Center for Infectious Diseases Metabolomics at PHRI
Jyothi F Nagajyothi, Ph.D.
Associate Professor of Microbiology, Biochemistry & Molecular Genetics
The Center for Infectious Diseases Metabolomics (CIDM) at the Public Health Research Institute (PHRI) carries out metabolomics studies to improve prognosis, prevention and monitoring of many infectious diseases. Host-pathogen interactions are known to alter the metabolic state of both the host and the pathogen. Metabolic homeostasis in the host is regulated in part by the pathogen to promote its survival, persistence, and drug resistance. Many factors, including diet, exercise and drugs, affect the host metabolic homeostasis both during acute infection and, especially profoundly, during chronic infectious disease. The global profiling of small metabolites involved in micro (cellular) and macro (organ) physiology, such as glycolytic, TCA and pentose cycle metabolites, essential and non-essential amino acids, and lipid metabolites (fatty acids, acyl carnitines, phospholipids, di- and tri-glycerides), is a powerful approach to study pathophysiology and to predict cellular and organ function. The CIDM is focused on identifying novel metabolomics biomarkers that will help diagnose and prevent infectious diseases including tuberculosis, Chagas Disease, HIV, multi drug resistant bacterial infections, fungal infections, etc.). The CIDM supports investigators in the design and execution of multi-faceted metabolomics studies of infectious disease.
The CIDM is developing and applying mass spectrometry-based quantitative global analysis of endogenous metabolites from cells, tissues, fluids or whole organisms at different stages and states of infection. The CIDM also provides a resource facility for storing biopsy samples.
The objective of the CIDM is to help the investigators studying infectious diseases and interested in carrying out metabolomics studies as follows:
- Providing support in the development of a research study
- Finding potential collaborators and funding
- Matching your research needs with resources available at CIDM, PHRI Rutgers and other collaborative centers (e.g. imaging mass spectroscopy, grant writing assistance, data management services, outsourced services, and more)
- Identifying mentors and collaborators for your project from within the International Center for Public Health, from other institutions, and from the scientific community at large
- Offering educational programs and workshops
By fitting our services to the individual needs of each investigator/team, we provide seamless support from concept to closure.
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.
In the Vinnard lab, we are interested in the patient factors that relate to variability in the pharmacokinetics and pharmacodynamics of anti-infective therapies, with a focus on anti-tuberculosis therapies. Of particular interest are the metabolic and immunologic characteristics that are drive differences in drug absorption, distribution, and metabolism. Current efforts in our laboratory are focusing on the expression and activity of membrane drug transporters and key drug metabolizing enzymes relevant for anti-TB therapies. The goal of this work is to link the observations of low anti-TB drug serum exposures in patients with diabetes mellitus or HIV infection with a mechanistic understanding of the regulation of drug pharmacokinetics in the context of metabolic or inflammatory disease.
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.