Hemolytic uremic syndrome (HUS) in history--part 4: the bigger picture

As I've laid out this week (part 1, part 2, part 3), the realization that a fairly simple, toxin-carrying bacterium could cause a "complex" and mysterious disease like hemolytic uremic syndrome came only with 30 years' of scientific investigation and many false starts and misleading results. Like many of these investigations, the true cause was found due to a combination of hard work, novel ways of thinking, and simple serendipity--being able to connect the dots in a framework where the dots didn't necessarily line up as expected, and removing extraneous dots as necessary. It's not an easy task, particularly when we've had mostly culture-based methods to rely on since the dawn of microbiology.

If you read start digging around in the evolutionary medicine literature, you'll see that one oft-repeated tenet is that many more "chronic" and "lifestyle" diseases are actually caused by microbes than we currently realize. (I'll note that there is active disagreement here in the field--one reason noted is that many of these diseases would decrease one's fitness and thus they are unlikely to be genetic, but many of them also have onset later in life than the prime reproductive years, so--still controversial). But whether you agree on the evolutionary reasoning or not, I think it's safe to say that those who make this claim (like the Neese & Williams book I linked) are probably right on the overall assertion that more and more of these "lifestyle/genetics" diseases are going to be actually microbial in cause than we currently realize.

Why do I agree with this claim? History is a great indicator. Many infectious diseases were thought to be due to complex interactions of genetics (or "breeding," "lineage," etc.) with "lifestyle." Think of syphilis and tuberculosis in the Victorian era. Syphilis (and many other diseases which we know now to be sexually-transmitted infections) was considered a disease which affected mainly the lower social classes ("bad breeding"), and was thought to be rooted in both family history as well as an over-indulgence in sex or masturbation. Tuberculosis, because it affected those throughout the income spectrum, was still blamed on "poor constitution" in the lower classes, but was a disease of the "sensitive" and "artistic" in the upper classes. It was also thought to be due to influences of climate in combination with genetics. Or, look to more recent examples of Helicobacter pylori and gastric ulcers, which were also ascribed to dietary habits and stress for a good 30 years before their infectious nature was eventually proven. And from that same era, HIV/AIDS--which even today, some are still all too ready to write off as merely a behavioral disease, rather than an infectious one.

So, we still view many of these diseases of unknown etiology as multi-factorial, "complex" diseases. And undoubtedly, genetic predisposition does play a role in almost every infectious disease, so I'm not writing off any kind of host/pathogen interplay in the development of some of these more rare sequelae, such as HUS as a consequence of a STEC infection. But looking back over history, it's amazing how many diseases which we view now as having a documented infectious cause were studied for years by researchers thinking that the disease was the result of exposure to a toxin, or diet, or behavior, or a combination of all three.

I've mentioned the example of multiple sclerosis in previous posts. Multiple sclerosis is an autoimmune disease; the body produces antibodies that attack and eventually destroy parts of the myelin sheath covering our nerves. The cause of MS, like HUS 40 years ago, is unknown, though it's thought to be a combination of genetics and environmental influences. Going through the literature, it seems like almost everything has been implicated as playing a causal role at one point or another: pesticides, environmental mercury, hormones, various other "toxins," and a whole host of microbes, including Chlamydia pneumoniae, measles, mumps, Epstein-Barr virus, varicella zoster (chickenpox), herpes simplex viruses, other herpes families viruses (HHV-6 and HHV-8), even canine distemper virus. They've done this looking at both microbe culture (from blood, brain tissue, CNS, etc.) as well as using serology and DNA/RNA amplification in various body sites. None have shown any strong, repeatable links to the development of MS--much like the spurious associations that were seen with adenovirus and HUS.

Although no microbial agent has been convincingly implicated to date, there are tantalizing hints that MS is caused by an infectious agent. There have been "outbreaks" of MS; the most famous occurred in the Faroe Islands in the 1940s. Studies of migrants show that the risks of developing MS seem to be tied to exposures in childhood, suggesting a possible exposure to an infectious agent as a kid. And one of the most common mouse models used to study MS has the disease induced by infection with a virus called Theiler's murine encephalitis virus (TMEV). If it can happen in mice, why not humans?

It might seem implausible that infection with some microbe could lead to the eventual neurological outcomes of MS, but again, examples abound of weird connections between microbes and health outcomes. For STEC, it might not be intuitively obvious at first glance how a fecal organism could be a cause of kidney failure. The respiratory bacterium Streptococcus pyogenes usually causes throat infections ("strep throat"), but if left untreated, it can also cause kidney damage (glomerulonephritis) or even heart failure due to rheumatic heart disease. A microbial cause of MS could lie in a virus, bacterium, parasite, or fungus--maybe one that we haven't even discovered yet, but that perhaps will pop up as we learn more and more about our metagenome. Perhaps 30 years down the road, the way we view many of these "complex" diseases will look as short-sighted as it does looking back at old HUS papers from today's vantage point.


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It's nice to see some in-depth and thoughtful commentary about HUS. Thank you.
The long-term consequence of HUS is of great importance in our work representing foodborne illness victims. William Clark's recent papers based on data from the Walkerton outbreak further demonstrates that long-term sequelae exist in patients who were originally thought to have made a full recovery. Whether or not such sequelae occur in a given case, the threat of it increases the emotional burden experienced by innocent victims of these outbreaks.

Thank you for this insightful articles about HUS;
And as a minor addition: Group A Streptococci (S. pyogenes) can cause neurological symptoms as well; Infektion with S. pyogenes can lead to a form of chorea; chorea minor or Sydenham's Chorea;

As a young adult I spent about twenty years believing that stomach ulcers were caused by executive stress. Indeed whole sections of american literature were at one time devoted to this meme. Then it turned out that most ulcers were caused by a mere bacteria.

By Gordon Walker (not verified) on 25 Jun 2011 #permalink

I'm not aware of HUS, but several months ago I read an article about this topic. The article claimed that both MS and schizophrenia may be caused by a virus trapped in our own DNA, and proposed that early childhood illness could "disable" the mechanisms that keep these viruses locked and harmless.

The article could be found at http://discovermagazine.com/2010/jun/03-the-insanity-virus

I found this article really intriguing; and since my sister is a diagnosed schizophrenic, the article even gave me a large degree of hope. It has also made me wonder just how many of our disorders are actually the results of diseases in one form or another.

(I also recall a couple of co-workers discussing the possibility that a cold virus can give someone a tendency to overeat, and this may explain the high obesity rates in the South.)

Thanks--hadn't seen that one yet. There's one I'm hoping to get to this coming week on the link between MS and shingles, though.

Re: cold--that research refers to adenovirus, a respiratory virus that can cause "colds."

All I am thinking of now is that human metabolic syndrome and also nonalcoholic fatty liver disease probably fit the bill.

By NAME REDACTED (not verified) on 25 Jun 2011 #permalink

People in the past were a much smarter lot than you give them credit for. The above is a generalization based on caricature. Soft. Very soft.

By teapartydoc (not verified) on 26 Jun 2011 #permalink

I'm not sure what you're critiquing--I'm certainly not accusing anyone of stupidity; just showing that many of these diseases are difficult to investigate and can generate misleading and contradictory results, until the right framework is found (eg, HUS and E. coli).

I find it completely plausible that infections can cause autoimmune diseases: If a pathogen produces an antigen that has some similarity to a chemical structure in body tissue, T cells that recognize this structure will proliferate and may react to both the pathogen and the body tissue. They're supposed to be weeded out in the thymus but this mechanism isn't 100% since nothing in biology ever is and mutations may make the thymus less effective at its filtering function, or environmental influences may reduce that function.