Professor Jerome Etienne ranks at #9 in our March
2008 Special Topic on MRSA research over the past
decade, with 40 original articles and review papers
cited a total of 1,369 times. In
Essential Science IndicatorsSM
Thomson Scientific, his record includes 202
papers cited a total of 4,759 times from January 1,
1997 to December 31, 2007. Of these papers, 114 with a
total of 3,213 cites are classified in the field of
Clinical Medicine, and 45 with a total of 825 cites are
classified in the field of Microbiology.
Professor Etienne is a professor at the University of Lyon as well as a
practitioner at the hospital and deputy director of the National Reference
Centre for Staphylococci.
In the interview below, he talks with
ScienceWatch.com correspondent Gary Taubes about
his highly cited MRSA research.
When did you begin research on
I am a clinical microbiologist. I began my research with Staphylococcus
aureus at a time in the early 1990s when most researchers were
particularly interested in antibiotic resistance. I was more interested in
virulence factors, and the first thing I wanted to do was see how the
virulence factors of S. aureus were distributed in the kinds of
diseases I was seeing in the patients.
What exactly are virulence factors?
Virulence factors are the weapons that the bacteria use to overcome the
host defenses and thrive. When I was a young medical student, at the very
beginning of genetics, we were unable to characterize the genes that coded
for these virulence factors. With the introduction of PCR we could easily
I’ve always been particularly interested in what’s called
Panton-Valentine leukocidin (PVL). This is a toxin that was described by
two researchers—Panton and Valentine—in 1935. They demonstrated
that a strain of S. aureus with this particular toxin was very
virulent. It would destroy leukocytes, which is where the term leukocidin
"We don’t understand why
these strains emerged in the community, particularly
because there were no specific antibiotic pressures,
which is what you would normally expect to explain the
emergence of resistance."
In 1999, we published a paper in Clinical Infectious Diseases
(Lina G, et al., "Involvement of Panton-Valentine
leukocidin-producing Staphylococcus aureus in primary skin
infections and pneumonia," 29: 1128-32, November 1999) just saying very
simply that the presence of PVL genes was correlated with skin and
soft-tissue infections in the community and with pneumonia. There was
nothing new about the PVL association with skin infections, but the fact
that PVL-positive strains of pneumonia were infecting children hadn’t
been reported before.
Where did you go with that finding?
We did a prospective study in France to collect all pneumonias associated
with S. aureus. This took us from 2000 to 2002. If my memory is
correct, we had 16 cases of PVL-positive strains, and we compared the
clinical characteristics of these cases with those from PVL-negative
strains. As we noted in a paper we published in the Lancet in 2002
(Gillet Y, et al., "Association between Staphylococcus
aureus strains carrying gene for Panton-Valentine leukocidin and
highly lethal necrotising pneumonia in young immunocompetent patients,"
359: 753-9, 2 March 2002), there is a clinical entity called
necrotizing pneumonia, which would occur after a viral infection such as
What we observed was that this was sometimes a secondary infection with
PVL-positive strains. It occurred mainly in children with a median age of
14 and it caused destruction of the lung. The mortality rate was absolutely
awful—75 percent. So what we were reporting was something very
dramatic: the description of a highly lethal clinical entity due to the
PVL-positive strains of S. aureus. And, in fact, the relationship
between PVL and S. aureus in this disease had not been previously
recognized because the children had been dying so rapidly. The median time
for death was 4 days after admittance to the hospital.
Did this bring you directly to what is your
most-cited original paper in our database—the 2003 Emerging
Infectious Diseases article, "Community-acquired
methicillin-resistant Staphylococcus aureus carrying
Panton-Valentine leukocidin genes: worldwide emergence," (Vandenesch
F, et al., 9: 978-84, August 2003)?
In part. After we reported on this necrotizing pneumonia, two things
happened. One is I read a paper in JAMA about the deaths of four
children in North Dakota and Minnesota due to MRSA. What I had reported in
the Lancet were strains of PVL-positive S. aureus, but
they had all been methicillin susceptible. When I read this 2001
JAMA paper, I thought to myself that these were PVL-positive
strains of MRSA.
So I contacted one of the authors of the paper, Tim Naimi, who works at the
CDC, and I introduced myself and asked him if we could test these MRSA
strains to see if they were PVL-positive. They sent something like 30
strains of S. aureus to France, and they mixed together
community-acquired and hospital-acquired strains and gave them to us
blinded, and we tested them for PVL. When I called Tim back to tell him our
results, which strains were PVL-positive, he said, "You’ve hit the
jackpot. We have an emergence of MRSA in the community, and you’re
telling me that they are all PVL-positive, and this is totally new for us."
