Onset of immunity and inflammation (G. Lutfalla)

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Vertebrates are constantly subjected to threats arising from their living environment. To survive, they have evolved a highly complex immune system that can recognize a myriad of danger signals issued upon invasion by foreign organisms or produced endogenously during the onset of a pathology. While the immune system is instrumental to eliminate these threats, an exacerbated immune response can lead to excessive inflammation, tissue damage and eventually diseases.
Understanding how the cellular and molecular effectors of the immune system recognize these threats, how immune cells are reprogrammed to efficiently fight the danger, and how this fighting may be controlled not to harm the host, are the major questions our team tries to address. To meet these challenges, our team has set up a multiscale approach, ranging from studies at the molecular level based on biochemical and structural methodologies, to investigations in a whole organism, the zebrafish, using live imaging.

News


March 2022 - Audrey Bernut receives the Michel Chignard Prize from the French association Vaincre La Mucoviscidose.

"The Michel Chignard Prize rewards a young researcher or teacher-researcher who has distinguished himself/herself both for his/her scientific excellence in the field of cystic fibrosis and for his/her educational qualities."


December 2021 - Welcome to Audrey Bernut who joins our team as CNRS CR Researcher!









September 2021 - Welcome to our 3 new PhD students from the MSCA-ITN European network INFLANET: Liz, Maria and Resul!








 
Research Projects

Theme 1: Immune cell activation

Theme leader : Dr. Mai NGUYEN CHI

Innate immunity is at the front line to thwart microorganism invasion. The zebrafish has proven particularly suitable for studying immune response to infections and injury. Thanks to the genetic amenability and transparency of its larvae and embryos, it provides an outstanding opportunity to decipher the dynamics of immune cell activation in infected and damaged tissues.
Our group uses the zebrafish larvae to unravel how phagocytes differentiate and fight microbes.

Theme 2: Danger signals and chronic inflammation

Theme leader : Dr. Laure YATIME

Inflammation is a natural process generated by our immune system in response to an external or internal aggression. A healthy organism is usually able to down-tune it and restore homeostasis when the threat is eliminated. Conversely, uncontrolled inflammation can be deleterious to the body and cause serious damage, potentially leading to diseases or exacerbating an underlying pathology if the inflammation becomes chronic.
We are interested in the molecular actors of the innate immune system whose excessive activation by pathogenic or endogenous danger signals causes chronic inflammation related to human pathologies such as hemolytic diseases, inflammatory bowel diseases or cancers. Our current work aims to understand how the recognition of these danger signals by specific immune receptors generates a pro-inflammatory response promoting the progression of these pathologies. To this purpose, we use a multidisciplinary approach combining biochemistry, cell biology, structural biology and in vivo modeling in zebrafish.

Theme 3: Antibacterial defenses and inflammation during cystic fibrosis

Theme leader : Dr. Audrey BERNUT

Cystic fibrosis is one of the most frequent fatal genetic diseases in the world. In patients with cystic fibrosis, mutations in the cftr gene trigger the accumulation of thick mucus in the respiratory airways. This promotes recurrent colonization by different pathogenic bacteria as well as an exaggerated immune response, which together conspire to cause fatal lung damage. In addition, mutations in cftr may impact the patients' immune responses, making these responses more harmful to the host and less effective in fighting bacterial pathogens. However, the mechanisms by which CFTR acts on these processes are poorly understood.

In order to increase our understanding of this altered immune response in cystic fibrosis, we developed an approach based on the use of CFTR-deficient zebrafish models. Thanks to its transparency, the zebrafish larva is an unparalleled in vivo system for visualizing and studying the direct effects of a dysfunctional CFTR on cell-scale anti-infective and inflammatory responses and it allows us to look at some aspects of the lung pathology associated with the disease.

Thanks to the use of zebrafish larvae, our work aims to:
1. assess how CFTR regulates innate immune responses and how its imbalance may promote infection and inflammation in CF,
2. identify therapeutic compounds likely to restore immune balance and infection control.

Theme 4: Lymphopoiesis

Theme leader : Dr. Paul GUGLIELMI

The similarities between mammalian and fish lymphopoiesis allow the identification of patterns of differentiation and robust mechanisms conserved during evolution. In Danio rerio, we have established fluorescent transgenic lines identifying B cells at all stages of their maturation, allowing us to take advantage of this model in terms of live animal imaging. Confocal imaging has established that Danio B-lymphopoiesis is carried out through two main pathways:
1 / the primitive hematopoiesis, which originates at 2 jpf from hemogenic buds on the surface of the yolk sac;
2 / the classical hematopoiesis, dependent on conventional stem cells and taking place first in the caudal hematopoietic tissue, then in the cephalic kidney. 
We complete our imaging work by analyzing the transcriptome of B cells during their maturation. Our aim is to develop analysis protocols on isolated individual cells. An analysis of the antibody repertoire by RNA-Seq completes this study.

Theme 5: Cellular communication in the hematopoietic niche

Theme leader : Dr. Etienne LELIEVRE

Following their emergence from the aorta hemogenic endothelium, hematopoietic stem cells (HSCs) join and seed a transient hematopoietic organ, the so-called caudal hematopoietic tissue (CHT). The CHT is a complex vascular plexus made of endothelial cells, stromal cells and neuronal extensions that allows HSC expansion and differentiation to give rise to progenitors as well as to mature hematopoietic cells.
HSCs homing in the CHT involves physical interactions with both endothelial and stromal cells triggering the rearrangement of endothelial cells to form “stem cell pockets” that provide the correct environment for HSCs proliferation and a proper balance between stemness maintenance and differentiation.
Our work is currently focusing on the characterization of the mechanisms at work in fish deficient for components of TGF-beta/BMP superfamily that display compromised HSCs engraftment in the CHT. Our current results will provide grounds to a broader project aimed at understanding at both cellular and molecular levels how HSCs, endothelial cells, stromal cells and nerves dialog to establish a fully operative hematopoietic niche.  



Team members
Publications
News

Head of the Team

Georges Lutfalla
Georges LUTFALLA
Research Director (DR1) CNRS
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Immune cell activation
(Mai Nguyen-Chi / Georges Lutfalla)

Lymphopoiesis
(Paul Guglielmi)

LPHI  Laboratory of Pathogen Host Interactions
UMR 5235 - Université Montpellier
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34095 Montpellier cedex 5

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