Intracellular survival in macrophages as a novel mechanism of resistance of Cryptococcus neoformans to anti-fungal therapy

Details

Cryptococcus neoformans is a fungal pathogen that causes life-threatening cryptococcal meningitis (CM), resulting in 1-200,000 deaths annually. Late-stage HIV infection is the greatest risk-factor and CM causes 20% of AIDS-related deaths. WHO HIV-treatment targets have been missed and CM often occurs in those with HIV-treatment failure (due to non-compliance or ART failure; ~50%). The other major risk factor is immunosuppressive therapy (e.g. following solid-organ transplantation or long-term anti-inflammatory therapy. Individuals at-risk of cryptococcosis are increasing due to multi-morbid disease and/or polypharmacy that results in immunocompromise.

Treatment of cryptococcosis is limited by availability and toxicity of anti-fungal drugs (especially in resource-limited settings) and a paucity of adjunctive therapy. The AMBITION trial suggests that survival is unlikely to improve beyond ~75% without new treatments regimens and a recent WHO report described C. neoformans as a pathogen requiring critical attention.

We others have extensively characterised the parasitism of macrophages by Cryptococcus, including in-macrophage growth. However, phagocytosis of Cn by macrophages is essential for surviving infection in both protective and susceptible animal models of cryptococcosis. This in vitro/vivo disparity was explained by us directly measuring macrophage parasitism in vivo in zebrafish and could demonstrate reduced overall fungal burden despite in-macrophage growth, even in a susceptible model. In agreement with this, human susceptibility to CM results from loss of inflammatory-activated macrophages. In CM, the levels of macrophage-targeting inflammatory cytokines that increase phagocytosis are a positive predictor of survival (independently of anti-fungal treatment).

However, we hypothesise that intracellular cryptococci might be protected from anti-fungal therapy and this might partly explain treatment failure in some individuals. The purpose of this project is to understand how intracellular cryptococci are protected from anti-fungal therapy and use this knowledge to propose changes to anti-fungal therapy to improve treatment of patients with cryptococcal meningitis.

Entry Requirements:

Candidates must have a first or upper second-class honours degree or significant research experience.

How to apply:

Please complete a University Postgraduate Research Application form available here: https://www.sheffield.ac.uk/postgraduate/phd/apply/applying. Please clearly state the prospective main supervisor in the respective box and select ‘School of Medicine and Population Health: Infection, Immunity and Cardiovascular Disease’ as the department.