Brigitte Gicquel - Biography#

Brigitte Gicquel's team has developed genetic tools allowing the study of Mycobacterium tuberculosis. The team developed the first methods using molecular biology for the rapid diagnosis of tuberculosis and study transmission (first PCR tests and genotyping of M. tuberculosis clinical strains). The team determined the first complete DNA sequence of a replicon from a mycobacteria and developed shuttle vectors, then using it in order to transfer DNA into mycobacteria, M. tuberculosis and BCG. They discovered the first transposon isolated from a mycobacteria, and set up procedures for random mutagenesis and allelic replacement. The team constructed the first library of M. tuberculosis mutants using transposons and discovered the first virulence genes of M. tuberculosis by adapting the signature tagged transposon mutagenesis (STM). They discovered mutants that failed to provoke lung infection in mice associated with the inactivation of a cluster of genes responsible for the synthesis and the transport of phtiocerol dimycoserosates through the cell wall. They had previously isolated the first M. tuberculosis virulence gene which product is also associated to the cell wall. These genes have been inactivated in a M. tuberculosis strain in which they had previously inactivated the PhoP/PhoR two component system also involved in virulence. This resulted in the construction of a vaccine candidate against tuberculosis which is now under clinical trials (collaboration with the University of Saragoza, Spain). They identified natural exchanges of genetic material between the family of mycobacteria (including major pathogens like M. tuberculosis) and other bacterial species of the environment as well as recent transmission between clinical isolates of M. tuberculosis. The team has discovered that DC-SIGN, located essentially on dendritic cells, is the major receptor for the entry of M. tuberculosis where the pathogen remains silent without replicating. The infected dendritic cells are responsible for disseminating M. tuberculosis to the lymph nodes were tuberculosis infection is observed at the same time as pulmonary tuberculosis. DC-Sign was also observed on macrophages in lungs specifically infected by M. tuberculosis making this cell population a marker of the tuberculosis infection of this organ.

The team has participated to the implementation of rapid tuberculosis diagnostic tests in low income countries and studied the acquisition of multi drug resistances (MDR). They showed that 50% of MDR M. tuberculosis isolates and more than 90% of MDR isolates that are resistant to fluoroquinolones are also resistant to pyrazinamide although this resistance is almost absent in non MDR isolates, thus emphasizing the rapid accumulation of additional resistances in MDR isolates. They have designed an algorithm for the utilization of remnants from GeneXpert samples tests for results confirmation, identified a large number of antibiotic resistances and typed the bacilli for case tracing. The team is now developing new drug screening approaches for the isolation of new antibacterials with activity against M. tuberculosis.