Muhamed-Kheir Taha Tackles Meningitis on the Molecular Level

Special Topic of Meningitis Interview, August 2010

Muhamed-Kheir TahaIn our Special Topics analysis of meningitis research over the past decade, the work of Dr. Muhamed-Kheir Taha ranks at #6 by total papers, based on 60 papers cited 1,062 times.

His record in the Web of Science® includes 64 original articles, reviews, and proceedings papers cited a total of 1,625 times between January 1, 2000 and July 16, 2010, and in Essential Science IndicatorsSM from Thomson Reuters, he has Highly Cited Papers in the field of Immunology.

Taha is Senior Associate Professor, Head of the Unit of Invasive Bacterial Infections, and Director of the National Reference Center for Meningococci at the Institut Pasteur in Paris, France.

 
ScienceWatch.com talks with him about his highly cited meningitis research.

SW: Please tell us about your educational background and early research experiences.

I obtained my M.D. from the University of Damascus, Syria, in 1983, my Ph.D. from the University of Diderot in Paris, France, in 1990. My thesis work, under the supervision of Dr. Christian Marchal, focused on the transcriptional regulation of the expression of a pilE gene in Neisseria gonorrhoeae.

This gene encodes the major subunit of the pili, filamentous appendices at the bacterial surface that are involved in several functions such as adhesion to target cells, competence for DBA transformation, and twitching motility. This work was also conducted in collaboration with the group of Dr. Maggie So at the Scripps Clinic, San Diego, USA, where I spent a short training period in 1988.

SW: What first drew your interest to meningitis?

I was first interested by the regulation of the expression of genes involved in the virulence of Neisseria meningitidis. This highly variable and exclusive human bacterium is the agent of meningitis and septicemia. It also shows duality between frequent asymptomatic carriage in the nasopharynx and occasional life-threatening disease. I was interested by the bacterial and host factors involved in this balance.

SW: One of your highly cited papers in our analysis is the 2000 Journal of Clinical Microbiology paper, "Simultaneous approach for nonculture PCR-based identification and serogroup prediction of Neisseria meningitidis." Would you tell us about the research behind this paper?

Culture-confirmed diagnosis of meningococcal infections is hindered by failure to isolate bacteria following early antibiotic treatment. Our work on gene expression allowed the identification of a conserved transcriptional regulatory gene in N. meningitidis, crgA, that is involved in the regulation of adhesion of N. meningitidis to target cells (Deghmane et al., Embo J., 2000).

"We are also developing molecular tools to better define meningococcal resistance to the antibiotics that are currently used in treatment and prophylaxis..."

I therefore developed a PCR assay that amplifies this conserved gene in N. meningitidis to ascertain the diagnosis of invasive meningococcal infections (Taha, J. Clin. Microbiol., 2000). I also developed a mutliplex PCR assay to predict the serogroups A, B, C, Y, and W135 by the amplification of the serogroup-specific alleles of the capsulargenes (Taha, J. Clin. Microbiol., 2000).

We used this method to detect the emergence of meningococcal isolates in Africa in 2001, one year before the first epidemic of meningitis due to these isolates in Burkina Faso in 2002 (Taha et al., J. Clin. Microbiol., 2002; Parent du Chatelet et al., Clin. Infect. Dis., 2005).

More recently, we designed a PCR method to detect serogroup X isolates that allowed detection of the first meningitis outbreak due to this serogroup in Niger in 2006 (Boisier et al., Clin. Infect. Dis., 2007) and Burkina Faso in 2010.

SW: Much of your research deals with the molecular pathogenesis of Neisseria meningitidis. Would you tell us about this aspect of your work, and some of the key papers you have published in this area (on our list or not)?

Informative cross-talk between N. meningitidis and target cells first allows the promotion of intimate bacterial adhesion. Other meningococcal surface components act then as pathogen-associated molecular patterns (PAMPs) to induce inflammation and apoptosis.

Part of our research focuses on the bacterial components that are involved in this process of signaling and the induction of the inflammatory response and apoptosis (such as lipooligosaccharide, the peptidoglycan and other meningococcal proteins). An intense inflammatory response accompanies and most probably determines the invasion of the host epithelial and endothelial barriers (Zarantonelli, et al., Infect. Immun., 2006; Deghmane et al., PLOS Pathog., 2009).

We have contributed to unraveling that peptidoglycan-mediated signaling through the two members of the NBS-LRR family (harboring nucleotide-binding site and leucine-rich repeat): Nod1 and Nod2. This recognition plays a role in regulating pro-inflammatory pathways through NF-B (Girardin et al., Science, 2003).

We also developed an animal model using transgenic mice expressing human transferrin. Indeed, one major element of the specificity of meningococci for humans is the bacterial iron uptake system by meningococcal proteins that bind specifically the human transferrin (transferrin-binding proteins). This animal model provides an original model to study meningococcal meningococcemia and meningitis (Zarantonelli et al., Infect. Immun., 2007).

