A postdoctoral position is available at the Centre of Immunology of Marseille-Luminy (CIML) on the role of Interferon Lambda (IFN-λ) in inflammatory bowel diseases (IBD): impact on the regenerative capacity of epithelial cells.
Project: IBD is characterized by a dysregulated immune response that results in damage to the gut mucosal tissues; therefore, an important area of therapeutic interest is promoting healthy mucosal healing. In our lab, we focus on IFN-λ, a cytokine that is of great importance in the protection of mucosal barriers. IFN-λ is known to protect the mucosa from viral infections as well as to down-modulate inflammation, thus avoiding barrier damage. However, its effect on epithelial biology in tissue recovery as well as the nature of the microbial stimuli that induce IFN-λ production in the gut are still undetermined.
In the framework of the FRM project: “Interferon Lambda (IFN-λ) in inflammatory bowel diseases (IBD): impact on the regenerative capacity of epithelial cells” the successful candidate will be appointed with a fully-funded two-year fellowship. Using both mouse models of IBD and in vitro intestinal organoid technology, he/she will study: a) the relevance of IFN-λ signaling in IECs in the control of tissue restitution. b) the microbial stimuli that govern IFN-λ production in the gut as well as the cellular source of IFN-λ in healthy and diseased mice.
He/she will benefit from the excellent scientific environment of the CIML and its state-of-the-art research facilities. This project will require a wide variety of techniques including growing intestinal organoids, scRNA-seq, microbiology, confocal microscopy, and animal experimentation.
Candidate qualification: We seek a highly motivated, creative and enthusiastic postdoctoral fellow, able to work independently with excellent communication skills. Applicants should have a Ph.D. with at least one first-author publication and a strong background in immunology or epithelial biology.
Basic knowledge of RNAseq and/or microbiome analysis is an asset but not requested.
Application: Candidates should send their application including CV, a brief description of research accomplishments, list of publications, cover letter and contact for at least two referees into a single PDF file to Achille Broggi(achille.broggi @ childrens.harvard.edu).
Selected candidates will be contacted for an interview.
The starting date is Sep 1, 2021.
PI profile:
I am interested in the biology of type III interferons, a class of cytokines that has risen to importance as a pivotal regulator of the mucosal responses. While IFN-λ is known to act directly on epithelial cells to exert local antiviral activity, I made the surprising discovery that IFN-λ can modulate neutrophil activation, inhibiting ROS production, and degranulation via a non-canonical transcription-independent mechanism. Notably, I was among the first to describe a role for IFN-λ in the gut in the absence of an acute viral infection. While my previous work focused on the acute inflammatory response, my current research interest lies in the characterization of the role of interferons in barrier healing at mucosal surfaces, both in the context of acute viral infections as well as in the context of basal IFN levels stimulated by commensal microbes in the gut.
I have discovered that in a model of viral pneumonia, IFN-λ is produced by dendritic cells in response to a synthetic viral RNA and inhibits lung epithelial cell capacity to proliferate and regenerate barrier function. This defect culminates in failure to tolerate pathogen invasion and causes lethality upon bacterial superinfection.
These observations raise the question of whether IFN-λ produced in response to the gut microbiota may influence tissue recovery in the context of intestinal inflammatory diseases.
My laboratory focuses on further dissecting the biology of IFNs in the regulation of epithelial cell functions at mucosal sites. In particular, we will explore the following open questions:
a) How IFN-λ influences epithelial cell biology during mucosal healing.
b) What is the contribution of different interferons classes to gut epithelial biology under inflammatory and homeostatic conditions.
c) Which microbial components induce production of IFN-λ in homeostasis and during inflammation in the gut.
d) How is IFN-λ production differently regulated both in immune and in epithelial cells in response to commensal microbes in health and disease.
Selected publications from the PI:
Sposito, B. *, A. BROGGI*#, L.Pandolfi, S.Crotta, R.Ferrarese, S. Sisti, Nicola Clementi, I. Zanoni #et al. 2021. “Severity of SARS-CoV-2 Infection as a Function of the Interferon Landscape across the Respiratory Tract of COVID-19 Patients.” bioRxiv. https://doi.org/10.1101/2021.03.30.437173.
*=equal contribution, #=Corresponding Author
BROGGI A, Ghosh S, Sposito B, Spreafico R, Balzarini F, Lo Cascio A, Clementi N, De Santis M, Mancini N, Granucci F, Zanoni I. Type III interferons disrupt the lung epithelial barrier upon viral recognition. Science. 2020 Aug 7;369(6504):706-712. doi: 10.1126/science.abc3545. Epub 2020 Jun 11. PubMed PMID: 32527925; PubMed Central PMCID: PMC7292499.
BROGGI A, Granucci F, Zanoni I. Type III interferons: Balancing tissue tolerance and resistance to pathogen invasion. J Exp Med. 2020 Jan 6;217(1). doi: 10.1084/jem.20190295. Review. PubMed PMID: 31821443; PubMed Central PMCID: PMC7037241.
Zanoni I, Granucci F, BROGGI A. Interferon (IFN)-λ Takes the Helm: Immunomodulatory Roles of Type III IFNs. Front Immunol. 2017;8:1661. doi: 10.3389/fimmu.2017.01661. eCollection 2017. Review. PubMed PMID: 29234323; PubMed Central PMCID: PMC5712353.
BROGGI A, Tan Y, Granucci F, Zanoni I. IFN-λ suppresses intestinal inflammation by non-translational regulation of neutrophil function. Nat Immunol. 2017 Oct;18(10):1084-1093. doi: 10.1038/ni.3821. Epub 2017 Aug 28. PubMed PMID: 28846084; PubMed Central PMCID: PMC5701513.
Zanoni I, Tan Y, Di Gioia M, BROGGI A, Ruan J, Shi J, Donado CA, Shao F, Wu H, Springstead JR, Kagan JC. An endogenous caspase-11 ligand elicits interleukin-1 release from living dendritic cells. Science. 2016 Jun 3;352(6290):1232-6. doi: 10.1126/science.aaf3036. Epub 2016 Apr 21. PubMed PMID: 27103670; PubMed Central PMCID: PMC5111085.
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