The more we know, the more complex the web

In light of our recent post on helminth infection and its possible protective effects, Dan Parker, our resident infectious disease expert, alerted us to a new paper (Nov 15, open access) in Malaria Journal from a group in French Guyana about the effects of helminth infection on malaria infection and transmission. Titled "Helminth-infected patients with malaria: a low profile transmission hub?," the authors propose that concomitant malaria and helminth infection are a special problem.

Studies in humans have shown increased malaria incidence and prevalence, and a trend for a reduction of symptoms in patients with malaria. This suggests that such patients could possibly be less likely to seek treatment thus carrying malaria parasites and their gametocytes for longer durations, therefore, being a greater potential source of transmission. In addition, in humans, a study showed increased gametocyte carriage, and in an animal model of helminth-malaria co-infection, there was increased malaria transmission. These elements converge towards the hypothesis that patients co-infected with worms and malaria may represent a hub of malaria transmission.  

If this is true, because helminth infection and malaria overlap in much of the world, helminth control could be an important aspect of malarial control (though, does that then set people up for the chronic autoimmune diseases that seem to be associated with helminth control in the industrialized world?). The question of co-infection has not been ignored in the last decade or so, the authors write, but the results have been somewhat confusing. Infection with hookworm, for example, has been associated with increased malarial infection while infection with Ascaris is associated with lower incidence of malaria and decreased severity. Mechanisms have been proposed, such as that anemia increases susceptibility, or that helminth infection modulates immune responses, and differing study designs may account for some of the discrepancy.

But, if co-infection really is a factor in increased transmission and higher prevalence of malaria, this shows yet again the insidious complexity of malarial control. The new 'longform' digital magazine, Aeon, recently posted an essay by David Barash, evolutionary biologist "and aspiring Buddhist" that, among other things, described a project to understand why some years trees were more infested with gypsy moths than others. Gypsy moths cause great damage to North Eastern forests of the US, but only periodically.

 The suspicion was that gypsy moth periodicity was somehow connected with acorn crops, which vary greatly from year to year. High crop years were associated with low gypsy moth infestations, and vice versa. High crop years, as it turns out, are also associated with high white-footed deer mouse populations, too, as they love acorns. And they also love gypsy moth larvae, and feast on both.

But, white-tailed deer also love acorns, and they carry deer ticks, often infested with Lyme disease.

What are the practical implications? Foresters might be tempted to try to distribute additional acorns, inhibiting gypsy moth outbreaks in order to improve lumber yields. But this might bring about Lyme disease epidemics: more mice mean fewer gypsy moths, but also more ticks. Alternatively, public health officials who want to reduce Lyme disease might look into various ways of chemically suppressing mast production, which might in turn bring about gypsy moth infestations. Finally, it’s possible that Lyme disease outbreaks might be correlated, oddly enough, with how many acorns are produced that year by the forest.

The interconnected, ecological nature of life is, in part, what makes controlling deadly diseases like malaria, or debilitating helminth infections, so difficult. Each tweak has potential unintended consequences, to some degree because we don't really understand the whole web in the first place. Which only means we need to get better at seeing the whole.

Treating autoimmune disease the low-tech way?

Helminths and asthma
A map of asthma prevalence around the world shows that it is higher in industrialized parts of the world; higher in urban than rural areas, including urban Africa and South America, higher in what was West Germany after the wall came down than what was East Germany, higher in temperate zones than the tropics, and so on.  The question of why has been the subject of much research, much of that focusing on the lowly helminth, at least in tropical regions, parasitic worms that infect the gut of a high fraction of rural children in poverty.  The generic explanation for this has been the 'hygiene hypothesis,' which we wrote about here; basically, too much cleanliness can be a very bad thing.

Worldwide prevalence of asthma; from 'Global Burden of Asthma,' 2004

So, what's the mechanism that could explain the benefit of chronic helminthic infection?  The idea is that the parasites may suppress allergic inflammation, thus protecting against asthma, and indeed the allergy often associated with asthma.

A 2002 paper, e.g., in The Journal of Translational Immunology suggests:

There is good evidence that the expression of inflammation caused by helminth infections can be modulated by the host immune response, and that the failure of the expression of similar mechanisms among individuals predisposed to allergy may be responsible for the clinical expression of allergic disease. Further, there is accumulating evidence that helminth infections, particularly those caused by intestinal helminth parasites (or geohelminths) may be capable of modulating the expression of allergic disease.

