Investigating the molecular mechanisms of vomocytosis

Gilbert, Andrew Stephen (2017). Investigating the molecular mechanisms of vomocytosis. University of Birmingham. Ph.D.

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Abstract

The opportunistic fungal pathogen Cryptococcus neoformans is the major etiological agent of the life threatening disease cryptococcosis, which is responsible for over half a million human deaths per annum. Professional phagocytes, such as alveolar macrophages, phagocytose inhaled spores and attempt to destroy the pathogen. However, this process is inefficient in immunocompromised hosts, such as those suffering from HIV/AIDS. In such hosts the macrophage is thought to behave like a “Trojan Horse”, acting as both a cryptococcal dissemination vector and as a protective niche against antifungal agents/cells present in the circulation.
Vomocytosis, first discovered in C. neoformans, is a non-lytic expulsive mechanism whereby C. neoformans or C. gattii exit the macrophage leaving both pathogen and the host macrophage with a morphologically normal phenotype. The clinical implications of vomocytosis are poorly understood however; data from this research suggests that the induction of a pro-inflammatory response increases vomocytosis rates, suggestive of a pathogen escape mechanism from a harsh antimicrobial environment i.e. the pro-inflammatory primed macrophage. Regulating the rates of vomocytosis in vivo may have dramatic consequences on pathogen dissemination and also patient prognosis. For instance, enhancing the rate of vomocytosis within circulation could allow other antifungal cells and compounds access to destroy the freshly released cryptococci, hence reducing pathogen burden and improving patient prognosis.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):