Press Release

Plague: the bacillus becomes resistant
to antibiotics in fleas

In 1995, teams from the Institut Pasteur in Paris and in Madagascar had isolated the first bacilli of plague (Yersinia pestis) that were resistant to antibiotics. They showed that these bacteria had acquired resistance genes from other non-related bacteria. These same teams, in collaboration with an American group, have just discovered that the flea, the vector of the disease, is the site where the bacterium could acquire resistance traits. According to the results published in the last issue of the journal Molecular Microbiology, the fight against the emergence of new bacterial strains of Yersinia pestis which are resistant to antibiotics might be quite difficult. It is even more worrisome that this resistance to antibiotics is emerging in one of the most pathogenic bacterial species for humans and that an infected person's chances for survival are directly tied to the rapidity of organizing an adapted antibiotic therapy.

Plague is a disease of rodents, due to the bacterium Yersinia pestis, which is principally carried by rats. It is transmitted to humans by bites from the fleas of infected rodents. Today, plague is considered to be a re-emerging disease. More than 20 countries currently report plague cases - mainly in Africa, and also in Asia. The United States itself has not been spared. Throughout the twentieth century, the discovery of antibiotic treatments, their effectiveness and the reinforcement of public health measures have strongly reduced morbidity and mortality caused by this disease, but they have not made it disappear.

Plague is a serious disease, one which in the absence of treatment can kill rapidly - hence the importance of an early diagnosis. Antibiotics (streptomycin, chloramphenicol or the tetracyclines) are very effective if they are administered starting in the first two days. However, resistant strains are beginning to emerge.

In 1995, teams from the Institut Pasteur in Paris and in Madagascar for the first time isolated a strain of Y. pestis which was multiresistant to antibiotics in a Malagasy patient; then a second strain resistant to streptomycin in Malagasy patients with Bubonic plague. Scientists showed that these two strains had acquired resistance genes originating from other non-related bacteria. These first observations indicate that such an event can be reproduced in any plague focus in the world.

The teams of Elisabeth Carniel (Yersinia Laboratory, Institut Pasteur in Paris), Marie-Laure Rosso (Institut Pasteur of Madagascar) and Joe Hinnebusch (NIAID, Rocky Mountain Laboratory, U.S.) have hence sought to understand how the acquisition of these resistance traits is carried out. Since Y. pestis has a very limited epidemiological cycle, the bacterium had to acquire the resistance plasmids by close contact with another bacterium, either in the infected host (human or rodent), or in the flea vector.

In mammals, Y. pestis circulates in sterile settings (lymph nodes, spleen, liver, blood), where the possibilities of contact with bacterial donors of resistance plasmids are very limited.

Hence the hypothesis, verified today by the researchers at the Institut Pasteur and the NIAID, according to which the acquisition of resistance genes would take place in the flea. To test this hypothesis, rat fleas were first fed on blood containing the bacterium E. coli carrying a streptomycin-resistance plasmid, and secondarily on blood containig a Y. pestis strain sensitive to this antibiotic.

The way in which Y. pestis develops in fleas facilitates the acquisition of foreign genes: bacteria multiply in the insect's midgut and aggregate in order to form dense micro-colonies. Researchers showed that close contact was produced in these clusters between the E. coli and the Y. pestis absorbed by the flea and that this prolonged contact led to frequent genetic exchanges.

After four weeks of co-infection, 95% of fleas housed in their midgut Y. pestis clones which had acquired the streptomycin-resistant plasmid. The researchers also demonstrated that the frequency of transfer of the resistance plasmid from E. coli to Y. pestis in the fleas' midgut was extremely high (10-3) and almost identical to that obtained in the laboratory under optimal conditions.

For the researchers, the fact that these genetic transfers are produced so easily and frequently in the experimental flea model suggests that this phenomenon is produced equally in the natural environment.

The emergence of Y. pestis strains that are resistant or multiresistant to antibiotics and the recent demonstration that the acquisition of this resistance can be produced outside of humans or mammals, in a setting which would be very difficult to control, reinforce the necessity of identifying new therapeutic targets and of developing an effective and well-tolerated vaccine against plague. The Institut Pasteur's actions are oriented in this direction.

Source :

" High-frequency conjugative transfer of antibiotic resistance genes to Yersinia pestis in the flea midgut ", Molecular Microbiology, 2002, 46 : 349-354
B. Joseph Hinnebusch1, Marie-Laure-Rosso2, Tom G. Schwann1 and Elisabeth Carniel3

1 Laboratory of Human Bacterial Pathogenesis, Rocky Mountain Laboratories, Natioal Institute of Allergy and Infectious Diseases, NIH, Etats-Unis
2 Institut Pasteur de Madagascar, Tananarive
3 Laboratoire des Yersinia, Institut Pasteur, Paris

Contacts :

- Elisabeth Carniel, Yersinia Laboratory- Tel.: +33 (0) 145 68 83 26 - Mél : carniel2@pasteur.fr

- Institut Pasteur Press Office- Tel.: +33 (0) 145 68 81 47 - e-mail : presse@pasteur.fr
http://www.pasteur.fr/actu/presse/infos/