Philippe Sansonetti

This work, on the entero-invasive Shigella species, has become one of the references in the field. A 1983 article in which, starting with Escherichia coli K12, he and his collaborators at the Walter Reed Institute of Research, where he was then a postdoctoral researcher, reported the step-by-step reconstruction of a totally invasive Shigella-like bacterium (transfer of the virulence plasmid containing the invasiveness genes he had identified, then chromosomal loci progressively increasing virulence in vivo until the phenotype of a wild Shigella strain was reached) truly opened the way to what has recently become cellular microbiology, i.e. the study of the interaction between microbes and cells, and which will rapidly become tissue microbiology, i.e. the detailed study of the behavior of micro-organisms within infected tissues/organs.

His subsequent work led him to develop this type of approach for other micro-organisms such as Listeria monocytogenes, Klebsiella pneumoniae and Entamoeba histolytica, but above all for Shigella, to considerably increase the level of resolution of the approaches by developing, at prokaryotic level, a detailed study of cell and tissue invasion genes and their regulation; at eukaryotic level, by introducing cell biology into the physiopathological concept. This led them to make pioneering observations on the mechanisms and signals of bacterial entry into cells via the reorganization of their cytoskeleton, on the mechanisms of intracellular movement via actin polymerization, on the mechanisms of cell-to-cell passage and induction of cell death, particularly apoptotic death in macrophages.

However, as emphasized at the outset, their research is characterized by a constant back-and-forth between in vitro and in vivo approaches, leading to the development of systems for studying infection in situ, in organs, making it possible to build up the general pattern of the disease and show how the micro-organism "plays" with the host's innate defenses, in particular inflammation, to destabilize its epithelia and invade them. This multidisciplinary approach has recently enabled them to uncover the existence of an intracellular perception system for invading bacteria (Nod proteins) and the bacterial ligand recognized by this system (peptidoglycan muropeptide fragments). This recognition leads to transcriptional activation of pro-inflammatory cellular genes induced by the NF--Bk and JNK systems. They then demonstrated how Shigella negatively regulated the inflammatory response it triggered, thereby inducing an aberrant adaptive response profile. This is linked to the injection into target cells of enzymatic effectors that precisely regulate pro-inflammatory signaling pathways, such as the suppression of I-Bk protein ubiquitination and epigenetic regulation of NF-kB promoter accessibility by suppressing MAPK and Histone A3 phosphorylation.

The award of the ERC Advanced Grant has enabled the launch of a new program to study the molecular dialogue between the microbiota and the intestinal epithelium, with particular reference to the expression of anti-infective factors, epithelial regeneration and the interface with mutation and metabolism.

Finally, on the basis of their understanding of the pathophysiology of shigellosis and their demonstration of the mechanisms of mucosal protection against the disease, they have developed the first live attenuated-virulence vaccine candidate against this disease. Shigellosis kills around 500,000 young children worldwide every year, and the development of a vaccine is considered a priority by the WHO. Clinical trials of these vaccines are currently underway, initially in collaboration with the US Army, and now as part of a collaboration between Institut Pasteur, Hôpital Cochin and St. George's Hospital Vaccinology Centre in London. Studies in volunteers have shown the vaccine to be protective. If confirmed, this vaccine would be an example of the effectiveness of a rational mitigation approach based on a detailed pathophysiological analysis of the disease. They are also developing a subunit conjugate vaccine approach based on the chemical synthesis of polyosides, as well as a protein c-vaccine that protects independently of serotypes.