Using a Transcriptional Network to Approach the Mechanism of Fungal Meningitis

Abstract

C. neoformans is the most common cause of fungal meningitis, but the molecular mechanisms of pathogenesis remain poorly understood. The pivotal pathogen transcriptional regulator Gat201 inhibits phagocytosis independently of the polysaccharide capsule and plays a central role in virulence (1). To define the corresponding transcriptional network, we performed chromatin immunoprecipitation and sequencing (ChIP-Seq) and expression profiling (RNA-Seq) experiments of Gat201 and two other transcription factors, also required for virulence, regulated by Gat201 that comprise a regulatory network intimately tied to C. neoformans' virulence. Within the set of genes whose promoters are bound by all three transcription factors assayed, there are three members of a six-member protein family in C. neoformans (Blp1-6), characterized by an N-terminal signal sequence and a double-psi beta barrel motif. One member of this family, Blp1, inhibits phagocytosis through an unknown mechanism (1). In addition, we found that the promoter of a peptide required for low-density growth of a C. neoformans tup1Δ mutant strain background is also bound by all three transcription factors (2). We are currently investigating the functional roles of these secreted proteins and their biochemical mechanisms of action.(1) Chun CD, Brown JCS, and Madhani HD. (2011) A Major Role for Capsule-Independent Phagocytosis-Inhibitory Mechanisms in Mammalian Infection by Cryptococcus neoformans. Cell Host & Microbe, 9: 243-251.(2) Lee H, Chang YC, Nardone G, Kwon-Chung KJ. (2007) TUP1 disruption in Cryptococcus neoformans uncovers a peptide-mediated density-dependent growth phenomenon that mimics quorum sensing. Molecular Microbiology 64(3): 591-601.