-war between parasites and their hosts.
Various helminths like Schistosoma mansoni and hookworm bias the immune system to favour regulation, activating populations of regulatory immune cells such as Tregs and promoting the production of anti-inflammatory cytokines, which act to dampen down the immune response, such as IL-10 and TGF-β. In so doing, the parasites partially protect themselves from the 'attack' side of our immune system, tipping the balance towards regulation and suppression. This is called the 'modified TH2 response', and is an excellent parasite strategy to evade destruction by our immune system.
And helminths are not the only organism to have this effect. Many other pathogens also establish long-term infections in humans and do so via 'artificially' promoting a dominant anti-inflammatory and immune-regulatory environment, so as to avoid immune-mediated oblivion.
Mycobacterium, the group of bacteria that includes the causes of leprosy and tuberculosis, induces the production of IL-10, an immune-dampening molecule. And a single-celled parasite called Giardia, which is a frequent cause of 'traveler's diarrhea', has been shown to adopt a similar strategy. It promotes a particular subset of cells called 'dendritic cells', which are known to normally help activate the immune response, to produce IL-10 and so suppress the immune system instead. Indeed, even abhorrent cells in cancers often promote Treg activity to suppress immune cells that would otherwise destroy them.
And, as with helminths, many of these organisms have been infecting and co-evolving with humans since before we were even recognizable as a modern species. For example, the body of a hominid ancestor in the Homo erectus group, which died around half a million years ago, had lesions on its spine consistent with late-stage tuberculosis.
Letting go in a tug of war
So, the immune system has evolved for millions of years to operate in the context of pathogens and parasites that actively attempt to suppress it, purely to aid their own survival.
Now, what happens when many of these infectious organisms are suddenly taken away, as has occurred in the developed world through the advent of greatly improved public hygiene, sterilizing food preparation techniques, antibiotic drugs and so on? It would be like if one side in a tug-of-war suddenly let go (Figure 4).
Without infectious agents that promote immune suppression and regulation present, the immunological scales swing back in the other direction, and our immune system is left excessively aggressive, attacking far too broad a range of targets and with too much zeal, causing diseases like autoimmunity and allergy.
We know that many of the immune-regulatory processes activated by parasites cause autoimmunity and allergic conditions when they go wrong. For example, one molecule that is a defining characteristic of Tregs and known to initiate their development into immune-suppressing cells is called 'Foxp3'. That's why Tregs are sometimes called 'Foxp3+ T-cells'. When the gene that encodes Foxp3 is faulty in humans, it causes a variety of autoimmune conditions such as psoriasis (Figure 5), which form part of the 'IPEX syndrome'. Dysfunction of Foxp3+ cells is associated with a whole range of immune-mediated diseases, including type 1 diabetes, multiple sclerosis and inflammatory bowel diseases. And Foxp3+ T-cells are precisely the type of cell that we see activated by the presence of parasites like Schistosoma mansoni. The effect of removing these parasites is therefore somewhat similar to the effect of having a faulty Foxp3 gene - a lack of immune regulation causing the immune system to go haywire and attack things it shouldn't do.
Another neat fit is the fact that certain genes involved in allergy and autoimmunity are also involved in anti-parasite immunity. There is a strong heritable component to many immunological diseases, implying a genetic component. Some of these genes have been identified as playing a direct causal role in the disease process. But why would disease-causing gene variants have been preserved in the population by natural selection? At least one answer is that they actually evolved to help fight off parasitic worms, but in the absence of these organisms the genes now cause autoimmune disease and allergy.
For example, a study in 2004 found that a particular variant of the gene coding for a protein called STAT6, was associated both with an increased risk of developing asthma and with resistance to a common parasitic worm, Ascaris lumbricoides (Figure 6). Asthma is an allergic condition in which immune cells become hyper-sensitive to certain particles in the air we breathe, causing the airways to constrict making breathing difficult. Many of the components of the TH2 response that would normally be used to fight off parasites are responsible for causing hypersensitivity in asthma, including IgE, eosinophils and certain cytokines. These same TH2 systems are also responsible for other allergies, such as hayfever and eczema.
STAT6 is a protein that turns other genes in the cell on, and drives the development of the TH2 response. It seems that a variant of STAT6 was useful to our ancestors in combating Ascaris lumbricoides, and so spread by natural selection. Indeed, in some parts of the world it probably still is useful for this reason. But in the developed world, where we no longer encounter Ascaris lumbricoides, the gene variant is a driving force for developing asthma. It's as if this branch of our immune system is no longer being 'kept busy' fighting off parasitic worms, and so misfires and targets innocuous particles like grass pollen and house dust mites instead.
And the effect of parasitic worm infection goes way beyond direct involvement with the immune system, too.
In the second article, we discussed the case of a man who infected himself with whipworm, Trichura trichiura, to treat his inflammatory bowel disease - an autoimmune condition affecting the intestine. A video camera led up inside the man's colon showed that patches of bowel colonized with worms tended to have the least inflammation, while sparsely colonized regions had the worst flare-ups. But interestingly, there were more Foxp3+ Tregs in the inflamed regions than there were in the worm-infested locations. So how were the worms helping?
