Cryptococcal meningitis (CM) is a severe disease that affects both HIV and non-HIV infected individuals with almost a half 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 since the 1950s.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) Role of autophagy in fungal disease and autoimmunity. Autophagy is an essential process whereby cells auto-eat portions of their cellular contents during periods of stress. Previously, we showed that fungal pathogens including Cryptococcus neoformans utilize this pathway to protect themselves within the stressful host environment by recycling nutrients when deprived of these by the host. Mammalian hosts including humans have adopted and modified this primitive autophagy mechanism to modulate host immunity in response to pathogen invaders. It also uses autophagy to dampen down host immunity, so it does not run away with itself and cause damage to the host. Using both C. neoformans and mouse models we have identified a novel post-transcriptional regulatory pathway that uses a central regulator, the target of rapamycin (TOR) to signal a controlled destruction of mRNA transcripts of autophagy. This pathway can provide important therapeutic strategies to a broad range of patient diseases including those with fungal or viral infections, autoimmunity and cancer. We previously used this new-found knowledge to understand excessive inflammation in a series of patients with a PIK3CD/p110 gain-of function mutation that present with autoimmune cytopenias. Presently, in collaboration with G. Azul in LCID, we are using this pathway to understand why patients with mutations in an autophagy gene are unable to mount an immune response to viral infections and develop lymphoproliferative processes within lung and brain. We are also applying this regulatory pathway to a role in TOR-dependent T-cell polarization which influences how a patients immune system responds to both cryptococcal fungal infections as well as neuro-inflammation (autoimmune encephalitis in mice) and are presently applying this to understanding the role of altered T-cell polarization in patients with mutations in the gene encoding cytotoxic T-lymphoctye-associated protein, CTLA-4. Furthermore, we have developed a specific monoclonal antibody reagent that can be used to quantitate TOR-dependent phosphorylation of a key player in this pathway, the mRNA degradative enzyme, Dcp2 to allow personalized tailoring of therapy of immune suppressing drugs such as rapamycin (sirolimus) as well as several new PI3K-directed therapies that alter TOR. 2) New drugs for Cryptococcal disease. Fungicidal activity of a drug is particularly important in cryptococcal meningitis where fungistatic drugs such as fluconazole have a 100% mortality despite therapy. In collaboration with the National Center for Advancing Therapeutics, we identified a novel drug target that results in fungicidal activity against Cryptococcus neoformans. We are also conducting pre-clinical studies in collaboration with Matinas Biopharma, to develop an orally available cochleate formulation of amphotericin B for CM.
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