Dendritic cells and immunoregulation in transplantation and immunopathology
Franck Halary
Research Scientist

Research Associate INSERM

The cytomegalovirus (HCMV) and the BK polyomavirus (BKPyV), two human opportunistic viruses, are a major viral cause of renal graft dysfunction ultimately leading to graft loss if a partial immunological control is not restored on time. My scientific interest is mainly focused on understanding how and why those viruses utilize myeloid dendritic cells to enter and spread into the body. I am also interested in identifying specific inhibitors of major molecular interactions driving the capture and transfer of both viruses. To overcome the lack of relevant experimental models and to validate the working hypotheses on HCMV entry at mucosal sites, we currently develop a 3D-bioprinted model of humanized mucosa including myeloid DCs in collaboration with “L’école Centrale de Nantes” (ECN). In addition, I am the scientific supervisor of the BIRDIE EU project (H2020 FET Open, lead. Dr Carlos Mota for U Maas, MERLN Institute, The Netherlands) for the Nantes Universtité. The main objective of BIRDIE is to put together cutting-edge 3D bioprinting and microfluidics-based technlogies developed by two private partners to build up an innovative model of renal human tubulo-interstitium. This model will be used as a platform to investigate various human kidney diseases.

Description

Transplant recipients are at increased risk of viral infections due to impaired control of viral replication, resulting from immunosuppressive protocols used to avoid alloimmune reactions. My research is focused on two opportunistic viruses, the cytomegalovirus (HCMV) and the BK polyomavirus (BKPyV), both associated with kidney allograft dysfunctions (McIlroy D, Halary F and Bressollette-Bodin C, Philos Trans R Soc Lond B Biol Sci, 2019). In that setting, I am interested in characterizing the virus/receptor interactions like the one involving the envelope glycoprotein B from HCMV and the DC-specific lectin, DC-SIGN. Recently, we get insights on this interaction at the molecular level showing that high-mannose sugars located in the antigenic domains 4 and/or 5 are detrimental to the binding of HCMV particles to DC-SIGN expressing cells. Moreover, we demonstrated that this interaction accounts for a major part of the HCMV binding ability to monocyte-derived dendritic cells (Chéneau et al, J Infect Dis, 2018; Brument et al, Org Biomol Chem, 2017; Taouai et al, Bioconjug Chem, 2019).

Another study was undertaken in my group to understand how BKPyV could benefit from a cellular help to spread out of the kidney, an almost unique site of reactivation for this virus, thus potentially leading to viremia onset. Our results suggest that myeloid dendritic cells might play unexpected roles in the pathophysiology of BKPyV infection in humans (Sikorski et al, PLoS Pathogens, in press). Virus-Like Particles (VLP) which recapitulate perfectly infectious particles are produced in the lab as tools to document these points (coll. Pr Antoine Touzé, Tours). Our group recently bought a nanocounter (Izon Science; SFR Bonamy equipment) to assess physical titers for non-infectious as well as infectious BKPyV particles (see picture). It allows us to finely compare binding of VLP from various genotypes or wild-type versus mutated VLP to cells of interest. Known cellular receptors for BKPyV are b-series gangliosides but in accordance with published papers and personal unpublished data, it seems that alternative receptors for BKPyV exist. Their identification has been undertaken in the group using home-made HEK293TT KO cell lines and clones.  

To overcome the lack appropriate models and challenge our hypotheses, my co-workers and I set up a collaboration with engineers from “L’école Centrale de Nantes” (Pr JY Hascoët and Dr Luciano Vidal) whose goal is to 3D print a biomimicking model of humanized mucosa including immune cells, notably myeloid DCs (Boucard et al., in preparation). We are also about to start another exciting project, BIRDIE. The BIRDIE EU project (H2020 FET Open, lead. Dr Carlos Mota for U Maas, MERLN Institute, The Netherlands) aims at putting together cutting-edge 3D bioprinting and microfluidics-based technlogies developed by two SMEs to build up an innovative model of renal human tubulo-interstitium. This model will be used as a platform to investigate various human kidney diseases, notably the BKPyV infection in the human kidney, through various approaches encompassing transcriptomics/bioinformatics and bioprinting/microfluidics.

Last update: January 29, 2021.