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Etienne Professor Jerome Etienne
Special Topic Interview

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 of 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 correspondent Gary Taubes about his highly cited MRSA research.

 When did you begin research on Staphylococcus aureus?

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 do it.

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 comes from.

"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[5]: 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[9308]: 753-9, 2 March 2002), there is a clinical entity called necrotizing pneumonia, which would occur after a viral infection such as the flu.

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[8]: 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 resistant?

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 community-acquired MRSA?

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[22]: 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 now?

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[5815]: 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.

Jerome Etienne
University of Lyon
Lyon, France

Professor Jerome 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 from Thomson Scientific.

Special Topics : Methicillin-Resistant Staphylococcus aureus (MRSA) : Professor Jerome Etienne - Special Topic of MRSA