Grant: CIHR Strategic Master's Award - Pandemic Preparedness and Health Emergencies

We are now acutely aware of the threat posed by viruses, and more are poised to emerge. Filoviruses, a group of viruses including Ebola virus (EBOV), have pandemic potential and cause deadly outbreaks with mortality rates of up to 90%. Outbreaks are occurring with increasing frequency as the geographical range of bats carrying these viruses expands. Not all filoviruses are deadly but we are not sure why this is, nor do we understand how bats harbour viruses without experiencing disease. Toll-like receptor 4 (TLR4), an immune receptor, is thought to influence the severity of EBOV disease. A specific EBOV component called the glycoprotein activates TLR4, which can cause excessive inflammation leading to death. SARS-CoV-2 Spike and viral glycoproteins of other emerging viruses also activate TLR4, although the mechanisms are poorly understood. I propose to investigate how TLR4 activation is influenced by differences in filovirus glycoproteins, genetic variation in TLR4 receptors expressed on immune cells, and genetic differences in TLR4 between bats and humans. I will compare glycoproteins of filoviruses that do and do not cause disease in humans to study virus-related factors affecting TLR4 activation. I will investigate how genetic differences in TLR4 present in the human population impact responses to filovirus glycoproteins. Finally, I will compare bat and human TLR4 activation to help explain how bats harbour and transmit viruses without becoming ill. Studying the interaction of filovirus glycoproteins with TLR4 will provide a model for understanding other novel viruses with pandemic potential. We may be able to prevent pandemics if we can predict the risk of emerging viruses. We can improve our pandemic response by understanding why some individuals experience more severe disease. Understanding what makes bats resistant to viral disease will inform new treatment approaches to prepare us for future viral outbreaks and pandemics.