Helminths and autoimmune disease in general
It turns out that a map of prevalence of any autoimmune disease around the world would show much the same trend as that of asthma -- higher prevalence in richer countries than lower, and presumably this is a true effect, not simply due to ascertainment bias based on poor access to health care in poorer parts of the world. Thus, the same question has been asked of other autoimmune 'diseases of westernization,' -- inflammatory bowel disease of Crohn's, rheumatoid arthritis, type 1 diabetes and multiple sclerosis. There are even suggestions that perhaps a third of the cases of autism could be due to autoimmune disease, as described in this piece in The New York Times in August. Could helminth infection be protective?  Many studies looking at preventing or treating these diseases with infection in mouse models have been reported, a few done in humans, including some self-experimentation, and many have been found to prevent disease entirely, or to alleviate symptoms (here's a pretty extensive table of the studies that have been done, in Parasitology Research Monographs). 

Now a piece in Nature ("Autoimmunity: the worm returns") reports the work of a gastroenterologist as he endeavors to determine the effects of helminth infection specifically on people with inflammatory bowel disease and multiple sclerosis. The author, Joel Weinstock, has worked for decades on inflammatory bowel disease, long wondering why it has become so prevalent in the last century.  He also knows his parasites, so that thinking about the possible connection between eliminating parasite infections and disease was not at all far-fetched.

Of course, as Weinstock also points out, parasite infections can have disastrous consequences, damaging the liver, bladder, or eyesight, e.g., so he had to proceed with caution.  But, as he describes, history and the map of the US seem to lend support to the idea of too much hygiene being a dangerous thing, so this was an insight he couldn't not pursue. 

In the United States and Europe, Crohn's disease first emerged in affluent populations living in hygienic conditions in the more northerly latitudes, where colder temperatures are less hospitable to soil-borne helminths. One of the last US groups to present with Crohn's disease was African Americans, who are, on average, poorer than their white counterparts. Similarly, in Europe, autoimmune diseases are more common in the richer Western Europe than in Eastern Europe.

Today, Native American reservations, which have relatively high rates of infection with parasitic worms, also have lower rates of inflammatory bowel disease. Latinos born and raised in South America rarely develop this gut disorder. If their children are born in the United States, where conditions are often more sanitary, they have a much higher risk of the disease.

Correlation does not equal causation, however, and the link had to be demonstrated. So, he began giving helminths to the mice in his lab that were models for inflammatory bowel disease, and did in fact show that they were protected against disease. He then moved on to treating volunteers, in whom he saw no adverse effects, and usually actual attenuation of disease, both bowel disease and MS. Pharmaceutical companies are now becoming interested, and double-blind studies of the effect of helminth infection on autoimmune disease are now being done.

How might parasites be protective?
Weinstock suggests that worms 'seem to have three major effects on the immune system.'  First, they cause changes in regulatory T cells so that they tone down the immune response, including autoimmune responses.  Second, they 'seem to act on other cells -- dendritic cells and macrophages,' which prevents the ramping up of the inflammatory response.  Yes, this is redundant, as Weinstock has shown in experimental studies.  And, third, they 'seem to alter the bacterial composition of intestinal flora,' in a way similar to ingesting 'probiotics,' helping to maintain intestinal health.

So if this work is right, and if cleanliness is next to godliness, it's starting to look as though the gods don't mind having a whole lot of sick people at their sides.  Weinstock is not suggesting that the industrialized world return to the heavy parasite loads of the recent past, rather that controlled infection might be a good thing.

So low-tech, and yet with the potential to eliminate a huge disease burden.  And not a word about genes!  Of course, one can expect the massive, heavy-handed vested gene industry to start to argue about genetic variation in susceptibility to the parasites.  Of course there will be some of that, but it is likely to be more GWAS minutiae rather than major causal factors.

BUT!
Herein we must add a caution, however.  One-size-fits-all explanations are rife these days, and it seems unlikely that intestinal worms could explain so many increasing disorders of different types. Usually, the miracle discovery turns out to be a mirage, relevant in some particulars but usually minor ones.  In this case, neither the immune system nor autoimmune diseases nor how the immune system responds to infection with helminths is well-enough understood for the cause and effect here to be convincing.

Empirical data seem suggestive, but the tropics/temperate zone gradient is also associated with numerous other factors, which has lead, e.g., to the sun/vitamin D exposure hypothesis with respect to multiple sclerosis, and clustering of cases has been suggestive of infectious causation.  The hygiene hypothesis is not confirmed in all studies, and data quality is surely not comparable across regions of the world, and so on.  A lot of caveats.  We'll just have to see how this one turns out.