My lab has two main goals 1) explain why the complex network of interactions between a host and an opportunistic pathogen only sometimes results in a stable infection and how it does so, and 2) develop new antifungal and antibacterial drug treatments based on technology we developed to exploit interactions between drugs. We primarily use the fungus Cryptococcus neoformans as a model system. C. neoformans causes ~1 million infections and 600,000 deaths annually, most of which occur in patients with a compromised immune system. Despite near universal environmental exposure to C. neoformans, the vast majority of people do not exhibit any adverse health consequences. When C. neoformans does cause disease, it is extremely difficult to treat, commonly causing meningoencephalitis and requiring a year or more on toxic anti-fungal medications.
We investigate the infection process from the perspective of both the fungus and the host, including how C. neoformans interacts with and evades destruction by the host immune system. We also identifying the genes which allow the fungus to be virulent and discovering their molecular mechanisms of action. Many of these genes are poorly conserved in traditional model organisms, so their characterization opens broad new opportunities to understand immunity and to design more targeted, less toxic anti-fungal drugs.
On the treatment discovery side of the lab, we have developed high-throughput methods to rapidly identify interactions between drugs. These interactions amplify each other’s activity, allowing these combinations treatments to inhibit infectious microbes who are resistant to one drug in the pair. Once we elucidate the molecular mechanisms underlying these interactions, we can re-engineer drug combinations to bypass drug resistance. We are applying this technology to a number of different fungal and bacterial diseases.
Our major research questions include:
- How does C. neoformans escape from its initial site of infection in the lungs and spread to the brain? What fungal and host genes are involved and how do the gene products interact?
- How are the cell surface polysaccharides of C. neoformans involved in immune system evasion? How is the mix of these polysaccharides regulated? Are these pathways pathogen-specific, and can pathway members serve as drug targets?
- Can we use drug combinations to improve treatments of bacterial and fungal diseases?
My lab takes 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.
- Wambaugh MA, Denham ST, Ayala M, Brammer B, Stonhill MA, Brown JCS (2020). Synergistic and antagonistic drug interactions in the treatment of systemic fungal infections Elife 9: e54160. PMCID: PMC7200157.
- Denham ST, Wambaugh MA, and Brown JCS (2019). How environmental fungi cause a range of clinical outcomes in susceptible hosts. Journal of Molecular Biology 431(16): 2982-3009. PMCID: PMC6646061.
- Denham ST, Verma S, Reynolds RC, Worne CL, Daugherty JM, Lane TE, Brown JCS (2018). Regulated release of cryptococcal polysaccharide drives virulence and suppresses immune cell infiltration into the central nervous system. Infection and Immunity 86(3). PMCID: PMC5820953.
- Wambaugh MA*, Shakya VPS*, Lewis AJ, Mulvey MA, and Brown JCS (2017). High-throughput identification and rational design of synergistic small-molecule pairs for combating and bypassing antibiotic resistance. PLoS Biology 15(6): e2001644. PMCID: PMC5478098. *These authors contributed equally to this work.
- Brown JCS, Nelson J, VanderSluis B, Deshpande R, Butts A, Kagan S, Polacheck I, Krysan DJ, Myers CL, and Madhani HD (2014). Unraveling the biology of a fungal meningitis pathogen using chemical genetics. Cell 159(5): 1168-87. PMCID: PMC4243055.
- Jarosz DF*, Brown JCS*, Walker GA, Datta MS, Ung WL, Lancaster AK, Rotem A, Chang A, Newby GA, Weitz DA, Bisson LF, Lindquist S (2014). Cross-kingdom chemical communication drives a heritable, mutually beneficial prion-based transformation of metabolism. Cell 158(5): 1083-93. PMCID: PMC4424051.*These authors contributed equally to this work.
- Jarosz DF*, Lancaster AK*, Brown JCS, and Lindquist S (2014). An evolutionarily conserved prion-like element converts wild fungi from metabolic specialists to generalists. Cell 158(5): 1072-82. PMCID: PMC4424049. *These authors contributed equally to this work.
- Butts A, Koselny K, Chabrier-Rosello Y, Semighini CP, Brown JC, Wang X, Annadurai S, DiDone L, Tabroff J, Childers WE Jr, Abou-Gharbia M, Wellington M, Cardenas ME, Madhani HD, Heitman J, Krysan DJ (2014). Estrogen receptor antagonists are anti-cryptococcal agents that directly bind EF hand proteins and synergize with fluconazole in vivo. mBio, 5(1), e00765-13.
- Brown JC, Madhani HD (2012). Approaching the functional annotation of fungal virulence factors using cross-species genetic interaction profiling. PLoS Genet, 8(12), e1003168.
- Chun CD*, Brown JC*, Madhani HD (2011). A major role for capsule-independent phagocytosis-inhibitory mechanisms in mammalian infection by Cryptococcus neoformans. Cell Host Microbe, 9(3), 243-51.
- Brown JC, Lindquist S (2009). A heritable switch in carbon source utilization driven by an unusual yeast prion. Genes Dev, 23(19), 2320-32.