1). GM-CSF-mediated epithelial to neutrophil crosstalk licenses sterilizing antifungal immunity in the lung
2). Plasmacytoid dendritic cell to neutrophil crosstalk regulates neutrophil NADPH oxidase activity and innate antifungal immunity in the lung
3). Loss of neutrophil antifungal effector functions by pharmacologic blockade of Bruton’s tyrosine kinase
4). Microbiota-mediated colonization resistance against Candida parapsilosis in the intestinal tract
5). Immune-mediated control of Candida parapsilosis homeostasis in the in the intestinal tract
6). Interaction between antiviral and antifungal immunity in the lung
The focus of my research program is to decipher the molecular and cellular basis of immunity against Candida and Aspergillus species, major causative agents of invasive mycoses in patients with cancer. We have developed fluorescence-based reporters of fungal physiology to examine the outcome of fungal cell-host cell interactions with single-encounter resolution at the portal of infection. Fluorescent Aspergillus reporter (FLARE) conidia (i.e., vegetative spores, the infectious fungal propagule) change their fluorescence properties when phagocytes inactivate fungal cells at the portal of infection (Figure 1). Using this bioreporter, we quantify host leukocytes on the basis of fungal cell uptake and killing of internalized conidia.
Figure 1
This technique enables us to examine leukocyte effectors implicated in fungal uptake and killing, identify and functionally characterize the antifungal activities of neutrophils, monocytes, plasmacytoid dendritic cells, and epithelial cells, and to analyze fungal genetic circuits implicated in pathogenesis. A major goal of this research is to develop an integrated model of sterilizing barrier immunity against inhaled mold pathogens.
We harnessed a human bone marrow transplant cohort to examine the relationship of the mycobiota, endogenous fungal communities, with invasive fungal disease. We discovered that fungal dysbiosis and intestinal domination precedes bloodstream invasion and is a marker for transplant outcomes. We are investigating the intestinal tract as a site in which Candida species acquire heteroresistance to antifungal prophylaxis (echinocandin drugs) which leads to antifungal prophylaxis failure and life-threatening systemic disease (Figure 2).
Figure 2
Biography
Distinctions.
Member, American Academy of Microbiology (2021)
NIH Merit Award Nomination (2021)
Fellow, European Society of Medical Mycology (2019)
Member, American Society of Clinical Investigation (2016)
Investigator in the Pathogenesis of Infectious Diseases Award, Burroughs Wellcome Fund (2014)
Fellow, Infectious Disease Society of America (2012)
Young Investigator Award, American Society of Microbiology (2009)
