Seminar: Investigating Viral Infection Mechanisms In Situ, and Viral Immunity

ABSTRACT

Understanding the intricate mechanisms of viral entry is crucial for developing effective antiviral strategies. My research reveals the complete spectrum of intermediate stages in class I membrane fusion, using SARS-CoV-2 as a model. By leveraging cryo-electron tomography within a near-native fusion system that closely mimics the virus's entry mechanism, I have delineated the progressive stages of SARS-CoV-2 fusion with unprecedented detail. This study uncovers dynamic conformational changes in the Spike protein, transitioning from extended intermediates to fully folded states that precede fusion pore formation. These transitions are driven by ACE2 receptor binding and S2' cleavage, which induce structural rearrangements and Spike clustering at native membrane interfaces. Furthermore, cryo-ET and subtomogram averaging have provided novel mechanistic insights into S2-targeting antibodies, including their binding to the Spike's stem-helix on virions and their ability to inhibit fusion. These findings elucidate the complete process of Spike-mediated fusion and SARS-CoV-2 entry, highlighting the neutralizing mechanism of S2-targeting antibodies and offering significant insights for antiviral intervention.

BIOGRAPHY

Caner Akıl is a Senior Postdoctoral Research Scientist at the Nuffield Department of Medicine, University of Oxford. He received his PhD in late 2019 from the Agency for Science, Technology and Research (A*STAR), National University of Singapore (NUS), and subsequently worked at the Earth-Life Science Institute (ELSI) in Tokyo, Japan, as a Postdoctoral Fellow of the Japan Society for the Promotion of Science (JSPS), where he investigated the mechanisms and molecular evolution of the cytoskeleton using structural biology, protein biochemistry, and cell biology, making significant contributions to the field. At Oxford, his work centers on two main areas: (i) viral binding, membrane fusion, and the inhibition mechanisms of neutralizing antibodies; and (ii) immune signalling in health and disease, with a particular emphasis on the structural basis of antigen recognition by T cell receptors in viral infection and cancer. His research is driven by the development and integration of cutting-edge technologies, particularly in situ cryo-electron tomography, complemented by computational and biophysical approaches. Throughout his career, he has led numerous peer-reviewed publications in leading journals spanning topics cytoskeleton biology, molecular evolution, and infectious diseases