Defining neuroinflammatory pathways in cryptococcal meningitis

Hain Porter, Sofia Alicia ORCID: 0000-0001-7993-2828 (2024). Defining neuroinflammatory pathways in cryptococcal meningitis. University of Birmingham. Ph.D.

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Abstract

Cryptococcus neoformans is a fungus that is ubiquitous in the environment and can cause lethal meningitis in immunocompromised individuals, with deficits in T cell responses, such as HIV/AIDS, being particularly vulnerable. Cryptococcal meningitis (CM) causes approximately 100,000 deaths per year and those who do survive often suffer from long-term neurological disorders. Tissue-resident macrophage populations in the CNS are the first line of defence against invading pathogens. In this thesis, I have explored the early immune response in the brain when C. neoformans first invades, focusing on microglial responses and inflammation in the surrounding meninges. This work has shown that the immune response in the brain and meninges is generally delayed. In the brain, a unique population of microglia develops that hosts live C. neoformans and may contribute towards inflammation and interaction with lymphocytes. In the meninges, complement activation and macrophage-platelet interactions coincided with C. neoformans proliferation in this tissue. Taken together, this work demonstrates C. neoformans has evolved strategies to overcome innate immune responses at the brain borders and within the brain parenchyma. This has important implications for developing immune therapies to treat and prevent cryptococcal meningitis, as targeting adaptive immune defects may not be sufficient to prevent disease.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):