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Where Do These Bugs Come From?

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.[1] 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[2] likely existed some 20,000 years ago.[3] E. coli O157:H7 is a relentlessly evolving organism[4], constantly mutating and acquiring new characteristics, including virulence factors that make the emergence of more dangerous variants a constant threat.[5]

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.[6]

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[7] may be acquired by STEC to facilitate survival and persistence in the bovine gut.[8]

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.[9] There is evidence that H. pylori provide protection against gastroesophageal disease (GERD) and some esophageal cancers.[10] 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.[11] 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.

[1] Kaper JB and Karmali MA.  The Continuing Evolution of a Bacterial Pathogen.  PNAS vol. 105 no. 12 4535-4536 (March 2008); Wick LM, et al.  Evolution of genomic content in the stepwise emergence of Escherichia coli O157:H7.  J Bacteriol 187:1783-1791(2005).

[2] A group of biological taxa (as species) that includes all descendants of one common ancestor.

[3] Zhang W, et al.  Probing genomic diversity and evolution of Escherichia coli O157 by single nucleotide polymorphisms.  Genome Res 16:757-767 (2006).

[4] Robins-Browne RM.  The relentless evolution of pathogenic Escherichia coli.  Clin Infec Dis. 41:793-794 (2005).

[5] Manning SD, et al.  Variation in virulence among clades of Escherichia coli O157:H7 associated with disease outbreaks.  PNAS vol. 105 no. 12 4868-4873 (2008).  (“These results support the hypothesis that the clade 8 lineage has recently acqui
red novel factors that contribute to enhanced virulence.  Evolutionary changes in the clade 8 subpopulation could explain its emergence in several recent foodborne outbreaks; however, it is not clear why this virulent subpopulation is increasing in prevalence.”)

[6] Steinberg KM and Levin BRGrazing protozoa and the evolution of the Escherichia coli O157:H7 Shiga toxin-encoding prophage Proc. R. Soc. B (2007) 274, 1921-1929

[7] Encoding for hemolysin, an exotoxin which can lyse–cut apart–red blood cells and  extracellular serine protease which can cleave coagulation factors.

[8]Shiga Toxin-producing Escherichia coli Strains Negative for Locus of Enterocyte Effacement
Hayley J. Newton,1 Joan SloanEmerging Infectious Diseases • www.cdc.gov/eid • Vol. 15, No. 3, March 2009

[9]Ahmed N, 23 years of the discovery of Helicobacter pylori: Is the debate over? Ann Clin Microbiol Antimicrob. 2005; 4: 17.

[10] Shahabi S, et al, Protective effects of Helicobacter pylori against gastroesophageal reflux disease may be due to a neuroimmunological anti-inflammatory mechanism.  Immunology and Cell Biology 86, 175-178 (February 2008).

[11]Ahmed N, et al, Helicobacter pylori – a seasoned pathogen by any other name.  Gut Pathogens 2009, 1:24.

© Food Safety News
  • hhamil

    Like you, Mr. Clark, I am not a microbiologist and I am quite interested in your query. Thanks very much for your article.
    I am concerned that modern industrial agriculture is creating conditions in which the ongoing evolution you describe will lead to dangerous pathogens that can establish themselves ubiquitously in nature. Were that to happen, the impact on the future safety of raw food from plants would be horrific.
    FYI, according to “Hemorrhagic colitis associated with a rare Escherichia coli serotype” by
    Riley LW, et al in the March 24, 1983 “New England Journal of Medicine”(see http://www.ncbi.nlm.nih.gov/pubmed/6338386?dopt=Abstract), there was a “previous isolation of this serotype [in] a sporadic case of hemorrhagic colitis in 1975.” All I have read is the abstract so I don’t know what else the article contains.

  • Harry Hamil

    Like you, Mr. Clark, I am not a microbiologist and I am quite interested in your query. Thanks very much for your article.
    I am concerned that modern industrial agriculture is creating conditions in which the ongoing evolution you describe will lead to dangerous pathogens that can establish themselves ubiquitously in nature. Were that to happen, the impact on the future safety of raw food from plants would be horrific.
    FYI, according to “Hemorrhagic colitis associated with a rare Escherichia coli serotype” by
    Riley LW, et al in the March 24, 1983 “New England Journal of Medicine”(see http://www.ncbi.nlm.nih.gov/pubmed/6338386?dopt=Abstract), there was a “previous isolation of this serotype [in] a sporadic case of hemorrhagic colitis in 1975.” All I have read is the abstract so I don’t know what else the article contains.

  • bruceclark

    I would add as a postscript that recent work by Zhou Z et al, (Derivation of Escherichia coli O157:H7 from its O55:H7 Precursor. PLoS ONE 5(1): e8700. doi:10.1371/journal.pone.0008700 (2010)), suggests that O157 may have emerged from its O55:H7 ancestor as recently as 400 years ago. While both strains continue to change, there have been more changes in the O157:H7 lineage reinforcing the high mutability of O157 clones and implying the potential for near term changes in virulence factors of EHEC.

  • In answer to your remark “I am often asked what will be the next big pathogen of concern.”
    Circovirus in its many manifestations and forms must be a prime contender. It gave rise to the excessive use of antibiotics in pigs and thereby MRSA st398.
    A deady new cattle disease called “Bleeding Calf Syndrome” is spreading and the Germans consider that circovirus is involved.
    Regards Pat Gardiner

  • Bruce Clark

    I would add as a postscript that recent work by Zhou Z et al, (Derivation of Escherichia coli O157:H7 from its O55:H7 Precursor. PLoS ONE 5(1): e8700. doi:10.1371/journal.pone.0008700 (2010)), suggests that O157 may have emerged from its O55:H7 ancestor as recently as 400 years ago. While both strains continue to change, there have been more changes in the O157:H7 lineage reinforcing the high mutability of O157 clones and implying the potential for near term changes in virulence factors of EHEC.