An innovative, interdisciplinary platform for the dissection of Pneumocystis, a deadly fungal pathogen of humans

The goal of my research project is to enable a vital breakthrough in the study of a major fungal pathogen of humans. Pneumocystis kills hundreds of thousands of people each year, and yet only a few groups are studying this pathogen because, currently, it is not possible to culture it in vitro independently of its host. My goal is to release this major experimental bottleneck by developing, for the first time, in vitro culture methods for Pneumocystis. I will address this using a powerful combination of in silico metabolic modelling and experimental phenotyping. The potential benefits of my project are vast. In addition to providing major insights into the co-evolution of Pneumocystis pathogens with their mammalian hosts, my project will empower the research community, leading, in the longer-term, to dramatic advances in Pneumocystis biology and therapy.

Pneumocystis jirovecii is an opportunistic pathogen causing life-threatening pneumonia in immunocompromised patients and it colonizes the lungs of healthy infants. The worldwide incidence of Pneumocystis pneumonia exceeds 400,000 cases per year with mortality rates of 20 - 80%. This is a serious problem for developing countries where the population of HIV-infected individuals is over 6 times that in developed countries.
Challenge: The inability to culture Pneumocystis in vitro despite 3 decades of research makes this pathogen uniquely difficult to study. Diagnosis and treatment of Pneumocystis infections has relied primarily on microscopic detection in respiratory specimens. The lack of in vitro culture methods has been recognized as the major obstacle in Pneumocystis research.
Recent genome sequencing has identified a potential explanation for the inability to culture Pneumocystis: it has an extremely reduced genome that lacks essential metabolic pathways. This has prevented growth independently of its mammalian host. Pneumocystis has developed unique dependencies on the host for nutrients as well as highly efficient strategies to evade the host's innate and acquired immune defences. Thus, intimate host-fungus cross-interactions are essential for growth of the pathogen, and simple supplementation of growth media to overcome predicted auxotrophic requirements has not been sufficient to solve the problem.
Principal hypothesis: The metabolic issue is more subtle: the pathogen also relies on the host to maintain redox and/or energy homeostasis.
Innovative approach to resolve this issue: I will develop an in silico metabolic model of Pneumocystis growth and metabolism based on new genomic data.
Outcomes: This work will release a critical bottleneck in Pneumocystis research, and provide major insights into the co-evolution of Pneumocystis pathogens with their mammalian hosts.