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How does the host influence the pathogen?

Primary Supervisor: Dr Rebecca Drummond, Institute of Immunology & Infection

Secondary supervisor: Elizabeth Ballou

PhD project title: How does the host influence the pathogen?

University of Registration: University of Birmingham

Project outline:

This PhD project aims to understand how the microenvironment of different organs affects microbial virulence and disease pathogenesis. We will focus on the fungal pathogen Cryptococcus neoformans which causes cryptococcal meningitis, a disease that is responsible for over 150,000 deaths every year, principally affecting HIV/AIDS patients in sub-Saharan Africa. C. neoformans fungal spores are inhaled into the lung, and if the immune system does not contain them there, they are able to disseminate to the central nervous system (CNS) causing disease and death. Like most fungi, C. neoformans can exist is a variety of morphological forms, including haploid yeast cells and giant polyploid Titan cells. Titan cells form in response to signals experienced inside host organs and are thought to be important for dissemination to the CNS. However the exact mechanism(s) of CNS dissemination that cause cryptococcal meningitis is poorly understood, yet by understanding this is more detail we would have the opportunity to design therapies and drugs that could provide better treatment for patients suffering from these infections. This project will therefore try to understand how C. neoformans responds to the microenvironment in the mammalian host and how this shapes the behaviour of the fungus, such as how the fungus interacts with immune cells and spreads to the CNS. For this, the student will isolate yeast cells from infected mouse organs (e.g. lung, brain, spleen) and analyse the genetic content/ploidy of these cells, their antifungal drug resistance profiles and interactions with immune cells ex vivo (e.g. measuring intracellular survival and proliferation rate by microscopy). The student will use various clinical strains of C. neoformans that can either form Titan cells normally, do not form Titan cells at all, or mutant strains that can form Titans but not daughter cells, to understand how the Titan-isation process affects disease pathogenesis using in vivo animal infection models.

We welcome students wishing to expand on this theme and explore other areas that interest them. For example, different organ environments can exert a wide variety of stresses (e.g. exposure to hypoxia, nutritional limitations) on fungal cells that subsequently affect their morphology and division rates. The student will be jointly supervised between two laboratories; one that focuses on the immunology of cryptococcal meningitis and how different types of immune cells drive inflammation in the brain (Drummond lab), and one the focuses on how C. neoformans Titan cells form and drive disease pathogenesis (Ballou lab). The student will have the opportunity to become involved in ongoing projects in both of these laboratories and contribute to publications, thereby developing a valuable skill set in immunology and microbiology, while addressing an important human health problem with an unmet clinical need.

References:

  1. Dambuza et al (2018). The Cryptococcus neoformans Titan cell is an inducible and regulated morphotype underlying pathogenesis. PLoS Pathog, 14(5): e1006978; https://doi.org/10.1371/journal.ppat.1006978
  2. Drummond (2017). Neuro-Immune Mechanisms of Anti-Cryptococcal Protection. J Fungi, 4(1): 4;

BBSRC Strategic Research Priority: Understanding the Rules of Life: Microbiology

Techniques that will be undertaken during the project:

  • Mouse models of fungal infection
  • Flow cytometry
  • Microscopy
  • Fungal culture
  • Fungal genetics and molecular biology
  • Tissue culture

Contact: Dr Rebecca Drummond, University of Birmingham