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.

Infected zebrafish

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.

Host and pathogen determinants of infection spread and dissemination

Work from two recent PhD graduates shed light on both how the growth shape of Candida and host cells and processes combine to allow the non-motile fungus to move from tissue to tissue and spread the infection. Using transparent zebrafish, Brittany Seman discovered that only the yeast form of Candida can disseminate; the filamentous form instead damages tissue and causes death. Allison Scherer found that Candida can either use host macrophages as Trojan Horses to get to new areas of the host.  In the absence of macrophages and neutrophils to attack it and move it around, Candida can also get through into the bloodstream and spread through the circulation. These complementary mechanisms of dissemination make Candida a successful pathogen in different host conditions.

Polymicrobial infections and their effect on antimicrobial drug action

Our recent published work has shown two surprising aspects of Candida interaction with the bacterial pathogen Pseudomonas aeruginosa. Surprisingly, we found that the microbes have enhanced virulence during co-infection of the zebrafish. This suggests that they can promote each other’s growth and virulence in the face of immune attack. But this enhanced virulence comes at a cost for the fungus, Candida, because it then becomes exquisitely sensitive to the antifungal drug fluconazole. In the presence of P. aeruginosa, fluconazole changes from a fungistatic to a fungicidal drug and kills the Candida instead of just slowing its growth. In the future, we plan to discover how P. aeruginosa causes this enhanced effect against Candida and which pathways it affects in the fungus.