CV Science

Amélie Bigorgne PhD Immunology

Course and current status

SCIENTIFIC EXPERTISE: IMMUNOLOGY, LIVER AND INTESTINE

SKILLS : FACILITATE, CONVINCE, COMMUNICATE

2016-2019 Staff scientist, Inserm U1163, Necker Hospital, France. O. Hermine Lab, Imagine, Gut-derived serotonin in liver metabolism. Liver immune signature in metastatic cancer; CR1 since Sept 1^st 2017.

2015-2019  Consultant, Cancer Immunotherapy Program, Drug Development Dept (DITEP), Gustave Roussy Cancer Campus, Villejuif, France. Project, budget and human resource management.

2015-2019 Co-founder, COOPETIC Recherche. Scientific entrepreneurship.

2013-2015 Postdoc, Inserm U1135, CIMI, Pitié-Salpêtrière, Paris, France. Christophe Combadière Lab, Olivier Silvie Team. Molecular biology and immunology of malaria liver infection. FP7 PathCo, VHC/malaria co-infection.

2011-2013  Postdoc, Inserm U768, Imagine Institute, Necker Hospital, Paris, France. Alain Fischer Lab. Immunogenetics, TTC7A mutations reverse intestinal apico-basal polarity in a combined immune deficiency.

2009-2011 Postdoc, Seattle BioMed, Seattle, WA, USA. Nick Crispe lab. Role of hepatic stellate cells derived CXCL1 in systemic immune homeostasis.

2008-2009 Postdoc, University of Rochester Medical Center, NY, USA. Nick Crispe lab. CD8+T cell homing to the liver in Flu infection. Liver Immunology and gut microbiota.

2003-2007 PhD student, Inserm U131, A. Béclère Hospital, Clamart, Dominique Emilie Lab, G. Perlemuter team. Liver inflammation, obesity, NASH, chemokine-induced lymphocyte homing to the liver.

Scientific summary

Since 2003, I have been interested  in the contribution of the gut-to-liver axis in the maintenance of both immune and metabolic homeostasis. 

During my PhD (2003-2007), I showed that a deregulation of the metabolic status of the liver is sufficient to enhance the response of circulating lymphocytes to chemokines, which are expressed by bile-duct epithelial cells (CXCL12, CXCL13) and a subsequent liver inflammation. In addition, gut-derived bacterial compounds participate to the low-grade inflammation in fatty liver¹. We participated to the understanding of the relationship between liver metabolic imbalance (i.e.hepatocyte fat storage) and the immune system (i.e.lymphocyte homing): the high-fat content of the liver has consequences not only on surrounding parenchymal liver cells but also on the activation of systemic immunity. In addition, I participated to the identification of the potent anti-inflammatory role of GILZ, which down-regulation in the liver and in circulating monocytes explains the hypersensitivity to inflammation in alcoholic hepatitis². These findings explain for the first time the beneficial effect of glucocorticoid treatment in patients with severe alcoholic hepatitis, abrogating monocyte/macrophage sensitivity to LPS and cytokine secretion (D. Emilie Lab, G. Perlemuter Team, Inserm, Clamart).

During my postdoc in USA (2008-2011), working on the steady state liver this time, I showed that hepatic stellate cells secrete specifically one chemokine, CXCL1, for the recruitment of neutrophils, participating to the response of the liver to physiological levels of gut bacterial compounds³. Thus, the liver mediated-immune function is not restricted to bone-marrow derived lineages (i.e.Kupffer cells), but involves other liver subpopulations such as liver sinusoidal endothelial cells, stellate cells and even hepatocytes -which can all present antigens (Seattle BioMed, I. N. Crispe Lab, Seattle, WA). This work provides for the first time the quantification of the respective secretion profiles of highly-enriched fractions of hepatocytes, KC, LSEC, HSC which were isolated from the same liver by in situliver perfusion of collagenase, followed by appropriate density gradients.  

