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Monika Bajorek (équipe BMP) va soutenir son HDR le vendredi 26 janvier 2024 à 14h dans l’amphithéâtre Jacques Poly du bâtiment 440.

Son HDR s’intitule "Molecular mechanism for Respiratory Syncytial virus (RSV) assembly and virus-host interactions". 

Membres du jury : Xavier Saelens (DR, University of Gent, Belgium), Clarisse Berlioz (DR, Inserm, Institute Cohin Paris), Cyrille Mathieu (CR, CNRS, CIRI-Lyon), Christina Sizun (DR, CNRS, Institute de Chimie des Substances Naturelles, Gif-sur-Yvette), Delphine Muriaux (DR, CNRS, IRIM Montpellier),

Abstract : 

My virus research started during my post doctorate training when studying the Endosomal Sorting Complexes Required for Transport (ESCRT) fission machinery. ESCRT pathway functions in a series of important membrane-remodeling processes, including multivesicular body vesicle formation at endosomal membranes, enveloped virus budding from the plasma membrane and midbody abscission during cytokinesis. My work revealed the molecular basis for ESCRT-III protein autoinhibition/activation, and to show its biological relevance in HIV-1 budding and in midbody abscission during cytokinesis.

As an independent researcher I moved to study the Human Respiratory Syncytial virus (RSV) assembly and budding. RSV, a major target for vaccines and anti-viral drugs, is the leading cause of infantile bronchiolitis and pneumonia worldwide, with a comparable burden to influenza in the elderly.

My research at INRAe is divided into three axes:

A. RSV assembly mechanism

RSV assembles and buds from the host cell plasma membrane by forming mostly filamentous infectious viral particles. The minimal set of RSV proteins required for filament formation are the cytoplasmatic tail of the fusion glycoprotein F, the phosphoprotein P and the matrix M protein. The key step in RSV assembly is the interaction of plasma membrane lipids with the M layer forming at the assembly sites. However, the exact interactions driving this process and their dynamics are poorly understood. My previous structural data showed that M forms dimers that are critical for filament assembly and production of virus-like particles (VLPs). Our recent findings demonstrate that M clusters at the plasma membrane by selectively binding to phosphatidylserine (PS), and that M oligomerization is critical for PS clustering. My next goal is to conduct structural and functional characterization of the protein-lipid nanodomain platform for RSV assembly.

B. RSV interaction of the host chaperon system

RNA viruses, like RSV, encode only a small number of proteins which are multifunctional and multioligomeric. A number of events in the RSV viral cycle are particularly sensitive to misfolding and likely depend on cellular chaperones, such as the RNA encapsidation and viral assembly. 

Hsp70 and Hsp90 molecular chaperones are essential cellular components that ensure proper protein folding. Inhibition of Hsp70 or Hsp90 chaperones negatively affect RSV replication, but also causes severe proteotoxicity, as the proper function of these two central chaperones is essential for cell survival. We propose to instead focus on the first molecular chaperones that recognize clients and deliver them to the downstream Hsp70 and Hsp90 machineries - Hsp40s/JDPs. We hypothesize that targeting the specific subset of JDPs that interact with key viral proteins will inhibit their folding and assembly in the host cell. This project aims to identify the specific JDPs interacting with RSV proteins, to characterize the protein complexes formed and to show their functional relevance to RSV replication.

C. RSV interaction with the host cell and innate immune response

RSV elicits a remarkably weak innate immune response. The nonstructural NS1 protein, which antagonizes interferon (IFN-I) pathways, is a main player in host innate immune response evasion by RSV. It was recently shown that NS1 also acts on transcription of host genes. A possible mechanism relies on the direct interaction between NS1 and the MED25 subunit of the Mediator complex and competition with transactivation domains (TADs) of transcription factors for binding, which would lead to downregulation of specific genes. We have found that NS1 interacts with MED25 using two interaction domains, the NS1 a3 and the NS1 ab core domain. We are now set up to carry out a high-resolution structural characterization of the NS1-MED25 complex and to study how RSV antagonize the innate immune response by binding MED25.