Respiratory viral infections remain a significant health burden in the human population, and there exist limited resources for the treatment of many of these pathogens, including influenza (IAV) and respiratory syncytial virus (RSV). The current proposal brings together a team of researchers with diverse expertise in medicinal chemistry, virology, and RNA processing to explore novel approaches to control these infections. As obligate parasites, viruses depend on host cellular processes for new virus assembly, rendering both viral and host molecules potential targets, and most drug development has focused on protein components. Members of our group, however, have previously identified inhibitors of HIV-1, picornavirus, and coronavirus replication from libraries of both RNA binding molecules and RNA processing inhibitors. With funds provided, we propose to perform similar screens to identify compounds able to suppress IAV and/or RSV replication by altering viral RNA-host protein interaction or viral RNA processing. Once compounds are identified, additional work will establish the stage of virus replication affected. Upon completion, the studies will provide lead compounds for further commercial development as well as insights into alternative strategies to control IAV and/or RSV replication.

In addition, this proposal will serve to integrate Professor Amanda Hargrove, newly named Canada Research Chair in RNA-targeted Drug Discovery, into the EPIC research landscape. Hargrove recently (July 2024) moved her laboratory to the Centre for Medicinal Chemistry at the University of Toronto Mississauga after 11 years at Duke University (USA) where her lab published compounds targeting regulatory RNA in HIV, EV71, and SARS-CoV-2.

Sterile site infections, such as those affecting the brain, heart, and eyes, can cause severe disease morbidity and mortality. Rapid accurate diagnosis is critical for effective treatment. However, the wide variety of possible pathogens—viruses, bacteria, fungi, and parasites—is a key unaddressed challenge. Currently available testing methods are time consuming, require multiple tests, performed at several testing laboratories, and often are limited in the pathogens they can detect. Internal infections of the eye serve as a useful model to develop improved diagnostic tests because they present similar challenges as other sterile site infections. The aim of this project is to develop a rapid molecular, all-in-one, test that can identify nearly all pathogens causing eye infections. We will design a custom panel to detect over 95% of ocular infections and use next generation sequencing technology to identify the causative pathogens. Performance will be evaluated compared to current testing standards, and will also be compared to current diagnostic tests on the basis of cost and turnaround time. The test being developed in this project has the potential to reduce the time to diagnosis, increase test result accuracy, lead to faster initiation of therapy, improved patient care/outcomes (e.g. preserving vision), and lower total cost of testing. In addition, the development approach used here to design and test this custom panel for eye infections can be used to further develop rapid all-in-one diagnostic tests for diagnosis of infection at other body sites where the potential for disease and mortality are also high.

Fungal infections cause 150 million severe cases and 1.5 million deaths annually, yet research on fungal pathogens remains limited. The WHO has urgently called for research on fungi like Candida albicans, due to rising resistance and the limited availability of antifungal classes. Two major gaps in knowledge exist: lack of chemical diversity and druggable targets. For millennia, plants emit symbiosis compounds into soil to acquire nutrients from fungi or inhibit fungal infections. Our outside-the-box strategy is to harness plant symbiotic compounds as novel sources of antifungals. We have developed a yeast-based pipeline that successfully identified a conserved fungal target of a plant symbiotic signal. Our approach led to the identification of a new compound class and druggable target in fungi.

We will leverage transcriptomics, genome-wide mutant collections, and CRISPR-based tools to validate the compound’s target and antifungal mechanism. Our proof-of-principle study will unlock new sources of antifungal drugs and druggable targets, impacting the fight against deadly fungal infections.

Measles is a highly infectious, acute viral illness that can lead to severe complications. It is preventable by vaccination, but recent outbreaks in Canada have been occurring in susceptible populations. In the face of this global and local measles resurgence, we expect an increase in imported cases presenting for healthcare, which has led to a review in infection prevention and control and occupational health practices to ensure adequate protection for healthcare workers (HCW). Of particular interest is HCW immunity to measles.

While hospitals require proof of vaccination or immunity for onboarding, it is acknowledged that documentation may be suboptimal at several institutions, especially for HCWs that have been employed for longer periods of time. It is therefore essential to get a better understanding of measles immunity in HCWs to ensure that measles exposures in healthcare settings do not result in outbreaks, as has occurred in other jurisdictions.

We have previously completed a multicenter study at 15 hospitals across Ontario assessing SARS-CoV-2 seropositivity. As part of this study, we collected demographic information and stored serum on over 3000 HCWs and obtained consent from the majority of participants to perform additional testing on the stored sera. The primary objective is to determine the proportion of HCWs that are seropositive for measles and characterize how seropositivity varies by age, sex, ethnicity and role in the healthcare system.