Autophagy Machinery in Infections – AMI

Research themes

Our team studies the interactions between pathogens (viruses and bacteria) and the host cell response throughout the pathogen’s life cycle. In particular, we investigate the role of autophagy mechanisms and, more broadly, atg8ylation, during infections. Our projects are based on fundamental aspects that aim to better understand the mechanisms involved in infections, with the goal of identifying targets for the development of translational approaches that could lead to new anti-infectious strategies.

Our projects are structured around two main axes:

1. Role of autophagy and atg8ylation in the entry of pathogens into their target cells.

Pathogen entry is, by definition, the first event in the microbial life cycle that triggers a cellular response. This response can radically alter the outcome of the infection because, during and shortly after entry, pathogens have not yet expressed their full genetic repertoire, giving the cell a significant selective advantage to block the infection. The aim of this research axis is to determine the mechanisms by which the autophagy machinery is involved in the entry of pathogens into their target cells. Our work has notably shown that atg8ylation promotes HIV-1 entry via membrane fusion in CD4+ T lymphocytes, independently of autophagy. We are investigating whether this process is common to the entry of other enveloped viruses, particularly SARS-CoV-2. We are also exploring the role of autophagy and atg8ylation in the early stages of infection of macrophages by different Nocardia species, for which nothing is currently known.

2. Role of autophagy and atg8ylation in pathogen replication and the maintenance of cellular homeostasis.

The autophagy pathway is well known for controlling infections and maintaining cellular homeostasis. Pathogens exploit or neutralize these mechanisms to ensure their replication, potentially impacting the survival of infected cells. In this context, we are studying the role of autophagy in the innate immune response triggered by infection with various enveloped viruses. The role of the autophagy machinery in maintaining cellular homeostasis during infections is also being investigated. In the case of the Nocardia bacterial model, nothing is currently known about its replication mechanisms within host cells. However, the fact that this bacterium multiplies efficiently in its target cells strongly suggests that it has adapted to block or use the autophagy machinery to its advantage. We will therefore use various approaches to determine the bacterial determinants that allow Nocardia spp to survive and multiply, by investigating their interactions with the autophagy machinery.

