HEADDr ALONSO Jean-Michel /
  MEMBERSDr TAHA Muhamed- Kheir/, Dr, Dr /, Dr LARRIBE Mireille/

  Annual Report

Research activities of the Neisseria unit are in the field of the molecular epidemiology and pathogenesis of infections due to Neisseria meningitidis(Nm).

1. The pathogenesis of meningococcal infections. Nm is a common host of the human rhinopharynx. Invasive infection is a rare event that implies bacterial crossing of the epithelial and endothelial barriers to provoke bacteremia. We studied the regulation of the expression of bacterial structures such as the pili and the capsule during Nm-host cells interactions. However, functional genomic studies are impaired by the lack of laboratory animal model. We have developed a mouse model of sequential respiratory infection with the influenza A virus and Nm that reproduces meningococcemia. Also, infection of transgenic mice expressing the human transferrin, which is essential for iron uptake by Nm, offers the possibility to quantify experimental infection in this original model of meningococcemia and meningitis.

2. Inflammation and virulence. The meningococcal disease, resulting from blood borne invasion of the host’s body by replicating bacteria, is dominated by the activation of pro-inflammatory cytokines. Nm lipooligosaccharide (LOS) is a potent endotoxin. However, the study of specific LOS mutants has revealed that other bacterial products (such as peptidoglycan) also play an important role in stimulating inflammatory responses and virulence.

3. Impaired virulence of N. meningitidisstrains with reduced susceptibility to penicillin G. Such isolates are altered in the gene penAencoding the penicillin-binding protein (PBP) 2. Studies of PBP2 variants show that they have modified peptidoglycan as well as impaired virulence and inflammatory properties.

4. Evaluating PBP2 as new vaccine candidates. PBP2 share conserved N and C terminal domains in either penicillin susceptible or strains. PBP2 is naturally immunogenic, as assessed from serological studies in . Both passive and active immunization of mice with PBP2 induce protection against Nm challenge.

4.1. Tailor made vaccines. There is a strong need of vaccineam serogr B, promineninand in tAme outsicle (OMV) protein-based vaccines to serogroup B epidemic strains has been effectively applied in Cuba, Norway and New Zealand. In France, an outbreak of meningoccal disease, dominated by Nm B:14:P1.7,16, ST-32 strains, persists since 1997, in Normandy. the Normandy strain is to the vaccine strain B:15 :P1.7,16/ ST-32 used in Norway, we tested the bactericidal activities of from Norwegian vaccinees and found equivalent bactericidal titers to both strains. These results helped the health authorities to decide to vaccinate the exposed children.bactersample of 250 vaccinthis vaccination.

5. Reference activities. In France, the annual incidence remains stable at <1/100,000. Serogroup B remains the most frequent (>6%), followed by serogroup C (2%), serogroup W135 (3), and serogroup Y (3.6%)Our laboratory also participates actively in the efforts of the European Monitoring Group on Meningococci. We have led several inter laboratory studies to standardize the techniques of detection and typing of Nm. We are currently conducting a large study of penA sequencing and have already included >1500 isolates, among which 139 different alleles have been identified to date, in a database accessible through the internet (



Taha MK, Vázquez JA, Hong E, Bennett DE, Bertrand S, Bukovski S, Cafferkey MT, Carion F, Christensen JJ, Diggle M, Edwards G, Enríquez R, Fazio C, Frosch M,Heuberger S, Hoffmann S, Jolley KA, Kadlubowski M, Kechrid A, Kesanopoulos K, Kriz P, Lambertsen L, Levenet I, Musilek M, Paragi M, Saguer A, Skoczynska A,Stefanelli P, Thulin S, Tzanakaki G, Unemo M, Vogel U, Zarantonelli ML. Target gene sequencing to characterize the penicillin G susceptibility of Neisseria meningitidis. Antimicrob Agents Chemother. 2007 Aug;51(8):2784-92. Epub 2007 May 21.

Lancellotti M, Guiyoule A, Ruckly C, Hong E, Alonso JM, Taha MK. Conserved virulence of C to B capsule switched Neisseria meningitidisclinical isolates belonging to ET-37/ST-11 clonal complex. Microbes Infect. 2006 Jan;8(1):191-6. Epub 2005 Aug 15.

Holst J, Feiring B, Naess LM, Norheim G, Kristiansen P, Høiby EA, Bryn K, Oster P, Costantino P, Taha MK, Alonso JM, Caugant DA, Wedege E, Aaberge IS, Rappuoli R, Rosenqvist E. The concept of "tailor-made", protein-based, outer membrane vesicle vaccines against meningococcal disease. Vaccine. 2005 Mar 18;23(17-18):2202-5.

Parent du Châtelet I, Traore Y, Gessner BD, Antignac A, Naccro B, Njanpop-Lafourcade BM, Ouedraogo MS, Tiendrebeogo SR, Varon E, Taha MK. Bacterial meningitis in Burkina Faso: surveillance using field-based polymerase chain reaction testing. Clin Infect Dis. 2005 Jan 1;40(1):17-25. Epub 2004 Dec 8.

Deghmane AE, Giorgini D, Maigre L, Taha MK. Analysis in vitro and in vivo of the transcriptional regulator CrgA of Neisseria meningitidisupon contact with target cells. Mol Microbiol. 2004 Aug;53(3):917-27.

Activity Reports 2007 - Institut Pasteur
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