Immune protection and disease during host-fungal interactions
The overarching theme of my research is to better understand why humans develop fungal infections. Through studying the molecular responses by fungi and the mammalian host that skew health towards disease, we can leverage these insights for personalized medicine. Fungi are encountered very early in life, yet for the majority of healthy individuals these interactions lead to benign commensalism at mucosal surfaces (i.e. Candida (Ca)) or clearance /dormancy within the host (i.e. Cryptococcus (Cn)). This indicates that the human immune system appropriately senses fungal pathogens and elicits effective immune responses. This isn’t true for all individuals. Recently, with the advent of novel immunosuppressive pharmacological agents, fungal infections in the previously healthy are becoming more prevalent, underscoring the need to determine the molecular basis for immune dysfunction altering fungal-host immune interactions towards disease. My lab’s approach is innovative in that it allows the study of human genetic and lifestyle factors to drive discovery of immune correlates of protection and disease. These discoveries will have major clinical implications for the treatment of all patients with fungal infections. Also, it will help identify future patients at risk for developing disease and aid in development of novel therapies to restore specific immune responses deficient in specific patient populations.
Understanding the molecular and immunologic mechanisms behind genetic susceptibility of previously healthy patients to severe cryptococcosis.
Cn species have a global impact on human health as an environmental, opportunistic fungal pathogen that most commonly presents as pulmonary disease or meningoencephalitis (CM) causing an estimated 180,000 deaths annually. In 2022, the WHO identified Cn as a fungal pathogen of critical priority. Indeed, because of reductions in vaccine preventable bacterial meningitides, CM has become the most common cause of non-viral meningitis in the US. Despite antifungal therapy, the previously healthy (PH) population-without obvious immune dysfunction-carries a mortality rate upwards of 30-50%, underscoring the need to understand the pathophysiology of CM and its associated post-infectious inflammatory response syndrome (c-PIIRS). Very little is known about the molecular mechanisms driving the immune defects that lead to cryptococcosis in the PH. Analysis of human genetic variants related to primary immunodeficiencies associated with cases of cryptococcosis in this population provides an effective and the most direct method to define specific immune defects; however, thus far only a few have been identified. The long-term goal of my lab will be to identify and validate the major genetic, host lifestyle, and immunological determinants of Cn– and c-PIIRS susceptibility (Figure A). These discoveries will have major clinical implications for the treatment of cryptococcosis as it will not only help identify future patients at risk for developing disease, but also aid in the development of novel therapies to restore specific immune responses deficient in patients (Figure B). Finally, it will help to construct new paradigms to understand Cn-human interactions.
Dr. Jessica C. Hargarten received her B.S. from the University of California, Davis and her Ph.D. from the University of Nebraska-Lincoln. She did her postdoctoral training at the National Institute of Allergy and Infectious Diseases (NIAID) and the NIH Clinical Center under the mentorship of Dr. Peter R. Williamson, MD/PhD in the Translational Mycology Section where she began to uncover the genetic and immunologic factors underlying human susceptibility to invasive fungal disease. Her work also identified the predominant pathway underlying a post-fungal infection inflammatory syndrome and a new treatment modality for cryptococcal- post-infectious inflammatory response syndrome in patients. After her training, she moved to Rutgers where she is an Assistant Professor in the Department of Pathology, Immunology, and Laboratory Medicine and member of the Center of Immunity and Inflammation. Dr. Hargarten’s long-term research goal is to define and interrogate human genetic, immunologic, and lifestyle factors that skew immune responses towards severe disease following fungal infections in previously healthy populations in order to inform precision medicine approaches to care and treatment. Her lab utilizes relevant in vivo and in vitro models of disease and clinical samples to further determine the role of these genes (particularly MTOR pathway genes) in immunity and susceptibility to disease caused by the fungus Cryptococcus. Her research is currently supported by extramural funding from NIAID.