Pandemics are periodic events characterized by rapid and widespread transmission of infectious disease affecting a significant proportion of the population over a large geographical area. Zoonotic strains of influenza viruses and coronaviruses have both caused pandemics in the recent past. Although vaccination is the often the most effective way to prevent infection or serious outcomes of infection, vaccine development, production, distribution, and deployment are all time- consuming and logistically challenges processes. Alternative readily deployed approaches must be quickly executed to mitigate the toll of future pandemics, especially during the early phases. The work described in this thesis describes some of these approaches.
Firstly, I describe the process by which I performed genome-wide CRISPR-Cas9 knockout screens using SARS-CoV-2 variants of concern to discover crucial host factors as targets for broad-acting antivirals. I found that all variants rely on similar host pathways to replicate in the glial cell line used for the screen. I identified BCL-xL, a regulator of apoptosis, as a potential target for a broad- acting antiviral. I show that chemical inhibition of BCL-xL results in accelerated cell death in infected cells in vitro, but improved clinical signs and disease mortality of SARS-CoV-2 in our murine infection model.
Secondly, I describe a unique mechanism for cooperative antiviral combination therapy. I demonstrate that chemical inhibition of neuraminidase by oseltamivir improved immune effector cell activation by hemagglutinin stalk-binding antibodies. Combination therapy of oseltamivir and stalk-binding antibodies also improved clinical signs and disease mortality of influenza in our murine infection model compared to monotherapy in both prophylactic and therapeutic contexts.
Finally, I show that non-pharmaceutical public health interventions used to restrict the spread of COVID-19 were also effective against several other infectious diseases. I used an interrupted time- series analysis on Ontario public health administrative data during the early COVID-19 pandemic period and found a drastic and sustained decline in outpatient visits for diseases that are typically caused by viruses that transmit by droplet or aerosol.
The three projects described in this thesis outlines broadly-protective and distinct strategies to curb the spread of novel respiratory viruses. These new tools may be leveraged to improve the response and to mitigate the burden of future pandemics. / Thesis / Doctor of Philosophy (PhD) / Most pandemics in recent history have been caused by viruses that infect the respiratory tract. Vaccination is often the best way to prevent the spread of these pandemic viruses, but making these vaccines takes time. Vaccines also work less well in the very young, the elderly, and those with a compromised immune system. These people are often also the most vulnerable to severe disease. My work describes three novel approaches to help combat the next pandemic, especially during the early phases when vaccines are still being developed, or for the segments of the population that respond poorly to vaccination. These include discovering and using new drugs that work against a wide range of viruses, using combinations of previously-discovered antiviral drugs, and using non-pharmaceutical methods such as physical distancing and wearing masks.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/29730 |
| Date | January 2024 |
| Creators | Zhang, Ali |
| Contributors | Miller, Matthew, Biochemistry and Biomedical Sciences |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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