Probing the innate immune response to invasive fungal infections

Seoane Denicola, Paula I. ORCID: 0000-0001-6323-5470 (2020). Probing the innate immune response to invasive fungal infections. University of Birmingham. Ph.D.

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Abstract

Cryptococcus neoformans is an opportunistic fungal pathogen, which is widespread in the environment. Due to its global distribution and association with pigeon excreta, human exposure to this pathogen is frequent but initial infection is rapidly cleared or contained in immunocompetent hosts. In immunocompromised hosts, however, C. neoformans can cause severe disease often with dissemination to the central nervous system. Without rapid treatment disseminated infection is invariably lethal. With the rise of transplant and cancer therapy patients, the pool of vulnerable hosts is ever larger. Thus, studies of the interaction between Cryptococcus neoformans and the immune system are paramount for the development of novel treatment options.
In this study, different aspects of the interaction between C. neoformans and phagocytic cells, such as macrophages and dendritic cells, were explored.
One of the key features of Cryptococcal pathogenesis is its ability to persist and replicate within macrophages, as well as its ability to escape via a novel non-lytic mechanism known as vomocytosis. The impact of vomocytosis on disease progression is not yet fully appreciated, but it has been linked to dissemination of the fungal cell within the host. Vomocytosis is a highly regulated process, influenced by both fungal and host parameters. Macrophage polarisation is one such parameter, whereby alternatively activated macrophages show diminished occurrence of vomocytosis events. In this work, the interplay between two modulators of vomocytosis was explored. It was found that inhibition of the atypical MAP kinase ERK5, a known regulator of vomocytosis, limits alternative activation of macrophages, thus, providing a link between both phenomena.
Cryptococcal meningitis occurs mainly in HIV+ patients. The effect of chronic viral exposure on vomocytosis has not been studied before. My work revealed that viral exposure significantly enhances vomocytosis, acting through low levels of type-I interferons. Preliminary work expanded this finding to include bacterial co-infection settings, which can also elicit a type-I interferon response.
Lastly, the consequences of prolonged exposure to Cryptococcal cells or components on antigen presentation and antigen-induced T cell proliferation were explored. This setting emulates long-term latent infection within the lungs of immunocompetent hosts, which are frequently exposed to this fungus. The presence of Cryptococcal capsule components negatively impacts antigen-induced T cell proliferation by altering the antigen processing capabilities of antigen presenting cells.
Overall, this work highlights the complex interaction between C. neoformans and the innate immune system and underscores the importance of incorporating biological context cues into our experimental systems.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):