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Getting To Know Helicobacter
Not so long ago, Helicobacter pylori was not a household term. However, fueled by the discovery that H. pylori causes gastric ulcers and other serious disorders in the digestive tract, investigators are scrutinizing this microorganism and its close relatives with heightened curiosity--characterizing its habitats, associative habits, and its genomic potential, according to several researchers who spoke during various sessions at ICAAC, including two symposia, ``New and Emerging Pathogens I,'' and ``From Genes to Screens to Anti-Infectives.''
One of the mysteries surrounding H. pylori is where it comes from to infect humans and cause gastric disease. For example, some investigators reported earlier this year that the microorganism can contaminate well water, which may serve at least as a temporary reservoir for the pathogen (ASM News, October 1999, p. 668). Behind that finding lurk other questions, such as: Where else may this microorganism be found? And is it or closely related bacterial species associated with other mammalian species that serve as carriers?
The only proven animal reservoirs for H. pylori other than humans are ``macaques and one colony of cats,'' says James Fox of Massachusetts Institute of Technology in Cambridge, Mass. However, he says, several related Helicobacter species, particularly H. heilmanni, are commonly associated with cats and dogs, which typically do not develop symptoms of disease beyond inflammation localized to the stomach, and perhaps represent a zoonoses. Also, non-H. pylori gastric helicobacters are widely suspected of colonizing livestock en route to humans. So far, he adds, there are about 20 named Helicobacter species and more than 30 other unnamed species ``on the horizon.'' The ecological picture of Helicobacter spp. is further complicated when one searches for it along the lower reaches of the mammalian gastrointestinal tract, according to Fox. For instance, some Helicobacter species appear to give rise to inflammation of the lower intestine and liver disease in mice, including a progressive disease leading to liver cancer, he says. Investigating these microbe-mouse associations, particularly when they involve retrieving this microbial pathogen, requires diligence and fine-tuning of culture conditions, with a microaerobic, hydrogen-enriched atmosphere essential for enabling H. hepaticus to thrive in the laboratory.
Although H. hepaticus can infect the livers of mice, it persistently colonizes the crypts along the surface of the lower intestinal tract of such animals, according to Fox. Besides causing liver disease leading to the development of liver tumors, the microorganism also can cause, in certain strains of mice, a syndrome very much like inflammatory bowel disease in humans. He and his collaborators are following these observations with experiments to determine whether such infections cause a similar naturally occurring syndrome in nonhuman primates, a finding that could lead to development of a better animal model for colitis in humans.
Meanwhile, other researchers are studying the H. pylori genome, searching for important genetic clues about the pathogenic properties of this organism and where it may be vulnerable to medical counterattack. Recently, separate research groups determined the genomic sequences of two different isolates of this pathogen. During ICAAC, a representative from one of those groups at Genome Therapeutics in Waltham, Mass., reviewed several features that emerge from this comparison. For example, the H. pylori genome lacks a readily identifiable origin of replication, contains unlinked 16S and 23S ribosomal RNA encoding sites, and apparently allots considerable encoding space to outer membrane and DNA restriction proteins.
Several other features, perhaps pertinent to understanding different pathogenic patterns between strains, emerge from this analysis. For instance, even though the overall genomic organization is substantially the same between the two analyzed strains, there is substantial sequence diversity between them, about 5% (compared to about 3% found between strains of Escherichia coli). About half the strain-specific genes of each of those two H. pylori isolates are found in a hypervariable region, or ``plasticity zone,'' a portion of the genome that resembles several other ``pathogenicity islands,'' which are thought to encode specialized functions accounting for virulence and infectivity in other bacterial pathogens.
The extensive genetic diversity between isolates within a single H. pylori species, taken together with the substantial genetically determined differences being observed among separate Helicobacter species, suggests that many more insights will be needed before the current, medically inspired curiosity surrounding these organisms can be satisfied.
Jeffrey L. Fox
December 8, 1999
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