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Research Overview

Hospital acquired infections are on the rise.Infections from drug resistant pathogens are too common < CDC report >. Candida albicans, is 4th most common infection in hospitals. It is a commensal organism that colonizes virtually all humans, and can become a life threatening pathogen in susceptible individuals. The prevailing view is that reduced immunocompetence simply allows the reproduction of commensals that would normally be kept in check by the host. However, virulence and/or drug-resistance can increase rapidly during the course of an infection.

A major challenge to understanding the commensal to pathogen shift has been the difficulty in studying the process in a systematic and comprehensive manner in the context of a live host.  In preliminary studies we sequenced the genomes of dozens of Candida strains isolated over time from immunocompromised patients, and found that the commensal-to-pathogen shift includes persistent and recurrent genomic changes during infection. We further found that these changes are important for virulence in an experimentally tractable model of virulence, providing a model system to mechanistically and functionally characterize variants.  Some genes are found in multiple copies in fungi capable of a pathogenic lifestyle but not in non-pathogenic fungi underscoring the importance of duplication and diversification of these genes in pathogens. We use genomic approaches – in particular sequencing of the genome (DNA) and transcriptome (RNA) to build a regulatory network of genes important for pathogenesis. Next combination of CRISPR technologies and high throughput live cell microscopy provides an extraordinary opportunity to identify novel host factors in immune cells. Finally we employ non-conventional functional approaches to identify antimicrobials that can be widely useful as a novel therapeutic and/or as a prophylactic coating on medical devices.

Our research goal is to systematically decipher the molecular mechanisms that are important at the host–pathogen interface. Using state of the art high throughput genetic and genomic approaches we explore: 1. The regulatory network for key factors that regulate fungal virulence in a live host. 2. The specific mechanisms in innate immune cells that invoke appropriate response to specific pathogen insults. 3. The development of novel antimicrobials and/or prophylactic to manage the growing.