Human body temperature as a driver of fungal pathogenicity in the lung (Manchester-Melbourne Dual Award)

Fungal lung diseases are an often fatal consequence of spore inhalation which occur with high prevalence across the globe in settings of immune dysfunction and genetic risk.

The often-fatal fungal lung disease invasive aspergillosis (IA) has claimed more than 8 million human lives since its emergence ~ 40 years ago. IA-related mortality is unacceptably high (50- 90%) and usually results from respiratory failure due to haemorrhage occurring at sites of fungal invasion. The mechanistic basis of tissue invasion by A. fumigatus remains unknown, however our recent work on fungal gene expression during lung infection has shown that adaptation to stresses encountered within the human lung dominate the tissue colonisation transcriptome.

Talaromyces marneffei infection is an important emerging public health problem, especially among patients infected with human immunodeficiency virus in southeast Asia, India, and China where T. marneffei infection is regarded as an AIDS-defining illness. Common manifestations of disseminated P. marneffei infection in AIDS patients are fever, anemia, weight loss, lymphadenopathy, hepatosplenomegaly, respiratory signs, and skin lesions. Patients who do not receive the appropriate antifungal treatment have a poor prognosis; however, primary treatment with amphotericin B and secondary prophylaxis with itraconazole are effective, however, growing concerns around increases in clinical azole antifungal resistance are cause for concern around the globe.

Fungal lung pathogens typically exist as several distinct morphological forms, the interconversion between which might, by species, be an obligatory component of the fungal life cycle or conditionally dependent upon extracellular stimuli. In Aspergillus species, a morphological switch from fungal spore to hyphal form is undergone within the first few hours of spore inhalation into the mammalian lung. The prominence of Aspergillus fumigatus as a human pathogen is governed by the ability of the organism to undertake the spore to hyphal transition under elevated temperatures, a trait not observed in lesser pathogenic species of the genus. In thermally dimorphic fungal pathogens, such as Talaromyces marneffei the conversion to yeast within healthy and immunocompromised mammalian hosts is essential for virulence. In the yeast phase, the thermally dimorphic fungi upregulate genes involved with subverting host immune defences, however, the mechanistic basis of phase transition is poorly defined.

This project will build upon our recent findings and state-of-the-art tools in genetic manipulation of fungal pathogens to identify the regulatory common ground between fungal pathogens which have become adapted to life inside the human host via evolution of thermotolerant growth cycles and acquire the mechanistic insight to target such mechanisms with novel antifungal agents.

See https://www.manchester.ac.uk/study/postgraduate-research/golden/melbourne/