Publications

• Pradel B, Cantaloube G, Villares M, Deffieu MS, Robert-Hebmann V, Lucansky V, Faure M, Chazal N, Gaudin R, Espert L. LC3B conjugation machinery promotes autophagy-independent HIV-1 entry in CD4+ T lymphocytes. (2024) Apr 7:1-12.
• Feuillard J, Couston J, Benito Y, Hodille E, Dumitrescu O, Blaise M. Biochemical and structural characterization of a class A β-lactamase from Nocardia cyriacigeorgica. Acta Crystallogr F Struct Biol Commun. 2024 Jan 1;80(Pt 1):13-21.
• Villares M, Espert L, Daussy CF. Peroxisomes are underappreciated organelles hijacked by viruses. Trends in Cell Biology. (2024) Dec 11:S0962-8924(24)00248-4.
• Ung KL, Poussineau C, Couston J, Alsarraf HMAB, Blaise M. Crystal structure of MAB_4123, a putative flavin-dependent monooxygenase from Mycobacterium abscessus. Acta Crystallogr F Struct Biol Commun. 2023 May 1;79(Pt 5):128-136.
• Couston J, Guo Z, Wang K, Gourdon P, Blaise M. Cryo-EM structure of the trehalose monomycolate transporter, MmpL3, reconstituted into peptidiscs. Curr Res Struct Biol. 2023 Nov 8;6:100109.
• Alsarraf HMAB, Ung KL, Johansen MD, Dimon J, Olieric V, Kremer L, Blaise M. Biochemical, structural, and functional studies reveal that MAB_4324c from Mycobacterium abscessus is an active tandem repeat N-acetyltransferase. FEBS Lett. 2022 Jun;596(12):1516-1532.
• Ung KL, Alsarraf H, Kremer L, Blaise M. MmpL3, the trehalose monomycolate transporter, is stable in solution in several detergents and can be reconstituted into peptidiscs. Protein Expr Purif. 2022 Mar;191:106014.
• Miller RH., Zimmer A., Moutot G., Mesnard JM. and Chazal N. Viruses. (2021). Retroviral Antisens Transcripts and Genes: 33 Years after First Predicted, a Silent Retroviral Revolution? Viruses (2021) 13(11), 2221.
• Coralie F Daussy, Mathilde Galais, Baptiste Pradel, Véronique Robert-Hebmann, Sophie Sagnier, Sophie Pattingre, Martine Biard-Piechaczyk and Lucile Espert. HIV-1 Env induces pexophagy and an oxidative stress leading to uninfected CD4+ T cell death. Autophagy. (2021) Sep;17(9):2465-2474.
• Savoret J., Mesnard J.-M., Gross A., and Chazal N. Antisense transcripts and antisense protein : a new perspective on human immunodeficiency virus type 1. Front. Microbiol. (2021) 11: 625941./li>
• Chazal N. Coronavirus, the King Who Wanted More Than a Crown: From Common to the Highly Pathogenic SARS-CoV-2, Is the Key in the Accessory Genes? Front Microbiol. (2021) Jul 14;12:682603.
• Arnaud-Arnould M, Tauziet M, Moncorgé O, Goujon C, Blaise M. Crystal structure of the TLDc domain of human NCOA7-AS. Acta Crystallogr F Struct Biol Commun. 2021 Aug 1;77(Pt 8):230-237.
• Ung KL, Kremer L, Blaise M. Structural analysis of the N-acetyltransferase Eis1 from Mycobacterium abscessus reveals the molecular determinants of its incapacity to modify aminoglycosides. Proteins. 2020 Jan;89(1):94-106.
• Blaise M, Kremer L. Self-control of vitamin K2 production captured in the crystal. J Biol Chem. 2020 Mar 20;295(12):3771-3772.
• Chazal N, de Rocquigny H, Roussel P, Bouaziz S, Barré-Sinoussi F, Delfraissy JF, Darlix JL. The three lives of Pierre Boulanger. Retrovirology. (2020) Apr 30;17(1):9.
• Baptiste Pradel, Véronique Robert-Hebmann, Lucile Espert. Regulation of Innate Immune Responses by Autophagy: A Goldmine for Viruses. Frontiers in Immunology. (2020) Oct 6;11:578038.
• Wong JEMM, Blaise M. Report of false positives when using zymography to assess peptidoglycan hydrolytic activity of an endopeptidase with multiple LysM domains. Biochimie. 2020. Oct;177:25-29.
• Küssau T, Van Wyk N, Johansen MD, Alsarraf HMAB, Neyret A, Hamela C, Sørensen KK, Thygesen MB, Beauvineau C, Kremer L, Blaise M. Functional Characterization of the N-Acetylmuramyl-l-Alanine Amidase, Ami1, from Mycobacterium abscessus. Cells. 2020 Nov 4;9(11):2410.

Composition de l'équipe

Dr Lucile ESPERT (DR2 CNRS) / Team Leader, PI)
Dr Mickaël Blaise (DR2 CNRS / Team Leader, PI)
Dr Marylene Mougel (DR1 CNRS / PI)
Pr Nathalie CHAZAL (Professor UM / PI)
Dr Coralie DAUSSY (CRCN CNRS / PI)
Dr Sébastien LAINE (MCU - UM)
Célia Chamontin (Engineer UM)
Jerôme Feuillard (Technician de recherche)
Dr Marie Villares (Post-doctoral fellow ANRS-MIE)
Julie Couston (PhD student UM)
Guilhem Cantaloube (PhD student UM)
Fiona Nicole (Master 2 student UM)
Romane Detève (Master 1 student UM)
Lucas Boulet (Master 1 student UM)