The authors suggest that the body has evolved to expel intestinal worms, like Trichura trichiura, via the production of an immune signaling chemical called IL-22. IL-22 causes the gut lining to produce more mucus, and also to shed its top layer of cells at a faster rate than normal, sort of like exfoliation for the intestine. The combined effect destabilizes the worm's foothold and causes it to get washed away through the gut and out of the body.
A byproduct of increased mucus production and more rapid cell turnover in the gut lining is that it improves the symptoms of inflammatory bowel disease. This is a case where an anti-parasite immune attack mechanism - expelling intestinal worms by altering the gut lining - improves symptoms in an autoimmune disease purely as a happy coincidence.
Indeed, infectious organisms have been co-evolving with humans in an evolutionary tug-of-war for so long that there are probably a huge number of ways in which these creatures influence our physiology. It is hardly surprising that suddenly removing them can make the body's systems behave non-optimally, as we are no longer operating in the wormy world in which we evolved.
So it's not that parasitic worms have evolved to 'help' us - they are not our evolutionary allies in the same sense as mitochondria are, which are the descendants of free-living bacteria that became incorporated into our cells and without which we can no longer survive. After all, by definition, parasites are ultimately out to exploit their host and promote their own reproduction. They're not sentimental creatures! Instead, it is simply that our body has gotten used to functioning relatively well in the context of their presence. Autoimmunity and allergy may well be the price we pay for removing our parasites and pathogens in the developed world.
However, in my view, we are undoubtedly better off without suffering anaemia due to blood-sucking hookworms; gut pain, malabsorption of food and diarrhea from Trichura trichiura and Ascaris lumbricoides; brain lesions caused by tapeworms like Taenia solium; blindness and massive swelling from filarial nematodes; and chronic liver damage from flukes like Schistosoma mansoni and Fasciola hepatica, and we should not for a moment think that the hygiene hypothesis suggests we should return to a parasite-filled 'golden age'. The rise of immunological diseases is a short-term problem for what will be, in the long run, the far better option.
In order to overcome the problem of autoimmunity and allergy, we will need to further our understanding of how worms and other infectious agents interact with our bodies', and use these organisms to generate synthetic products that can prevent us from developing immunological diseases in the first place. That is the ultimate implication of the hygiene hypothesis, and the challenge to which we must rise.
Glossary of terms:
Allergy - Diseases caused by an excessive and unnecessary immune reaction to harmless particles in our environment, like grass pollen, which causes hayfever.
Autoimmunity - Diseases caused by the body's immune system targeting its own tissues 'by mistake', resulting in tissue damage.
Helminth - A multi-cellular animal that lives in or on humans and which has an 'earthworm-like' shape. These include nematodes, like hookworm and whipworm, flukes, like Schistosoma mansoni, and tapeworms, which can grow to meters in size. These creatures are not actually very closely related to each-other.
Immune system - A complex network of molecules, cells and organs which have evolved to seek out potentially damaging threats, like infectious bacteria and viruses, and destroy them.
Immunological disease - Diseases characterized by a dysfunction of the immune system. See 'Allergy' and 'Autoimmunity'.
Inflammation - This is a strong response mounted by the immune system against potential threats. Causes the inflamed area to become hot, swollen and painful.
Inflammatory bowel disease - Autoimmune disease, where the immune system damages regions of the gut causing pain, diarrhea and blood in the stools. The immune system may be reacting to harmless bacteria that live in our gut. Includes Crohn's and Ulceratice Colitis (UC).
Parasite - An organism that lives in or on another creature, the 'host', from which it derives benefits at the host's expense. Most medical doctors think of parasites as separate from bacteria and viruses, covering 'all the rest'- from single-celled organisms like amoeba to helminths, like tapeworms.
References and further reading:
* For a thorough general overview of the hygiene hypothesis, see the 'Review series on helminths, immune modulation and the hygiene hypothesis', in Immunology, January 2009, Volume 126, Issue 1.
* Parasites are very ancient:
Ferreira, L.F., et al. 1983. The finding of helminth eggs in a Brazilian mummy. Transactions of the Royal Society of Tropical Medicine and Hygiene 77: 65-67
Aspöck, H., et al. 1996. Trichuris trichiura eggs in the Neolithic glacier mummy from the Alps. Parasitol Today 12:255-56 .
Poinar, G., Boucot, A.J. 2006. Evidence of intestinal parasites of dinosaurs. Parasitology 133(Pt 2):245-9.
Wolff, E.D., et al. 2009. Common avian infection plagued the tyrant dinosaurs. PLoS One 4(9):e7288.
Kappelman, J., et al. 2008. First Homo erectus from Turkey and implications for migrations into temperate Eurasia. Am J Phys Anthropol 135(1):110-6.
* Genes responsible for autoimmunity and allergy help protect against parasitic worms:
Peisong, G., et al. 2004. An asthma-associated genetic variant of STAT6 predicts low burden of ascaris worm infestation. Genes and Immunity 5:58-62.