Project Details
Description
PROJECT SUMMARY
Invasive fungal infections are estimated to kill one and a half million people annually, with Cryptococcus
neoformans (Cn) infection resulting in almost half of all deaths due to fungal infection. Cn is rare in healthy
individuals, suggesting the immune system is able to prevent disease. Yet the high mortality observed clinically
suggests current antifungal drug treatments are inadequate in immunocompromised individuals. This paradox
suggests we are missing critical components of the Cn-host interaction. Characterization of cryptococcal cells
during infection has revealed that Cn produces a unique cell type - referred to as “titan cells” - during infection
that alter the host-pathogen interaction. These titan cells are produced in response to the host pulmonary
environment and are 5-10x larger than typical-sized Cn cells.
We demonstrated previously that titan cell production is critical for virulence and impacts dissemination to the
CNS. We further showed titan cell formation alters the host response by reducing phagocytosis and stimulating
a detrimental Th2-mediated response. The interaction between pathogens and their human hosts can be very
complex, and the outcome depends on both host and pathogen responses. The host must sense pathogen
associated molecular patterns (PAMPs), and then produce an appropriate immune response to kill the
pathogen. Conversely, the pathogen must sense and respond to the host environment to promote its own
survival. This proposal aims to identify critical alterations involved in the genesis of titan cells and their
progeny, as well as define how their unique cellular structure impacts the host immune response and thereby,
pathogenesis.
Titan cells have a number of unique characteristics, thus the focus of our proposed investigations are to
determine how these traits influence: 1) pathogen adaptation/survival in the host, and 2) alteration of PAMPs
recognized by the host immune response. Our previous studies showed titan cells undergo ploidy changes
associated with their formation and replication, and lead us to hypothesize these changes are critical for
adaptation and survival in the host environment. Therefore, our first aim is to define cell cycle regulation
needed to generate titan cells and their progeny. In our second aim, we will test the hypothesis that
alternations in the titan cell wall impact PAMP recognition by the host, with the third aim determining how this
altered sensing generates the detrimental immune response observed in response to titan cells.
These studies will ultimately coalesce into multi-faceted antimicrobial therapies that combine targeting pathogen-specific processes to limit pathogen adaptation and modulation of the host immune response to maximize
beneficial host responses to reduce disease.
Status | Finished |
---|---|
Effective start/end date | 4/25/18 → 3/31/24 |
Funding
- National Institute of Allergy and Infectious Diseases: $502,026.00
- National Institute of Allergy and Infectious Diseases: $502,026.00
- National Institute of Allergy and Infectious Diseases: $502,026.00
- National Institute of Allergy and Infectious Diseases: $502,026.00
- National Institute of Allergy and Infectious Diseases: $502,026.00
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