Postdoc position at Welcome-Wolfson Institute for Experimental Medicine, Queen´s University, Belfast



A Postdoctoral Fellow position for an individual with training and demonstrated abilities in cell biology/cellular immunology/cellular microbiology is available in the Valvano group to investigate the inflammasome in human CFTR-defective macrophages and monocytes.

Project summary: Infection and chronic inflammation in patients with cystic fibrosis (CF) lead to progressive lung damage. CF-defective macrophages fail to kill engulfed opportunistic pathogens such as Burkholderia cenocepacia. Engulfed pathogens disarm macrophages and counteract immunity by deploying proteins (effectors) that alter central cellular pathways including actin cytoskeleton remodeling. Pathogen-induced disorganization of the actin cytoskeleton is both a remarkable anti-host strategy and a danger signal driving inflammation and cell death. However, the actin cytoskeleton dynamics in the context of the CF defect has not been explored. We hypothesize that intracellular opportunistic pathogens engulfed by macrophages, in combination with the CF genetic defect, induce disorganization of the actin cytoskeleton that leads to a

highly proinflammatory state. Our research established B. cenocepacia as a model organism for cellular microbiology. We discovered that a B. cenocepacia type VI-secretion system (T6SS) disrupts the macrophage’s actin cytoskeleton and elicits pyroptosis (proinflammatory cell death), and we recently identified TecA as the T6SS protein responsible for these phenotypes by causing the direct inactivation of Rho GTPases, which in turn activates the Pyrin inflammasome and the ASC complex formation. We will

investigate here the relationship between inflammation and B. cenocepacia-mediated modulation of macrophages’ actin cytoskeleton in CFTR-defective human monocytic macrophages. We will address 2 specific aims: (1) To assess the status of the pyrin inflammasome in B. cenocepacia-infected, CFTRdefective peripheral monocytes; and (2) To evaluate the role of the B. cenocepacia T4SS and T2SS systems in the activation of ASC-dependent inflammasomes upon infection in human macrophages.

Interested applicants should contact Prof. Miguel A. Valvano at m.valvano@qub.ac.uk and provide a CV, brief statement of interest, and references.