Translational Research: Host-Pathogen Interactions in Patient Fungal Diseases

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

1) Improving treatment of cryptococcal meningitis. Cryptococcus neoformans is the most common cause of non-viral meningitis in the U.S. and the disease continues to have an attributable mortality of approximately 30% despite therapy. We have recruited approximately 150 patients with both meningoencephalitis and pulmonary disease. The protocol utilizes the latest in immunological and genetic methods and is divided in two parts: 1) to characterize and apply novel therapeutics to the acute phase of the disease to improve outcomes and 2) identify genetic and immunological risk factors involved in susceptibility to the disease during the convalescence phase. 1) Previously, we identified a syndrome in cryptococcal infections in CM, a post-infectious inflammatory syndrome, (PIIRS), which results in a dysfunctional activated immune response within the brains of patients after microbiological control of the organism with standard therapies. Immunological profiling identified several biomarkers of PIIRS. Within the restricted confines of the skull, this excessive immune activity causes the brain to swell and become dysfunctional, resulting in coma and death. In collaboration with NINDS (B. Bielekova, O. Khan and A. Nath) and the neurosurgical service of the NIH clinical center (P. Chittiboina), we have extended these studies by developing post to treat patients referred to the NIH clinical center. We recently reported 15 patients treated with pulse corticosteroid-taper (PCT) therapy that has resulted in reducing the mortality approximately 10-fold to less than 2%. We have also employed this therapy in a new report of PIIRS in a patient with Histoplasma meningitis as well as patients with solid organ transplants and a patient with a CD40L deficiency. Furthermore, we advanced a role for innovative treatment key to the rapid development of PCT as a precursor to clinical research in an opinion piece in the Journal of Clinical Investigation to show a role for rapid development of new therapeutics. 2) Host susceptibility to cryptococcal disease in previously healthy individuals. a) Autoantibody to host cytokines: Previously, in collaboration with S. Browne of LCID, we had identified patients with C. gattii, a related form of Cryptococcus with an autoantibody to the macrophage stimulator granulocyte-monocyte stimulating factor, GM-CSF. We are presently studying the regulatory pathway of GM-CSF signaling and have found that autophagy plays a key role in concert with the macrophage inflammasome pathway, suggesting novel mechanisms for intervention. b) Genetic Defects: We have currently performed whole exome sequencing on 105 patients with CM disease and have identified the PI3K-AKT-MTOR pathway to be predominantly affected in these patients as well as a number of other mutations in the inflammasome and miRNA-regulatory circuits that are under active investigation.