Jessica Brown

Humans constantly interact with microbes in the environment, yet these organisms rarely cause disease. Among the 3-10+ million species in the fungal kingdom, only a few hundred species are capable of causing human disease and only a few dozen routinely do so. The environmental systemic human fungal pathogens also do not spread person-to-person, suggesting that the patient is an evolutionary dead end for the fungus and therefore that selective pressure for pathogenicity is from the environment. The Brown lab is interested in three main questions relating to fungal pathogenesis:

How does a disseminating fungal pathogen establish and cause disease within a mammalian host?

The environmental pathogen Cryptococcus neoformans causes severe, disseminated disease in patients with compromised immune systems, particularly low CD4⁺ T cell levels. In the environment, C. neoformans is associated with pigeon guano, although it does not appear to colonize or cause disease in pigeons. We are interest in how C. neoformans adapts to the guano environment, spreads to and survives in mammalian lungs, then escapes from the lungs and disseminates to the brain. Along the way, C. neoformans cells change shape and size, adjust to dramatically different environmental conditions, and must evade host immune responses. We are interested in fungal factors involved in these processes and how fungi manipulate the host to these ends.

How can we improve treatment of systemic fungal infections?

Systemic fungal infections are notoriously difficult to treat and limited by a paucity of approved drugs. Historically strategies for developing new antifungal treatments focus either on identification of new antifungal compounds or repurposing of existing drugs by identifying antifungal activity. We take a third approach: identifying combination therapies by determining how existing antifungal drugs interact with drugs approved for other diseases, then elucidating the molecular processes underlying these interactions so they can be exploited to improve antifungal treatments. These new treatments are then relatively economic for patients, since they consist of off-patent drugs. In addition, patients with fungal infections often have complicated drug treatment regimes. Some of these cause unintentional interactions, so understanding the biology and networks underlying these interactions is necessary for preventing treatment complication.

How do fungi adapt to a changing global climate and do those adaptations increase pathogenicity?

Mammalian body temperature is thought to be a major block to fungal pathogenesis. However, we do not think that temperature alone is sufficient because animals with core body temperatures below 37°C are not hypersusceptible to fungal infections. Instead, we think that a combination of temperature resistance and other stress responsive pathways are important for pathogenesis. However, these pathways are also potentially linked to fungal adaptation to a changing climate. We are using an experimental evolution approach to identify stress pathways involved in fungal adaptation to extreme weather events and whether this increases infection potential.

We take a highly interdisciplinary approach spanning genetics, cell biology, microscopy, genomics, whole genome sequencing, gene expression analysis, and molecular biology in microbial culture, cell culture, and mouse infection model systems. The ultimate goal is to apply our biological knowledge to additional pathogenic fungi and facilitate new anti-fungal therapy development.