Fungal host-pathogen interaction
There is an ongoing war between microbial pathogens and their hosts.For each mode of host immunity, the challenger has designed a defense, which in turn leads the host to devise a new avenue of attack. Opportunistic pathogens such as the fungus Candida, a leading cause of hospital-acquired infection and an increasingly important killer, must be able to constantly evade the attacks of the host and exploit any break in host defense caused by a compromise of immunity. The host, in turn, depends to a large part on innate immune responses to protect itself against this fungus. Using high throughput cell biology and genetics, we are elucidating this ongoing battle between fungi and host from both sides of the conflict.
Our work attacks fundamental biological questions that have clinical relevance. In the near term, we expect to understand the normal host-pathogen interaction in disease and during drug treatment. In the long term, we expect to identify new means to prevent and treat fungal infection through attacking the fungus and modulating immune response.
Microbial strategies for resisting immune attack
Candida is recognized by the innate arm of the immune system through evolutionarily conserved fungal surface molecules. Although innate immune cells can recognize several different surface molecules, the fungus can cover some molecules to tailor the immune response.
The sugar β-glucan is present throughout the cell wall of Candida, but as we discovered, the pathogen masks β-glucan from immune recognition to mute immune response. We discovered that a potent antifungal drug has an unexpected side-effect and can cause increased exposure of β-glucan in addition to killing fungi.We are devising and exploiting novel methodology to look at the clinical consequences of treating fungal infection with this antifungal drug.
Host strategies for clearing fungal pathogens
We have recently begun using a transparent zebrafish model to probe host-pathogen interactions (see Publications Webpage). This model permits the real-time visualization of innate immune attack. Using this model, we have found that Candida-innate immune interactions differ in vivo from our expectations based on in vitro experiments. We are currently using this model to probe the cellular effects of loss of phagocyte NADPH oxidase function. In the future, this model holds promise for understanding the molecular mechanisms that regulate Candida interaction with innate immune cells, endothelial cells and epithelial cells.