Center for Infectious Diseases Metabolomics at PHRI

The research in the Chauhan lab focuses on the biology and disease mechanisms of fungal pathogens of the Candida genus, predominantly C. albicans and C. glabrata. Over the last decade, we have focused our efforts on the discovery and characterization of fungal virulence factors. We are interested in understanding the fungal-host interactions and the mechanisms through which chromatin-mediated gene regulation modulates the commensal-pathogen switch in Candida spp. Current research is focused on a principally novel and unexplored area of Candida biology – the role of post-translational modification of proteins via lysine acetylation. Lysine acetylation is a well-established major mechanism of regulating protein function, and lysine acetylases (KATs) have been shown to play important roles in many cellular processes. However, while C. albicans contains several conserved lysine acetylases, their functions in fungal morphogenesis and virulence have remained unexplored. Current efforts are focused on deciphering the molecular roles of KATs/KDACs in fungal virulence, especially concerning the non-histone lysyl targets of KATs/KDACs. Our approaches include genetic, biochemical, immunological, proteomic and metabolomics techniques for the study of fungal-host interactions.

Nutritional immunity is a component of the innate immune response that reduces availability and restricts access of infecting microorganisms to essential micronutrients, like metal ions. The Rodriguez lab investigates the adaptive response of M. tuberculosis to iron deficiency imposed by the host. Because iron is essential for basic cellular functions, M. tuberculosis reprograms its metabolic activity in response to iron limitation. We are currently studying the metabolic signature of iron-limited M. tuberculosis to dissect its adaptive response to the host environment and identify new targets of therapeutic intervention. We also hope to identify metabolic markers of M. tuberculosis persisting in the host for diagnostic applications.

The Nagajyothi lab is currently analyzing the effect of metabolic regulators, such as drugs and diets, on the pathogenesis of chronic infectious diseases like Chagas disease and M. tuberculosis. The survival and persistence of the pathogen depends on the metabolic status and the immune response of the host. The metabolic status of the host can regulate immune response and vice-versa in chronic infections. Our objective is to identify key metabolites as biomarkers (both host and pathogen) that can be used as a therapeutic targets to prevent the pathogenesis of chagasic cardiomyopathy. In collaboration with Drs. Vinnard and Subbian we have initiated studies to elucidate the cross-talk between TB and Type-2 diabetes using a metabolomics approach.

The Pinter lab is currently characterizing the human humoral immune response to M. tuberculosis antigens. We are utilizing a retroviral vector generated in our lab that transduces several genes that stabilize memory B cells to long-term culture in vitro. These cells can be selected by binding specific antigens, and used to clone out the heavy and light chain antibody genes for further expression and characterization. Our initial studies are focused on surface glycolipids, particularly lipoarabinomannan (LAM), which are potential targets for point-of care immunodiagnostic applications. We hope to extend these studies to additional M. tuberculosis targets, and eventually to other bacterial pathogens as well. These antibodies will be useful for identifying and quantitating pathogen-specific biomarkers and metabolomics. In addition to diagnostic applications, we expect that many of these antibodies may possess therapeutic activity as well, and that these could be useful for treatment of antibiotic-resistant strains.

The Xue lab studies how human fungal pathogens sense extracellular signals and control intracellular signal transduction pathways that are important for cell development and virulence in Cryptococcus neoformans. Their approach is to apply genetics, biochemistry and molecular biology to investigate fungal-host interactions. They are particularily focused on the regulation of inositol metabolism and inositol-mediated signal pathways in fungal development and virulence. They demonstrated that inositol, an abundant metabolite in the brain, promotes fungal traversal of the BBB and plays a critical role in host-pathogen interactions during infection of the central nervous system (CNS). They showed that C. neoformans utilizes the inositol stores of its plant niches to complete its sexual cycle. C. neoformans is likely to be uniquely adapted to thrive in the inositol-rich environment of the CNS and to utilize inositol-dependent pathways for pathogenesis. Their preliminary results suggest that inositol can promote formation of a unique capsule structure enriched in M3 mannosyl triad structure reporter group that can help the fungus evade the host immune response. They aim to define inositol sensing and metabolic pathways required for modifying fungal cell surface structure by employing fungal mutagenesis analysis, metabolomic assays and polysaccharide structural analysis. They will attempt to elucidate the transcriptional circuits regulating inositol functions during cryptococcal infection. They will characterize the mechanisms of inositol-mediated promotion of Cryptococcus BBB crossing and CNS infection using an in vitro model of human BBB and animal infection models of CNS cryptococcosis.