A 18 months, ANR-funded post-doctoral position is available in the team 15 of the CIRI “GIMAP: Pathophysiology and biotherapies of mucosal infections”, University of Saint-Etienne. The team investigates the role of secretory immunoglobulins in the regulation of mucosal immunity and microbiota composition in inflammatory disorders.

Adaptive immunity evokes tolerance in part through the daily mucosal secretion of 3-5 grams of secretory IgA (SIgA). It is proposed that sIgA regulates gut microbiota through antibody-mediated immunoselection (AMIS). Indeed, sIgA regulates microbiota composition through two opposing mechanisms, immune-inclusion by niche formation and immune-exclusion through aggregation and peristaltic removal of rapid growing pathobionts. Murine models of IgA deficiency display striking modifications of the microbiome-immune interface. Models impairing IgA secretion into the gut lumen were associated with altered microbiota composition, increased susceptibility to induced colitis, higher bacterial translocation to mesenteric lymph nodes after Salmonella typhimurium challenge, and lack of protective immunity against cholera toxin. Altogether, altered microbiome composition, increased susceptibility to microbial translocation, reduced microbial diversity and reduced microbial fitness are shared features of IgA deficiency models. Human IgA deficiency can be induced temporarily by immune suppressive medication (e.g. in transplant patients), but also exist as a relatively common chronic primary immune deficiency, which occurs in 1 in 500 Caucasian individuals. Selective IgA deficiency (SIgAdef) patients suffer higher incidence of respiratory infections, atopy and autoimmunity. For IgG deficient patients it is common clinical practice to supplement the patients with intravenous injection of polyclonal IgG (IVIG), however no similar therapeutic protocol is available for IgA supplementation. Such supplementation could have important implications for a broad range of IgA deficient patients, including patients with primary immunodeficiency (e.g. SIgAdef) but also patients treated with immunosuppressive medicine, such as chemotherapy and corticosteroids. The latter patients suffer temporary deficiency of both IgG and IgA, including mucosal secretory IgA.  Here we propose to analyse the effect of sIgA supplementation in IgA deficient mouse models as well as the importance of host and donor sIgA in immune suppressed haematological cancer patients having received fecal microbiota transplantation (FMT) therapy. We will assess the influence of sIgA both with regards to the stability of gut microbiota composition and clinical outcome (inflammation, gut leakage and Graft versus Host Disease (GvHD) status). This work provides novel understanding of mechanisms with which IgA influences microbiota composition. The project will be develop by the team of Martin Larsen (CIMI INSERM U1135, Paris) and the company MaaTPharma.

The successful candidate is expected to possess a scientific background in one (or several) of the following fields: mucosal immunity, animal models, microbiota analysis.

A solid technological expertise in immunology (FACS, cell sorting, RNAseq), biochemistry (Igs purification in particular) and microbiology (16S analysis) will be appreciated.

Enthusiasm for human and mouse immunology, commitment and project leadership will be essential.

 References:

Rochereau N, Drocourt D, Perouzel E, Pavot V, Redelinghuys P, Brown GD, Roblin X, Verrier B, Genin C, Corthésy B and Paul S. Essential role of Dectin-1 in intestinal M cell-mediated reverse transcytosis of SIgA-antigen complexes. PLOS Biology (2013) Sep;11(9):e1001658.

Nicolas Rochereau, Vincent Pavot, Bernard Verrier, Agathe Ensinas, Christian Genin, Blaise Corthésy, Stéphane Paul. Delivery of antigen to NALT M cells via secretory IgA targets local dendritic cells and promote partially protective immunity. J Allergy Clin Immunol. (2016) Jan;137(1):214-222.e2.

Rémi GAYET, Francesco NICOLI, Blandine CHANUT, Mireille PAUL, Nicolas ROCHEREAU, Eva MICHAUD, Christophe GUILLON, Laura PAPAGNO, Gilles BIOLEY, Blaise CORTHESY, Stéphane PAUL. Impact of IgA structure on their ability to modulate adaptive immunity Eur. J. Imm. (2020) Apr 11. 

Eva Michaud, Nicolas Rochereau, Stéphane Paul. Human Secretory IgM: An Elusive Player in Mucosal Immunity. Trends Immunol. (2020) Feb;41(2):141-156. doi: 10.1016/j.it.2019.12.005.

Nicolas Rochereau, Xavier Roblin, Eva Michaud, Rémi Gayet, Blandine Chanut, Fabienne Jospin, Blaise Corthésy & Stéphane Paul. NOD2-dependent influence of secretory IgA complexes in inducing GALT inflammation in Crohn’s disease. Nature Communication (2020) In press.

Nicolas Rochereau, Eva Michaud, Rémi Gayet, Xavier Roblin, Blaise Corthésy, Stéphane Paul. Essential role of TOSO/FAIM3 in intestinal IgM reverse transcytosis. Cell Report (2020) In press.

Eva Michaud, Rémi Gayet, Blandine Chanut, Fabienne Jospin, Katell Bathany, Magali Monnoye, Coraline Genet, Amelie Prier, Caroline Tokarski, Philippe Gérard, Xavier Roblin, Nicolas Rochereau, Stéphane Paul. Alteration of microbiota antibody-mediated immune selection contributes to dysbiosis in IBD. soumis