Complement Activation Mechanisms : structure/function relationships - Jean-Baptiste REISER
The classical complement pathway is initiated by the direct or indirect binding of the C1 complex to different endogenous or pathogenic molecular units to trigger the complement proteolytic cascade, leading to the formation of the membrane attack complex and the elimination of the target, to its opsonization or to the control of inflammatory processes. The molecular mechanisms of the C1 complex activation have so far challenged their detailed characterizations due to the high complexity of the molecules and their interactions. We re-examine these fundamental questions through important new findings and methodological and technical improvements in recombinant protein engineering and biophysical and bio-structural characterizations.
Participants : Jean-Baptiste REISER, Andrea J. PINTO, Nicole THIELENS, Christine GABORIAUD, Véronique ROSSI
Fundings : C1qEffero (ANR-16-CE-0019, 2018-2022), Labex GRAL-UGA PhD funding for Andrea J. PINTO (CBH-EUR-GS, ANR-17-EURE-003)
• Department für Biotechnologie, Universität für Bodenkultur Wien, Austria – Renate Kunert’s team
• Electron microscopy (W. Ling, IBS)
• Functional recombinant human complement C1q with different affinity tags
• Transient pentameric IgM fulfill biological function-Effect of expression host and transfection on IgM properties
• Interaction of C1q with pentraxin 3 and IgM revisited : mutational studies with recombinant C1q variants
• Structures of the MASP proteases and comparison with complement C1r and C1s
Physiopathology of complement-pathogenic interactions - Nicole THIELENS, Chantal DUMESTRE-PERARD
We are interested in the recognition mechanisms for some pathogens by complement proteins, as well as the biological outcome of these interactions in terms of anti-microbial immune response or pathogen escape strategies.
In the context of COVID-19, we are developing a project aimed at understanding the role of the complement lectin pathway, a major player in the innate anti-viral immune response for the pathological SARS-CoV-2 infection. We are studying the molecular mechanisms of interaction of SARS-CoV-2 proteins, including the Spike glycoprotein, with the early components of the complement lectin pathway and their functional consequences, including viral neutralization and complement activation.
Participants : Nicole THIELENS, Chantal DUMESTRE-PERARD, Véronique ROSSI, Jean-Baptiste REISER, Christine GABORIAUD
• Isabelle BALLY, Pascal POIGNARD (AID team, IBS-CAID)
• Michel THEPAUT, Franck FIESCHI (MIT team, IBS-MP)
• Giovanna CLAVARINO, Federica DEFENDI, CHU Grenoble alpes immunology laboratory
Funding :COVI-COMPLECT (ANR RA-COVID-19)
DC/L-SIGN recognition of spike glycoproteinpromotes SARS-CoV-2 trans-infection.
Complement alternative and mannose-binding lectin pathways activation is associated with COVID-19 mortality.