PhD in innate immunity M/F

Job Description

Thesis Subject

The central premise of the PhD project is to investigate and characterize the unexpected role of NADPH oxidase in neutrophils as a key mechanism controlling caspase-1-dependent pyroptosis, and to model the dysregulated inflammation observed in patients with chronic granulomatous disease (CGD) during infection.

Chronic granulomatous disease (CGD) comprises a heterogeneous group of inherited immunodeficiencies, transmitted either in an autosomal or X-linked manner, resulting from loss-of-function mutations in genes encoding different NADPH oxidase subunits (p47-phox, p40-phox, p67-phox, p22-phox, and the catalytic subunit gp91-phox) or its regulatory proteins. Consequently, phagocytes—including monocytes, macrophages, dendritic cells, and neutrophils—are unable to efficiently eliminate certain fungal and bacterial pathogens, including Mycobacterium tuberculosis/BCG, Chromobacterium violaceum, Burkholderia cenocepacia, Francisella philomiragia, and Staphylococcus aureus, as well as the fungus Aspergillus fumigatus. These infections can therefore become life-threatening.

Although NADPH oxidase plays an essential role in pathogen clearance through the production of reactive oxygen species (ROS), a paradoxical feature of CGD is that patients exhibit markedly increased basal and infection-induced inflammation, characterized in particular by exacerbation of intestinal and pulmonary inflammatory diseases. This excessive inflammation does not appear to be directly related to an increased microbial burden, and its underlying mechanisms remain largely unresolved.

In this context, the overarching objective of the project is to investigate, at the molecular, cellular, and tissue levels, the role of neutrophil NADPH oxidase in the regulation of caspase-1-dependent pyroptosis, as well as the importance of this process in the immune, physiological, and pathological responses observed in patients and in NADPH oxidase-deficient models.

Thus, the project will aim to:

Elucidate the molecular mechanisms by which NADPH oxidase deficiency specifically sensitizes neutrophils to caspase-1-dependent pyroptosis.
Characterize the downstream signaling pathways involved in aberrant pyroptosis of NADPH oxidase-deficient neutrophils.
Assess the contribution of dysregulated neutrophil pyroptosis to disease manifestations in CGD models during infection.

Your Work Environment

The project will be carried out within the “Immune Sensing and Pathogen Elimination” team, under the supervision of Etienne Meunier and Caio Bomfim, at the Institute of Pharmacology and Structural Biology (IPBS, UMR 5089), CNRS and University of Toulouse, Toulouse, France.

The IPBS is a joint research unit (UMR) of the CNRS and the University of Toulouse. Located on a 12,000 m² site at the heart of the main campus of Toulouse-Paul Sabatier University, which offers high-level multidisciplinary training in science, health, and engineering, the IPBS is part of one of France's leading research hubs in health and biological sciences.

The position falls within an area subject to Protection of Scientific and Technical Potential (PPST) regulations. Consequently, in accordance with applicable regulations, the successful candidate's arrival must be authorized by the competent authority of the French Ministry of Higher Education and Research (MESR).

Constraints and risks

The student will be required to work with biosafety level 2 (BSL-2) bacteria (Pseudomonas, S. aureus, C. violaceum, B. cenocepaciae, M. abscessus, and F. novicida) and biosafety level 3 (BSL-3) bacteria (M. tuberculosis) in a restricted-access area.

Compensation and benefits

Compensation

2300 € gross monthly

Annual leave and RTT

44 jours

Remote Working practice and compensation

Pratique et indemnisation du TT

Transport

Prise en charge à 75% du coût et forfait mobilité durable jusqu’à 300€

About the offer

About the CNRS

The CNRS is a major player in fundamental research on a global scale. The CNRS is the only French organization active in all scientific fields. Its unique position as a multi-specialist allows it to bring together different disciplines to address the most important challenges of the contemporary world, in connection with the actors of change.

CNRS

The research professions