Back to France in 2011, I focused on a rare primary immunodeficiency with intestinal atresia. With linkage analysis and WES, I identified that TTC7A gene mutations were responsible for a disruption of cytoskeleton assembly leading to the inversion of apicobasal polarity in both intestinal and thymic epithelial cells⁴. This demonstrates that epithelial cell polarity is closely linked to the maintenance of the immune homeostasis. This altered polarity was also observed in the skin of two patients and in an IBD-like syndrome^5,6(A. Fischer Lab, G de Saint Basile Team, Necker Hospital). In another project, focused on the liver-mediated immunity in malaria, I showed the critical role of LAMP vesicules in parasite traversal through the hepatocyte (Ch. Combadière Lab, O. Silvie Team, CIMI, Pitié-Salpetrière).⁷

More recently, I initiated a project and demonstrated the contribution of digestive bacteria translocation in the pathology of pulmonary arterial hypertension, through collaboration with F. Perros (M Humbert Lab, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson), showing the critical role of the liver as a filter of bacterial compounds.⁸

Hired in 2016 in Olivier Hermine’s Lab,  Inserm U1163 Imagine Institute, I first focused on the role of digestive serotonin in the regulation of liver metabolism. I am now developing a new project focused on the immune signature of liver metastases in cancer. Liver metastases represent a peculiar challenge for cancer therapy. The driving hypothesis of this project is that the immune tolerance in the liver, among all other potential metastatic sites, is a critical clinical variable -independently of the primary cancer- associated with a poorer clinical outcome. The aim is to identify an immune signature associated to the negative impact of liver metastases, as compared to other potential metastatic sites. 

I am willing to provide my expertise as a specialist in the gut-to-liver axis physiology and immunology to competitive and productive projects.

1. Bigorgne AE, Bouchet-Delbos L, Naveau S, Dagher I, Prévot S, Durand-Gasselin I, Couderc J, Valet P, Emilie D, Perlemuter G. Obesity-induced lymphocyte hyperresponsiveness to chemokines: a new mechanism of fatty liver inflammation in obese mice. Gastroenterology 2008;134(5):1459.

2. Hamdi H, Bigorgne A, Naveau S, Balian A, Bouchet-Delbos L, Cassard-Doulcier AM, Maillot MC, Durand-Gasselin I, Prévot S, Delaveaucoupet J, Emilie D, Perlemuter G. Glucocorticoid-induced leucine zipper: A key protein in the sensitization of monocytes to lipopolysaccharide in alcoholic hepatitis. Hepatology 2007;46(6):1986.

3. Bigorgne AE, John B, Ebrahimkhani MR, Shimizu-Albergine M, Campbell JS, Crispe IN.TLR4-Dependent Secretion by Hepatic Stellate Cells of the Neutrophil-Chemoattractant CXCL1 Mediates Liver Response to Gut Microbiota. PLoS One 2016;11(3):e015106.

4. Bigorgne AE, Farin HF, Lemoine R, Mahlaoui N, Lambert N, Gil M, Schulz A, Philippet P, Schlesser P, Abrahamsen TG, Oymar K, Davies EG, Ellingsen CL, Leteurtre E, Moreau-Massart B, Berrebi D, Bole-Feysot C, Nischke P, Brousse N, Fischer A, Clevers H, de Saint Basile G.  TTC7A mutations disrupt intestinal epithelial apicobasal polarity. J Clinical Investigation 2014;124(1):328.

5. Leclerc-Mercier S, Lemoine R, Bigorgne AE*, Sepulveda F, Leveau C, Fischer A, Mahlaoui N, Hadj-Rabia S, de Saint Basile G. Ichthyosis as the dermatological phenotype associated with TTC7A mutations. Br J Dermatol. 2016;175(5):1061-1064.

6. Lemoine R, Pachlopnik-Schmid J, Farin HF, Bigorgne A, Debré M, Sepulveda F, Héritier S, Lemale J, Talbotec C, Rieux-Laucat F, Ruemmele F, Morali A, Cathebras P, Nitschke P, Bole-Feysot C, Blanche S, Brousse N, Picard C, Clevers H, Fischer A, de Saint Basile G. Immune deficiency-related enteropathy-lymphocytopenia-alopecia syndrome results from TTC7A deficiency. J Allergy Clinical Immunology 2014;134(6):1354-1364.e6.

7.Risco-Castillo V, Topçu S, Marinach C, Manzoni G, Bigorgne AE, Briquet S, Baudin X, Lebrun M, Dubremetz JF, Silvie O.  Malaria Sporozoites Traverse Host Cells within Transient Vacuoles. Cell Host Microbe 2015;18(5):593-603.

8.Ranchoux B, Bigorgne A, Hautefort A, Girerd B, Sitbon O, Montani D, Humbert M, Tcherakian C, Perros F. Gut-Lung Connection in Pulmonary Arterial Hypertension. Am J Respir Cell Mol Biol. 2017; 56(3):402-405