At that point we started to collect strains of community-acquired MRSA from
around the world—from France, Australia, and New Zealand—and we
reported in this 2003 paper that this parallel emergence of
community-acquired MRSA all over the world was all in strains that are
PVL-positive. This was totally new for MRSA, because at the time hospital
strains of MRSA were all PVL-negative. Moreover, as we reported, the
diseases in the different continents had different genetic backgrounds, but
the common marker was the presence of the PVL genes.
So did you consider the PVL genes to be the likely
reason why these community-acquired infections became methicillin
That I don’t know. It would be pure speculation. We don’t
understand why these strains emerged in the community, particularly because
there were no specific antibiotic pressures, which is what you would
normally expect to explain the emergence of resistance.
Why do you think your 2003 paper has garnered quite
so many citations?
Well, since then MRSA continued to spread and spread, and people wanted to
test it for the presence of PVL genes, to characterize the community MRSA,
particularly in the US. Ours was the natural paper to cite. In a sense, we
were very lucky—okay, maybe it wasn’t luck. But we were working
on a particular virulence factor, PVL, and the world happened to be
infected with strains of MRSA characterized by this factor.
Are there also PVL-negative strains of
You can find PVL-negative MRSA in the community but mainly in patients who
have risk factors for hospital-acquired MRSA. Usually, for instance, in
elderly populations that have been admitted to the hospital for two months
or more, and then spent time in long-term care facilities—these cases
are called healthcare-associated MRSA.
What I didn’t say before, and what we published in a JAMA
paper with Tim Naimi as the first author (Naimi TS, et al.,
"Comparison of community- and health care-associated methicillin-resistant
Staphylococcus aureus infection," 290: 2976-84, 10 December
2003), is that when you look at the clinical characteristics of the
PVL-positive MRSA infections, and you compare these to the PVL-negative
infections, you see a huge difference in median age. The former will infect
young people—young adults, and children with no risk factors for
healthcare-associated MRSA. The latter will infect older patients with a
past history of having spent time in hospitals.
What direction is your research taking
That is a long, long story, because there is a significant controversy in
the literature about what we reported and we have to clear it up. You have
to remember I am a medical doctor. When I see the severity of infections
due to PVL-positive strains, I want to develop tools to treat those
infections and treat the patients. That’s my first job. As I saw it,
I had no proof that PVL was the factor that caused the virulence of those
infections, it could be just a marker, but I had to find out.
So we developed an experimental model and tried to establish whether PVL
was the key factor. We reported last year in Science, working with
a team in Houston from Texas A&M University (Labandeira-Rey M, et
al., "Staphylococcus aureus Panton-Valentine leukocidin
causes necrotizing pneumonia," 315: 1130-3, 23 February 2007), that
PVL was the virulence factor responsible for the necrosis we observe in
pneumonia. This prompted other groups to try to reproduce our observation,
and there has not been total agreement. So now there is a huge controversy
about the role of PVL in the pathogenesis of these diseases, and several
groups think we got it wrong.
We think the solution is that the PVL genes in the MRSA strains found in
the US are different in two or three positions from the genes of other
clones, and this could explain the difference in what we see. So what
we’re working on now is trying to establish whether or not PVL really
is the relevant virulence factors, and if it is, can we develop specific
antibodies to block its effect, or can we develop vaccines against these
staph infections that include protection against these particular virulence
factors, as well?
Is there one message you’d like to give to
the lay public about your work and your research?
Just that we now have these very virulent strains of MRSA in the community
and, just as in hospitals, we now all have to take precautions to avoid
spreading them. We have to remember to use proper hygiene in the home. If
you’re infected with PVL-positive bacteria, you have to remember to
wash your hands. Not to share towels. If one of your children is infected,
you can’t use the same soap on him or her that you use on your other
children. Ten years ago this problem did not exist. Now it does and so we
all have to keep these rules of hygiene in mind.
University of Lyon
Etienne's most-cited paper
with 364 cites to date:
Vandenesch F, et al., “Community-acquired
methicillin-resistant Staphylococcus aureus carrying
Panton-Valentine leukocidin genes: Worldwide
emergence,” Emerg. Infect. Dis. 9(8):
978-84, August 2003. Source:
Essential Science Indicators