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 6000 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. Our previous work characterized the role of mammalian DDX6 in the post-transcriptional regulation of autophagy, a process of cellular protein turnover that regulates the inflammasome-associated cytokine IL1B and associated this new regulatory pathway with autoimmunity in a series of patients with PIK3CD/p110 gain-of function mutations. We have now utilized PAR-CLIP to identify a series of micro-RNAs that form partners with the targeted mRNA for recruitment and decapping by the DCP2-DDX6 complex. We also collaborated with the Serini laboratory (HIV pathogenesis Section) to identify the role of autoantibodies in idiopathic CD4 lymphopenia as well as the Deepe laboratory (Univ. Cincinnati) in the role of zinc in intracellular killing of fungi by macrophages. We also expanded the role of the newly developed animal model of cryptococcal post-infectious inflammatory response syndrome (PIIRS) in collaboration with M. Olszewski, Univ. Michigan, by showing the role of the chemokine receptor CXCR3 in this inflammatory condition. 2) New drugs for fungal diseases. Our previous work showing the role of an encochleated form of amphotericin has now been advanced to a clinical trial in Uganda and has thus far been shown to be well tolerated. Efficacy studies are now ongoing as part of an NIH-funded randomized controlled clinical trial NCT04031833. This trial has currently enrolled approximately 60 patients thus far with good safety and tolerability. Efficacy is unknown as the study has not been unblinded yet, but mortality overall has been about 6% which compares to historical mortality of 20% in this population and rates of CSF fungal clearance in all groups have been acceptable. We have also conducted a screen of over 4000 pharmacologically active compounds to find novel agents against the emerging pathogen Candida auris. C. auris has recently developed in a number of hospitalized settings globally and has been reported to be highly resistant to standard anti-fungals and to have a strong ability to persist in inanimate objects in the hospitalized setting. These studies, in collaboration with the National Center for Advancing Therapeutics identified several new agents including those targeting the sphingomyelin synthesis pathways integral to fungal virulence. Virulence-associated signaling in Cryptococcus. We have demonstrated the role of the ESCRT pathway in trafficking and secretion of the virulence factor laccase in C. neoformans. Laccase is an important virulence factor in the fungus and understanding mechanisms of expression may provide novel drug targets.