Project 3

Regulation of infection-induced inflammation: interplay between autophagy and inflammasome pathways

ESR3: Mayra Alejandra Aguirre Garcia

University of Leiden, Institute of Biology Leiden, Faculty of Science (Netherlands)

Supervisor: Prof. A.H. Meijer, co-supervisors: local: Dr M. Varela, external: academic: Prof S. Renshaw (P7)

Objectives: Studying the links between chronic inflammation and defects in both autophagy and inflammasomes, two critical cellular functions that cross-regulate each other’s activities. Using mammalian cell cultures and zebrafish larvae to study the inflammasome-autophagy interplay during inflammatory conditions characteristic of tuberculosis caused by mycobacterial infection. Aims: 1) Advanced imaging of autophagy & inflammasome components physical co-localization and functional interactions during mycobacterial infection; 2) loss-and-gain-of-function genetic approaches to determine how autophagy protects against pathological inflammation in tuberculosis models; 3) Elucidate the role of guanylate binding proteins (GBPs) in the interplay between autophagy and inflammation during mycobacterial infection.

Expected Results: 1) Understand if autophagy dampens inflammasome activity and, vice versa, if inflammasomes affect antibacterial autophagy mechanisms; 2) Understand how antibacterial autophagy factors modulate inflammatory cell death and tuberculosis progression; 3) Insight into GBPs as potential targets to modulate autophagy and inflammation.

Secondments: Academic: P6 Sheffield: S. Renshaw, Month 16, 2 months: comparison macrophage/neutrophil functions, P1 Montpellier: G. Lutfalla, Month 24, 1 month: Analysis of macrophage subpopulations.