Candidate. My career goal is to improve the detection and management options for disseminated infectious
diseases through investigation of host-microbe interactions. I plan to pursue this with a tenure-track appointment
as junior faculty with significant protected time for basic research. In the short term, my goal is to broaden my
skills as an investigator and build the foundation for my transition to independent research. The education
aspects of this proposal center around experimental mycology and gene expression analysis, new skills which
will enable me to improve our understanding of disseminated fungal infections from both host and pathogen
Research. Cryptococcal meningoencephalitis is a devastating disease most common in the
immunocompromised, such as AIDS or transplant patients. The brain infection is very difficult to treat and can
occur months or even years after the initial exposure—often an unnoticed pulmonary infection. Thus, the fungus
is thought to exist in a quiescent state for long periods in healthy individuals, and while in this state does not
appear to be susceptible to antifungal treatment. A better understanding of the quiescent state, how it is initiated
and maintained, should provide us with better detection and management tools and give us the chance to
manage this quiescent infection before it causes a deadly disease.
The zebrafish larva as a model host allows direct monitoring of microbial pathogenesis in vivo. In contrast
to findings in cell culture models, in the zebrafish we find that inoculated Cryptococcus can have multiple fates,
including clearance, replication and dissemination, or quiescence within phagocytes. This quiescent state, which
can last for as long as long as the larva is viable, is common after spore infection but rare when larvae are
inoculated with the yeast form. I will use spore infection as a model for early quiescent infection. The proposed
experiments are designed to define the features of the host response that allow for persistence, and to define
the state of cryptococcal cells that induce this response.
Career Development Plan. During the proposed research period, my primary goal will be to carry forward my
previous work in innate immunity to cryptococcal infection while adding considerations of fungal biology to my
approach to the disease. I will also obtain new training in gene expression analysis, biostatistics and fungal
biology through mentoring, hands-on bench research and didactic learning. Along with this I plan to develop new
skills in leadership, mentoring and management to enable my transition to independence. I plan to coordinate
my research and training activities to build toward a successful R01 application in the fourth year of the award.
Environment. I will be well supported in the Department of Pediatrics at the University of Wisconsin-Madison.
The institution is replete with a scientific and medical faculty of diverse backgrounds and interests, and the
infrastructure for computing, biotechnology, laboratory animal care and microscopy are excellent.