Activation of the inflammasome by Malassezia fungal species

Abraham, Lizette (2023) Activation of the inflammasome by Malassezia fungal species. PhD thesis, University of Glasgow.

Abstract

Background: The fungi Malassezia is a commensal present on the human skin. It is however also an opportunistic pathogen as it has been implicated in several diseases including dandruff and seborrheic dermatitis (SD), especially M. restricta and M. globosa. Dandruff and SD lead to a negative social image which could cause low self-esteem and therefore negatively impact the quality of life of those suffering from it. These diseases are characterised by skin hyperplasia, damage, and inflammation. Although the exact mechanism of Malassezia involvement is not known, some Malassezia species like M. furfur, have been seen to activate the inflammasome. Inflammasomes are immune system components involved in inflammation. When activated, proinflammatory cytokines like IL-1β and IL-18 are secreted, leading to inflammation. Inflammasome activation also results in pyroptosis, a type of programmed cell death resulting from pore formation in the cell membrane. Pyroptosis also allows the expulsion of active proinflammatory cytokines, further fuelling inflammation.

IL-1β secretion requires a priming signal, resulting in gene transcription, and an activation signal (inflammasome activation) which leads to the processing and release of this proinflammatory cytokine. Some treatments used for these diseases include anti-inflammatories and anti-fungals. Some Malassezia species like M. globosa are however resistant to some anti-fungals like azoles, with some anti-inflammatories not being specific enough as they also affect human cells, causing side effects. Recurrence following discontinuation of treatment is also an issue with these diseases.

Understanding the mechanisms by which these fungi act would therefore provide information on how they can be targeted to combat these diseases. This thesis therefore aims to understand the mechanisms of Malassezia-related inflammasome activation in different cell types, which could provide potential therapeutic targets for future use in combating the diseases involving Malassezia.

Main results: As well as having other gene-related differences, fungal growth experiments showed that different Malassezia species grow at different rates, with modified Dixon’s agar (MDA) media seen to be preferential for liquid growth of the fungi. Our standardisation of Malassezia growth in MDA media also allowed the same amount of live fungi to be used in all experiments, improving reliability.

All Malassezia species studied as part of this work, M. restricta, M. globosa, and M. furfur, were seen to activate the inflammasome in the cells of interest. The cells studied in this thesis include monocyte-derived dendritic cells (MDDCs) and normal human epidermal keratinocytes (NHEKs).
Inflammasome activation and subsequent release of IL-1β were seen to involve different mechanisms in the different cell types studied. While using a priming agent to improve gene transcription was not seen to be essential for IL-1β release from NHEK cells, this significantly improved IL-1β secretion from MDDCs. Also, while inflammasome activation following infection with any of the Malassezia species studied was seen to involve caspase-1 and caspase-8 in MDDCs, this was not the case in NHEK cells. The different Malassezia species were shown to activate the inflammasome and cause IL-1β secretion via differing mechanisms to one another in MDDCs. For example, while M. furfur and M. globosa were also seen to use caspase-5 and go through the CARD9/BCL-10/MALT1 axis, M. restricta-related inflammasome activation was not shown to be affected by the inhibition of these proteins.

The different cell wall components of M. globosa and M. restricta were then investigated to understand what part of the fungi is being recognised, resulting in inflammasome activation and the secretion of IL-1β. While the cell wall polysaccharides were not seen to affect IL-1β secretion in both MDDCs and NHEKs, both the cell wall lipids and proteins were seen to cause varying effects in the different cell types studied. These all suggest that the different parts of the fungi are recognised differently, leading to differences in the immune response to the different Malassezia species.

Conclusion: The work described in this thesis has provided previously unknown pathways involved in inflammasome activation following infection with different Malassezia species in different cell types. It has also provided some insight into the recognition of different cell wall components of the Malassezia fungi. These all provide a basis for more research to be done into the mechanisms involved in Malassezia-related inflammasome activation in these cell types. It also provides important information on areas which can be targeted by therapeutics, to relieve symptoms and potentially treat diseases associated with Malassezia infection.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Subjects: Q Science > QR Microbiology
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Supervisor's Name: Evans, Professor Thomas J.
• Date of Award: 2023
• Depositing User: Theses Team
• Unique ID: glathesis:2023-83645
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 14 Jun 2023 11:01
• Last Modified: 15 Apr 2026 09:10
• Thesis DOI: 10.5525/gla.thesis.83645
• URI: https://theses.gla.ac.uk/id/eprint/83645