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© K. Melican.
Human microvessel (red) colonized by N. meningitidis (green).
Domaines Scientifiques
Maladies
Organismes
Applications
Technique

Présentation

A number of infectious agents, including emerging pathogens and agents responsible for nosocomial infections, reach the blood during infection. Colonization of the bloodstream induces different types of severe pathological consequences such as septicemia and meningitis. Despite the availability of antibiotics these infections resulting in sequels and high death rates remain a major concern in intensive care units and emergency rooms. A better understanding of the mechanisms of disease is a necessary step to the identification of innovative treatments. We study the pathogenesis of Neisseria meningitidis (or meningococcus), a Gram-negative bacterium that recapitulates these different pathological effects. This bacterium asymptomatically colonizes the human nasopharynx and pathology is initiated when the bacterium crosses the nasopharynx epithelium and reaches the bloodstream where they survive and proliferate.

Outstanding questions in terms of understanding N. meningitidis pathogenesis include: how do bacteria cross the epithelium and reach the bloodstream? How do they survive in the blood? How do they damage vessels and reach the cerebrospinal fluid (i.e. cause septic shock and meningitis)?

Carriage and pathogenesis of N. meningitidis

We have recently identified a mechanism that facilitates the crossing of the epithelium by the bacterium. This mechanism relies on the activity of a bacterial transferase that modifies the major component of type IV pili.

We are now extensively characterizing this enzyme at the structural and biochemical level to design inhibitors. To study the blood phase of the infection we take advantage of in vitro models to explore the biogenesis and function of type IV pili and how they mediate intricate cross-talk with human endothelial cells in culture. Perhaps most importantly we have developed an animal model based on the xenograft of human skin onto immunodeficient mice. Because of its strict human specificity N. meningitidis type IV pili bind only to capillaries present in the human tissue. Strikingly, adhesion along vessels triggers local inflammation, coagulation and loss of vascular integrity, the three typical histological observations in human cases of infection. Availability of such a model of infection recapitulating the cardinal features of the blood phase of the infection now allows us to address key questions in terms of the bacterial and host processes involved in N. meningitidis-caused vascular damage. These results point out the importance of the interaction between bacteria and the endothelium in the context of Neisseria meningitidis sepsis. The role of these interactions in sepsis caused by other bacteria will now be explored.

We are thus well engaged in a global and multidisciplinary approach combining microbiology with cell biology, vascular biology, chemistry and physics to study the pathogenesis of N. meningitidis infection.

Whenever possible our basic findings are exploited to design preventive and therapeutic approaches in collaboration with pharmacological companies. It is also essential to us to take advantage of our progress in the knowledge of N. meningitidis to the study of other bacterial pathogens involved in similar pathologies.

 

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Alumni

Ximing Xu (Post-doctoral fellow 2014-2016)

Maëlys Loh (Summer student 2016)

Corinne Millien (Technician 2010-2015)

Flore Aubey (Engineer 2013-2015)

Anne-Flore Imhaus (PhD student 2009-2014)

Silke Machata (Post-doctoral fellow 2010-2014)

Valentina Lo Schiavo (Post-doctoral fellow 2012-2014)

Idonya Aghoghogbe (M2 student 2014)

Keira Melican (Post-doctoral fellow 2011-2013)

Magali Soyer (PhD student 2009-2012)

Paula Michea-Veloso (PhD student 2009-2012)

Tiffany Martin (M2 student 2011-2012)

Audrey Dumont (Post-doctoral fellow 2009-2010)

Guillain Mikaty (PhD student 2007-2010)

Benoît Rousseau (M2 student 2003-2004)

Fanny Lanternier (M2 student 2003-2004)

Emilie Mairey (PhD student 2004-2007)

Lab news

October 2016

Daria Bonazzi selected among the 10 finalists of the 2016 ASCB Kaluza Prize

Daria Bonazzi recipient of a L’Oréal-UNESCO For Women in Science Fellowship

June 2016

Valeria Manriquez-Rojas awarded best poster prize at the 2016 Pasteur-Curie joint retreat

May 2016

Arthur Charles-Orszag awarded best oral presentation prize at the 2016 Exocytosis-Endocytosis Club conference

Arthur Charles-Orszag awarded best oral presentation prize at the 2016 Young Researchers in Life Sciences conference

Images & Médias

 

Broad public diffusion of knowledge

  • The Duménil lab was selected to produce a CellDance video for the ASCB-EMBO 2017 conference that took place in Philadelphia in December. Check it out!

  • Conference by Guillaume Duménil on the Vascular Colonization by N. meningitidis

  • A video produced by the French ministry of education describing meningitis. This video appears on the CORPUS web site dedicated to teaching purposes on the human body:

  • A video produced by INSERM describing our results reported in the journal Science in 2011 (Chamot-Rooke et al., 2011):

Research videos

  • Adhesion of meningococcus aggregates to endothelial cells leads to ezrin protein accumulation (which represents plasma membrane remodelig). Ezrin-GFP transfected cells (in green) were infected by mCherry-expressing meningococcus aggregates (in red). Behaviour of ezrin was monitored over a 10 min period. As the aggregates reach the cells, ezrin started to accumulate. The scale bar corresponds to 20 μm.

    Author: Arthur Charles-Orszag
    Related to the article Soyer et al., Cell. Microbiol. 2014.

  • Meningococcus growth as a microcolony is accompanied by ezrin protein accumulation (which represents plasma membrane remodelig). Ezrin-GFP transfected cells (green) were infected by individual mCherry-expressing meningococci (red). Following initial adhesion (white arrows), behaviour of ezrin underneath the nascent microcolony was monitored over a 4 h period under flow conditions. As the microcolony reached a size of about 10 diplococci (30 min), ezrin started to accumulate and the cortical plaque size increased with the size of the microcolony. The scale bar corresponds to 20 μm.

    Author: Magali Soyer
    From the article Soyer et al., Cell Microbiol 2014.

  • Intravital microscopy showing a human vessel in the base of the skin graft labeled with UEA lectin (red) and perfused by the mouse circulation. Blood plasma is labeled with a 150 kDa FITC-dextran (green) introduced intravenously. Moving black silhouettes within the plasma are blood cells.

    Supplementary movie from Melican et al., PLOS Pathogens 2013.

  • Intravital microscopy showing adhesion of N. meningitidis (GFP, green) to a human vessel (UEA lectin, red) grafted onto an immunodeficient mouse, 30 min post infection.

    Supplementary movie from Melican et al., PLOS Pathogens 2013.

 

Contact

Pathogenesis of Vascular Infections Unit – Institut Pasteur

Centre François Jacob

28, rue du Docteur Roux

75015, Paris France