Translational research also figures into your highly cited work in our analysis. Would you elaborate on this aspect of your research?

Our ambition is to conduct fundamental works that have impact on clinical medicine and human health. Indeed, we are developing molecular tools for rapid detection of meningococcal invasive infections as I mentioned above.

We are also developing molecular tools to better define meningococcal resistance to the antibiotics that are currently used in treatment and prophylaxis (beta lactams, quinolones, and rifampicin) with the establishment of databases that allow physicians to predict antibiotic susceptibility to penicillin G, for example; Taha et al., Antimicrob. Agents Chemother., 2007).

My laboratory harbors the French National Reference Center for Meningococci. Our work on molecular biology and typing recently allowed the detection of the emergence of a new clone of N. meningitidis of serogroup C. This work impacted on the recent changes in the vaccination strategy against serogroup C isolates of N. meningitidis in France in 2009 (Deghmane et al., J. Infect. Dis., 2010).

"More recently, we designed a PCR method to detect serogroup X isolates that allowed detection of the first meningitis outbreak due to this serogroup in Niger in 2006..."

We have contributed to the validation and the use a tailor-made vaccination strategy against an outbreak of invasive meningococcal infections in the Normandy region that was provoked by a particular clone of N. meningitidis of serogroup B (Taha et al., Vaccine, 2007).

While no universal vaccination is yet available against the serogroup B of N. meningitidis, we are involved in international collaborations that aim to develop such a vaccine (Murphy et al., J. Infect. Dis., 2009). Our group has strong links with countries in Africa with several experiences in transfer of molecular technologies for the surveillance of meningitis to countries like Burkina Faso and Niger.

SW: Last year, your group published a paper in Infection and Immunity, "Influenza A Virus Neuraminidase Enhances Meningococcal Adhesion to Epithelial Cells through Interaction with Sialic Acid-Containing Meningococcal Capsules." Please tell us about this study and its implications.

This work was initiated on the basis of the spatiotemporal association between flu infections and secondary invasive meningococcal infections. We have first developed a mouse model of sequential infection with the influenza A (A/H3N2) virus (IAV) and N. meningitidis (Nm). IAV primary infection creates a transitory phase of susceptibility of mice to invasive respiratory superinfection by Nm, thus mimicking main steps of the human meningococcemia (Alonso et al., FEMS Microbiol. Lett., 2002).

More recently, we aimed to explore the mechanism(s) of this IAV-Nm connection. We showed that IAV neuraminidase (NA) could act directly on the capsule of N. meningitidis. Indeed, this capsule (for serogroup B, C, Y, and W-135) contains sialic-acid units that can be cleaved by the viral NA.

This cleavage may then expose bacterial surface components and allow enhancing bacterial adhesion to epithelial cells in the respiratory pathways (Rameix-Welti et al., Infect. Immun., 2009). However, other mechanisms may also contribute to this association between flu and invasive meningococcal infections.

SW: How much have we learned about meningitis in the past decade? What advances would you like to see in the future of meningitis research?

Molecular approaches allowed in the last 10 years the accumulation of a large bulk of data in population genetics that permitted a good understanding of the emergence and the spread of N. meningitidis isolates involved in outbreak and epidemics.

This knowledge also allowed better tailoring and understanding of vaccination strategies. The genomic, transcriptomic, and proteomic era should now permit high-throughput analysis of large worldwide collections of clinical isolates to relevantly address the interaction between this bacterium and its unique host.End

Muhamed-Kheir Taha, M.D., Ph.D.
Invasive Bacterial Infections Unit
National Reference Center for Meningococci
Institut Pasteur
Paris, France


MUHAMED-KHEIR TAHA'S MOST CURRENT MOST-CITED PAPER IN ESSENTIAL SCIENCE INDICATORS:

Girardin SA, et al., "Nod1 detects a unique muropeptide from Gram-negative bacterial peptidoglycan," Science 300(5625): 1584-7, 6 June 2003, with 473 cites. Source: Essential Science Indicators from Clarivate Analytics.

KEYWORDS: GENE EXPRESSION, GENE REGULATION, VIRULENCE, NEISSERIA MENINGITIDIS, HOST FACTORS, BACTERIAL FACTORS, PCR ASSAY, DIAGNOSIS, SEROGROUPS, MENINGOCOCCAL ISOLATES, AFRICA, CROSS-TALK, PATHOGEN-ASSOCIATED MOLECULAR PATTERNS, INFLAMMATORY RESPONSE, APOPTOSIS, PEPTIDOGLYCAN-MEDIATED SIGNALING, TRANSFERRIN-BINDING PROTEINS, VACCINATION STRATEGY, INFLUENZA A VIRUS NEURAMINIDASE.

Citing URL: http://sciencewatch.com/ana/st/men/10augSTMenTaha/

 
 

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