I am often asked what will be the next big pathogen of concern. And I respond that I have no idea, except that it is already here just waiting to be recognized. Indeed, it seems that some of our most noteworthy bugs appear abruptly out of nowhere. How is that possible? And if these bugs have been around for a long time, why hasn’t science recognized them?
Consider E. coli O157:H7 which was identified as a human pathogen in 1982, some 17 years after the serious complication it can cause, the hemolytic uremic syndrome (HUS) was first described by a Swiss physician. Does this mean that HUS causing E. coli had been around for a long time waiting to be recognized? Almost certainly. Remember, we are barely a century removed from the first direct lines drawn between various bacterial pathogens and the diseases they cause. We still have a lot to learn about the effect of bacterial and viral organisms on human health.
The entire E. coli O157:H7 genome has been sequenced and geneticists have identified numerous apparently intermediate forms that point to a common ancestor. It is now believed that E. coli O157:H7 evolved from enteropathogenic E. coli serotype O55:H7, a cause of nonbloody diarrhea, through the sequential acquisition of phage-encoded Stx2, a large virulence plasmid, Stx1, and additional chromosomal mutations. The phages that contribute to genetic change are viruses that can infect bacteria and plant their genetic material which is then incorporated into future generations of that bacterium.
So while bacteria are “descended” from common ancestors they are also changing constantly due to “horizontal transfer” of genetic material from other contemporaneous microbes. Geneticists can calculate the rate of change and thus the age of common ancestral forms by tracking genes that are basic to the function of the bacteria. The rate of genetic mutation of E. coli O157:H7 indicates that the common ancestor of current E. coli O157:H7 clades likely existed some 20,000 years ago. E. coli O157:H7 is a relentlessly evolving organism, constantly mutating and acquiring new characteristics, including virulence factors that make the emergence of more dangerous variants a constant threat.
And while we refer to E. coli O157:H7 and its brethren as Shiga toxin-producing E. coli, there are numerous other virulence factors within these bacteria that allow them to inflict damage. These factors include the ability of the bacteria to attach to human cells, transmit toxin into the cells, and secrete powerful inflammatory factors that incite host response that is itself injurious. These virulence factors are acquired over time and are constantly shifting among bacteria as they adopt to their host organisms. In this way horizontal gene transfer and genome plasticity likely contribute to the evolution of pathogenic variants from non-pathogenic colonizers. E. coli O157:H7 is adopted to live in the gut of cattle and other ruminants. It may be that some of the virulence factors enhance the survival of these bacteria by providing protection against predation by bactivorous protozoa, nematodes or other predators in the soil, water, or the gastrointestinal tract of their bovine hosts.
Therefore, pathogenic Shiga toxin producing E. coli (STEC) may arise when a given set of virulence genes come together in an E. coli host. What drives the selection of particular genes to create a STEC pathogen is unknown. However, because the existence of a primarily bovine animal reservoir of infection is a major difference between STEC and other pathotypes of E. coli, some genes, such as ehxA and espP may be acquired by STEC to facilitate survival and persistence in the bovine gut.
But haven’t we already discovered all the bugs that make us sick? Consider the curious history of one of the more common human ailments: peptic ulcer disease. Ulcers of the stomach and the duodenum, the first part of the small intestine, are exceedingly common. For almost all of the last century, modern medicine recommended diet and lifestyle changes to treat peptic ulcer disease. Avoid spicy foods, reduce your stress, and your ulcer problem should get better, physicians counseled patients. Unfortunately, that advice was largely useless because the true cause of the problem was not identified until 1982, yes, the same year that E. coli O157:H7 was first identified.
Two Australian researchers, Barry Marshall and Robin Warren identified a bacteria, Helicobacter pylori, that was consistently present in cases of peptic ulcer disease. Their investigations, including self-infection with H. pylori, demonstrated that antibiotic treatment could rid the gut of the bacteria and cure ulcers. The medical establishment initially responded with skepticism, but over the next twenty years the role of H. pylori in peptic ulcer disease and the treatment of it with antibiotics became an accepted part of basic medicine. Marshall and Warren were awarded the Nobel Prize for their work in 2005.
Most humans carry H. pylori in their stomachs, though only a modest percentage of us develop peptic ulcer disease. While H. pylori is today one of the more heavily researched bacteria, it was completely off the radar until very recently. How does a common bacterium responsible for a significant disease burden escape notice and why are so many of us carrying around this pathogen in our stomachs?
It is accepted that this organism has colonized humans for many thousands of years, and the successful persistence of H. pylori in human stomachs for such a long period suggests that this bacteria may be advantageous to its host. There is evidence that H. pylori provide protection against gastroesophageal disease (GERD) and some esophageal cancers. However, since H. pylori is also implicated in serious human disease, including carcinoma of the stomach, it is hard to consider this bacteria as co-evolving with its human hosts in a mutually beneficial relationship. Here again the geneticists offer insights. Research suggests that H. pylori’s acquisition of certain virulence factors is quite recent, perhaps as a result of human interaction with various animal populations. One of the many lessons about pathogenic bacteria is that what is tolerated or welcomed by one animal host made be disastrous to another. And today’s benign bacteria may become a serious pathogen in the hugely mutable world of microbes.
When the CDC talks about the risks of “emerging pathogens” it is fair to think of those pathogens as finally coming into our view rather than into existence. What we don’t know in a microbiological sense, can and will hurt us. It is fair to assume that the years ahead will lead to the “discovery” of new pathogens implicated in human disease that have been doing their damage for centuries just waiting for us to notice.
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 A group of biological taxa (as species) that includes all descendants of one common ancestor.
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 Encoding for hemolysin, an exotoxin which can lyse–cut apart–red blood cells and extracellular serine protease which can cleave coagulation factors.
Shiga Toxin-producing Escherichia coli Strains Negative for Locus of Enterocyte Effacement
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