Characterisation of a Novel Fungal Sensing/Signalling Axis

Fungal infections including aspergillosis, candidiasis and mucormycosis cause >1.6M deaths per year. Fungal infections are a major problem for immunosuppressed individuals (eg. patients with organ/bone marrow transplant, chemotherapy patients) or those with underlying health problems (eg. chronic lung disease, diabetes mellitus). Infections with fungal pathogens (Aspergillus, Candida, Rhizopus) have also recently emerged as a major problem for patients post-SARS-CoV2/COVID-19 infection.

These fungal pathogens were included on the recently published World Health Organisation (WHO) list of critical and high priority fungal pathogens that pose the greatest public health threat and urgently require further research to address gaps in our knowledge. These fungal pathogens are rapidly developing resistance to antifungal therapies which leads to prolonged therapy and hospital stays, increased used of highly toxic second-line antifungal therapies and increased mortality.

Due to many similarities between fungal cells and human cells, there are a very limited number of anti-fungal drugs and some fungal strains are resistant to one or all available anti-fungal drugs. This is a very serious problem and many more deaths will occur in the coming years unless new anti-fungal therapies, immunotherapies or vaccines are developed.

However, as recently highlighted by the WHO there are still significant gaps in our understanding of the immune response to fungal pathogens that need to be addressed to aid in the development of novel anti-fungal immunotherapies.

This proposal will use cutting edge technologies to characterise a hitherto unknown CLR-IFNa/b-PYHIN axis that senses and responds to life-threatening fungal pathogens including Aspergillus, Candida and Rhizopus. We will provide compelling evidence that the PYHINs (pyrin and HIN domain family) are essential to mediate immune responses to Aspergillus and other critical and high priority fungal pathogens.

By combining the expertise of the Orr, Bengoechea, Cook, Bowie, Bignell and Tiwari labs in the fields of fungal infection biology and signalling, Type I IFN and infection biology, myeloid cell subsets in response to Aspergillus, PYHIN signalling and biology, Aspergillus infection models and genomics, epigenetics and gene regulation, we will: (i) determine which fungal-induced immune responses are mediated by the CLR-IFNa/b-PYHIN axis and (ii) elucidate fungal-induced CLR-IFNa/b-PYHIN signalling pathway(s). Altogether, our research will cause a paradigm shift in our understanding of the immune response to life-threatening fungal pathogens.

This research will provide the foundation to determine whether components of this hitherto unknown pathway have potential as immunotherapy targets for the development of much needed new antifungal immunotherapies.