The Humane Research Trust is funding a research project at the University of Manchester to develop next-generation, animal-free lung models for studying deadly respiratory infections. Using a ‘lung-on-a-chip’ system, the scientists will replicate human lungs to study their response to fungal infections. This will help us understand more about antimicrobial immunity and begin to tackle the challenge posed by airborne pathogens.
Respiratory infections are the fourth leading cause of death worldwide. Among these, fungal infections pose a growing threat. Inhalation of spores from Aspergillus fumigatus - a major mould pathogen - causes over 3 million chronic and invasive diseases annually, resulting in 1.5 million deaths every year.
Invasive aspergillosis carries a staggering 50% mortality rate, and for drug-resistant strains or vulnerable patients, mortality can approach 100%. These infections are a serious complication for people with chronic obstructive pulmonary disease (COPD) and those recovering from viral illnesses like influenza or COVID-19.
In 2022, the World Health Organisation (WHO) published its first fungal priority pathogen list, highlighting fungal infections as a global health emergency. Aspergillus fumigatus sits in the WHO’s ‘critical group’, urgently in need of global attention.
Current treatments for invasive aspergillosis are limited and often ineffective, especially against drug-resistant strains. There is a major unmet requirement for new therapeutic strategies to save lives.
Respiratory infections caused by pathogens like Aspergillus fumigatus are notoriously difficult to study. Conventional research relies on mice, which involves immense suffering yet does not reflect the complexity of human lungs. The structural organisation of alveoli - the tiny air sacs where gas exchange occurs - is different in humans. Variations in immune responses between rodents and humans further limit the relevance of animal models.
Even when scientists use alternative tools such as organ-on-a-chip systems, these models rarely replicate the true architecture of the alveoli. In humans, Type I and Type II epithelial cells cover the lung surface and interact instantly with inhaled spores. Yet most in vitro models include only one cell type. Recent studies show that Type I cells internalise and kill twice as many fungal spores as Type II cells, emphasising the need for models that reflect this diversity.
“There is an urgent need for the development of novel strategies for the clinical management of fungal infection,” Dr Margherita Bertuzzi explains. “Current research models are limited, heavily reliant on animal-derived products and they still do not adequately reflect the complexity of the lung tissue and how disease progresses in humans.”
Without physiologically relevant systems, it is impossible to fully understand why antifungal responses fail in vulnerable patients, such as those with COPD. This knowledge gap limits the development of new therapies and contributes to the high mortality rates associated with invasive aspergillosis.
The Humane Research Trust is proud to fund a project that aims to overcome these challenges. Dr Bertuzzi’s team at the University of Manchester will develop a microfluidic ‘lung-on-a-chip’ platform - a miniature, artificial lung environment that mimics the structure and function of human alveoli. This next-generation model will integrate multiple cell types, including Type I and Type II alveolar epithelial cells and immune cells, within a fully humanised system.
Using this platform, researchers will study how the alveolar epithelium recognises and kills Aspergillus fumigatus and how these processes influence immune responses. They will also investigate what goes wrong in COPD, where epithelial dysfunction increases susceptibility to fungal infections. Importantly, the model will use animal-free culture media and recombinant antibodies, ending reliance on animal-derived products.
The team will apply innovative tools such as CRISPR-Cas9 gene editing to validate key mechanisms of antifungal immunity and explore why these processes fail in COPD patients. Data from the in vitro model will feed into an advanced computer simulation, enabling researchers to study infection dynamics digitally. This work will provide a powerful tool for testing new therapies in conditions that truly reflect human biology.
“This model will open new avenues for studying and testing treatments for lung diseases caused by Aspergillus fumigatus and other respiratory pathogens,” says Dr Bertuzzi. “This would help translate fundamental mechanistic knowledge into clinical settings.”
Dr Margherita Bertuzzi
Principal investigator
Dr Margherita Bertuzzi is a Lecturer in Molecular Microbiology at Manchester Fungal Infection Group at the University of Manchester. She specialises in fungal infection biology, and her current research focuses on understanding how inhaled respiratory pathogens cause disease, especially in patients with COPD.
Keira Gordon
PhD student
Keira Gordon is currently undertaking a PhD in Infectious Biology at the University of Manchester, having recently completed a Masters degree at the university. Her research focused on investigating the interactions between Aspergillus fumigatus and the respiratory system, specifically in regards to anti-fungal resistance emergence.
