The emerging fungal order Mucorales: species-specific pathogenic strategies and new diagnostics

Mucormycoses are emerging lethal fungal infections, with striking mortality rates of 50-90% depending on the clinical presentation, infection site and underlying host immune status. While generally rare, the incidence of these infections has dramatically increased since the beginning of the COVID-19 pandemic, with COVID-19-associated Mucormycoses accounting for approximately 28,252 cases up to June 2021.

Furthermore, other risk factors for the development of Mucormycoses, such as uncontrolled diabetes, neutropenia, haematological malignancies, organ transplantation, trauma and burn, and use of immunosuppressants such as corticosteroids, are drastically increasing due to modern clinical practices and co-morbidities in an overall aging population. Pulmonary mucormycoses are the second most common clinical presentation and are caused by inhalation and deep lung deposition of inhaled spores of a highly heterogenous and complex group of fungi, collectively known as Mucorales.

Angioinvasion and subsequent fungal dissemination is a hallmark of pulmonary mucormycoses and mortality rates upon dissemination rise to 96%. Current fragmented evidence indicates that successful treatment of Mucorales is largely species-dependent, with the interactions of Mucorales with innate immune cells and their outcomes differing significantly according to species.

However, i) the exact mechanisms driving fungal lung invasion and systemic dissemination of Mucorales are yet to be elucidated and ii) the identification and diagnosis of Mucorales up to species level has been hampered by the lack of robust tools for the genetic manipulation of Mucorales.

We hypothesise that the robust identification of Mucorales species and the characterisation of species-specific host-pathogen interactions are crucial in furthering treatment of mucormycoses. Thus, with this project, we aim to leverage our expertise in genetic engineering of filamentous fungi and single-cell in vitro modelling of fungal infection to:

develop tools for the generations of fluorescently-labelled and knockout strains of Mucorales; unravel the species-specific Mucorales-mucosal interactions and outcomes thereof;

design species-specific identification tool to apply in environmental and clinical samples. This will be done in collaboration with PiQ, a company focused on delivering diagnostic services to the food, feed, agricultural and healthcare sectors.

With the overall aim of obtaining a mechanistic understanding of species-specific Mucorales invasion strategies, this research ultimately aims to inform the identification of novel diagnostic and therapeutic strategies to facilitate clinical management of these and other lethal respiratory infections and ultimately reduce their disease burden in humans.