Investigating the role of Post-Translational Modifications in Mcl-1 in macrophage host defense against bacteria in chronic lung disease

About the Project

Regulation of Mcl-1 in Macrophage Host Defense

This PhD project offers an opportunity to explore immunometabolism and cell signaling, focusing on how macrophages decide whether to live or die to protect the host.

Macrophages are the sentinels of the innate immune system. When they encounter bacteria like Streptococcus pneumoniae, they often undergo a specialized form of cell death called apoptosis, which maximizes their ability to kill the invading pathogens. We have identified that a protein called Mcl-1 that acts as s regulator of this process.

While S. pneumoniae eventually leads to the degradation of Mcl-1 which triggers macrophage apoptosis to clear the infection, with other bacteria, like some strains of Haemophilus influenzae, Mcl-1 levels high and macrophages do not undergo apoptosis which allows the bacteria to survive and persist. This failure of the kill switch is particularly evident in patients with COPD, where high levels of Mcl-1 lead to impaired bacterial clearance and chronic infection.

The aim of this project is to identify the specific post-translational modifications (PTMs) that control Mcl-1 stability with the aim to develop new therapies that "reset" the macrophage defense system in patients with chronic lung disease. You will identify novel PTM of Mcl-1 following infection with respiratory pathogens. These modifications will be compared in healthy volunteers versus patients with COPD. Pharmacological inhibitors will be used to manipulate Mcl-1 PTMs with the aim to restore the macrophage's ability to kill bacteria.

The project provides interdisciplinary training in molecular biology, cell biology and microbiology including confocal microscopy and flow cytometry to measure cell death and mitochondrial health, immunoprecipitation and mass spectrometry to identify protein-protein interactions, microbiology and infection models, working with human macrophages and murine models.

Entry Requirements: Applicants should have (or expect to obtain) at least a 2:1 degree (or equivalent) in a relevant discipline.

Proposed start date: 01 October 2026

How to apply:

Please complete a University Postgraduate Research Application form available here: http://www.shef.ac.uk/postgraduate/research/apply

Please clearly state the prospective main supervisor in the respective box and select (School of Medicine and Population Health) as the department.

Enquiries: Interested candidates should in the first instance contact - Dr Helen Marriott, h.m.marriott@sheffield.ac.uk

Funding Notes

This is for a self funded candidate or a candidate who has a sponsor who will cover these costs.

This project is for 4 years, so will require 4 years of tuition fees and will require an additional £15,000 per year for project costs.

This is open to both UK and overseas students