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.

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Congratulations to Mai Nguyen-Chi who received the ANR JCJC Grant 2019!
Research Projects

Theme 1: Immune cell activation

Theme leaders : Dr. Georges LUTFALLA and 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: 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 4: Intron dynamics

Theme leaders : Dr. Georges LUTFALLA and Dr. Clement METTLING

Introns are a hallmark of metazoan genes, but their role in the evolution of genomes is still of debate: Selfish? exon shuffling? Their conservation in most species proves their extreme stability. The existence of independent and distant species not obeying this rule proves that introns can move and suggests that  metazoans with introns possess an active mechanism to prevent this dynamics.
According to Walter Gilbert's theory, introns are lost by homologous recombination with reverse transcribed cDNAs. To further assess this hypothesis, we study genome dynamics in a mouse model that accumulates reverse-transcription products and promotes homologous recombination.

Team members
Publications
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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)

Intron dynamics
(Clément Mettling / Georges Lutfalla)

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