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 Electron photomicrograph of Salmonella enterica serotype Typhimurium, a
bacterium that infects a wide range of hosts. Usually spreading via
fecal-oral transmission, Salmonella has been found on dust particles
and can survive for years on dried cow pats or pelleted feeds. Courtesy
David Goulding, Wellcome Trust Sanger Institute.
Until the 1980s, the numbers of Salmonella Typhimurium
cases identified in animals in the Pacific Northwest rose and fell
slightly from year to year, but on average stayed pretty much the
same. WSU researchers saw about 50 cases a year in cattle in the
state. Then came DNA fingerprinting and other strain-typing
techniques, and the discovery that not all Typhimurium are the
same.
“Instead of being a steady state, we learned that we were having
waves of infection due to different strains that are coming and
going,” says Besser. He and the WSU zoonotics group track outbreaks
of Salmonella and Escherichia coli in the Pacific
Northwest by analyzing the DNA fingerprint pattern of each sample
they’re sent from doctors, veterinarians, and public health
officials. They and their counterparts around the world have found
that an individual strain of Typhimurium will become dominant for a
few years and then decline, as a different strain becomes more
abundant.
The strain called Typhimurium DT104, for instance, was first
detected in wild birds in England in the early 1980s. It stayed
mostly confined to birds until 1989-90, when many cases appeared in
British cattle—and people. Within a few years it was found in
cattle and humans worldwide; by 1994 every case of
Salmonella Typhimurium tested by the WSU lab was DT104.
“It made the cover of U.S. News & World Report,” says
Besser. “That strain got attention because it was the first
widespread Typhimurium strain that was resistant to the antibiotic
chloramphenicol.” That was frightening, because at the time,
chloramphenicol was needed for treating severe cases of
Salmonella infection in humans. We appeared to be facing a
worldwide epidemic of untreatable Salmonella.
And then, DT104 went away. In Washington, within a few years it
dropped to about 10 percent of all Typhimurium cases. Subsequent
waves of other strains have come and gone since then—and nobody
knows why.
According to conventional wisdom, our over-use of antibiotics
could drive the process by selecting for antibiotic-resistant
pathogens. Sounds reasonable; decades of records show that within a
few years of introducing a new antibiotic, strains of bacteria
arise that are resistant to it. However, the role of antibiotic
resistance in emergence of new Salmonella strains isn’t
clear-cut. It certainly is very bad news to come down with an
infection that resists all the drugs available to fight it; but
whether the bug’s resistance has anything to do with your catching
it in the first place isn’t known. Emerging strains of
Salmonella don’t always have more antibiotic resistance than
the strains they’re replacing. Often they have less. In Belgium,
for instance, DT104 had less antibiotic resistance than the strain
it replaced. When another strain of Salmonella called DT10
swept across Canada and the U.S. in the 1970s, it was
pan-susceptible: all of our standard antibiotics killed it.
“There were actually papers written showing decreased ampicillin
resistance in Salmonella,” recalls Besser. “Some attributed
it to improved drug-use policies in hospitals, but really it was
the displacement of the ampicillin-resistant strains by DT10.” In
all likelihood, he says, the rise of DT10 was due to whatever
causes the normal cycling of different strains of
Salmonella.
“Antibiotic resistance undoubtedly can play a role in the
success of a strain,” he concludes. “It’s just that there’s enough
examples to the contrary to show that that’s not always the driving
force. It may only occasionally be the driving force.”
So what causes the cycling? Evolutionary ecologist Mark Dybdahl
has found a similar pattern in a very different system. He studies
the ongoing “arms race” between a species of snail and the
trematode worms that infect it. Native to New Zealand, the tiny
snails—each about the size of a grain of rice—and parasitic worms
engage in a seesaw relationship that looks a lot like the
predator-prey cycles between lynx and snowshoe hares we learned
about in high-school biology class. (See "New Zealand Mud
Snails," WSMO, February 2005.)
The snails come in two reproductive varieties, sexual and
clonal. Every now and then, for reasons we don’t yet understand,
sexually reproducing snails spawn female offspring that will
reproduce on their own, with no input from a male. Each of these
females becomes the founder of a new strain of snails that are
genetically identical to each other—they are clones. A single lake
may be home to a few, or many, different clones of snails. The neat
thing Dybdahl has found is that each clone of snails is preferred
by a different strain of the parasite.
Dybdahl uses genetic fingerprints to pinpoint which clone a
given snail belongs to and how often the worms infect each strain
of snail. He’s found a cyclical pattern: as one clone of snail
becomes abundant, parasites that are able to infect that strain
thrive. They produce more young, which hit that clone of snails
even harder. After a year or two of heavy infestation, that snail
population crashes. With fewer target hosts around, the parasite
able to infect that clone crashes too. As one snail clone crashes,
another snail clone becomes common, prompting a burst in the
population of parasites that are genetically adapted to infect
it.
“Whenever a genotype becomes common, there’s going to be a much
stronger advantage to the parasite that can infect that clone,”
says Dybdahl. “We expect the parasites to evolve to infect the most
common host genotype. The parasite evolves to the host, and the
host evolves in response to the parasite. And it keeps going.”
Molecular epidemiologist Doug Call says that kind of population
control could be at work with Salmonella. If microbes in our
digestive tracts target specific strains of the bacteria, then as a
strain of Salmonella becomes superabundant, the microscopic
predators that target it will thrive. Eventually they’ll hammer
that strain so hard it nearly disappears, to be replaced by another
strain whose own enemies aren’t so numerous yet.
In lab experiments, different gut protozoans do attack different
strains of Salmonella, says Call. Proving it happens inside
a living animal is not yet within our reach. Most gut microbes
can’t be grown in a lab; few have even been identified and
named.
“We don’t like to think of bacteria as being part of our
systems, but they’re there,” says Besser. “It’s a very complex
ecosystem.”
Although we don’t know whether our natural microbial flora are
responsible for Salmonella cycling, we have good evidence
that they do protect us from infection—if we haven’t decimated them
by long-term or frequent personal use of antibiotics. Helpful
bacteria are just as vulnerable to antibiotics as nasty ones, and
with the good guys gone, the way is clear for bad guys to move in.
Besser says the dose of Salmonella it takes to make a
healthy adult human sick “is in the Carl Sagan range. You know,
billions and billions. By taking an antibiotic, an oral pill
especially, that you would absorb [through the gut], you can get
down as low as 10 cells that could make you sick. So it’s a huge
factor.”
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