Research

Research in the Rosowski Lab is currently focused on the immune response to the fungal pathogen Aspergillus fumigatus.

A. fumigatus is estimated to cause disease in over 200,000 patients every year. We all inhale >100 spores of A. fumigatus every day from the environment, and yet only immunosuppressed people develop disease. If left untreated, A. fumigatus causes death in 100% of infected patients. However, even when patients are treated with frontline anti-fungal drugs, survival rates are still only ~50%.

Our research aims to combat this problem through two approaches:
1. Defining and harnessing pathways in macrophages to promote fungal clearance
2. Increasing our understanding of how and when anti-fungal drugs work in living hosts

Aspergillus fumigatus

Defining and harnessing pathways in macrophages to promote fungal clearance

Macrophages are one of the first immune cell types to respond to an infection. In larval zebrafish, macrophages phagocytose injected spores and form large clusters of cells surrounding the spores. And yet, these cells are not very good at killing the fungus and spores can remain alive in the fish for more than 7 days. The goal of this project is to better define and understand what genes and pathways in macrophages promote pathogen killing and what genes and pathways allow for pathogen persistence.

Long-term, findings resulting from these studies could be applied to the development of immunotherapies to treat infectious disease. Immunotherapies are currently used successfully to treat some cancer patients, by boosting the activity of the patient's own immune cells against a tumor. Similar principles could be applied in the context of infection. The immune system of patients could be amplified or modulated to help a patient's own immune system fight and kill pathogens.

Increasing our understanding of how and when anti-fungal drugs work in living hosts

Three main classes of anti-fungal drugs are used against Aspergillus infections in the clinic. The oldest of these, Amphotericin B, was first developed in the late 1950s, while the most effective drugs in the triazole and echinocandin families were developed more recently (after 2000). However, the efficacy of these drugs in patients is still poor, with one study from 2010 reporting that patients who underwent hematopoietic stem cell transplants and developed invasive aspergillosis had survival rates of only ~50%, even after receiving frontline anti-fungal treatment (Baddley et al., Clin. Infect. Dis.).

We aim to better understand a) how these drugs actually work inside an infected host and b) whether their efficacy depends on host immune status, extent of fungal growth, or other factors.

The results of this research will have implications for both how these drugs are used in the clinic and for developing a more successful pipeline for drug discovery in the future.