Molecular Pathobiology of Cryptococcus neoformans

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

Fungal diseases are a major source of morbidity and mortality globally. For example, cryptococcal meningitis (CM) is a severe disease that affects both HIV and non-HIV infected individuals with almost a quarter of a million deaths annually globally. Despite antiviral treatment of HIV, CM continues to be a problem in the U.S. with about 3000 infections annually. Attributable mortality remains at 30-50% despite therapy and no meaningful new anti-fungal therapies have been developed in the modern era. Candida is a second fungus that is a major source of morbidity and mortality and is currently the 4th major cause of blood stream infections. Our long-term objective is to assess the role of host and pathogen factors in the susceptibility and outcome of cryptococcosis to improve patient outcomes. 1) Host susceptibility to fungal disease and autoimmunity in candidemia. Candida albicans is an important pathogen that colonizes mucosal surfaces but little is known about events leading up to the pathogen invading the vasculature that results in its host invasiveness. Toward this end, we conducted an analysis of surface molecules on endothelial cells and identified a key molecule to which Candida hyphae bind, leading to invasion. Recombinant domains prevented binding and protected endothelial cells from binding by the fungus. Furthermore, analysis found a new biomarker that was associated with 30 day mortality in human candidemia. Structural studies are presently being conducted to validate and characterize these interactions. We also identified new roles of the biomolecule farnesol in the virulence of Candida albicans. 2) New drugs for fungal diseases. Our previous work showing the role of an encochleated form of amphotericin in combination with flucytosine was shown in pre-clinical studies to be efficacious against a mouse model of cryptococcosis. We have now published clinical studies have established safety and efficacy in 60 HIV+ patients in Uganda. The preparation was superior to intravenous amphotericin B in that it has equal efficacy and yet very little toxicity and could be given orally. It is thus a ‘game changing’ therapy that could be utilized at greatly reduced cost with little toxicity for a disease that currently continues to kill approximately a quarter of a million individuals yearly. 3) We have published a novel method, “pathway instructed therapeutics,” a non-biased approach for the identification of prominent signaling pathways in neuroinflammatory diseases. We have applied this in validation mouse models to confirm and identify mechanisms of a post-infectious inflammatory response syndrome identified in human studies of cryptococcal meningitis. These studies have identified a predominant role of the JAK/STAT pathway and the use of the JAK/STAT inhibitor ruxolitinib as an effective candidate agent for treating this syndrome. 4) Many cryptococcal genes have been identified to have the capacity to potentiate transmigration through the blood brain barrier in mouse models, but there is little information about mechanisms involved in human disease. We have utilized a cohort of human fungal isolates that either caused pulmonary disease or meningitis in transplant patients and utilized transcriptional analysis to identify a series of genes associated with transmigration to brains to cause meningitis. These were then further characterized in mouse models. Over expression of these genes increased transmigration through the blood brain barrier, facilitating brain infections. Mutations in regulators of these genes have been identified and represent potential new mechanisms for how cryptococcus became a neuropathogen.