Saturday, November 23, 2024
11/23/2024
Exceedingly high mutation rates permit most RNA viruses to rapidly explore protein sequence space. On the other hand, high mutation rates also result in widespread production of viral protein variants with poor biophysical properties and severe folding defects. Protein variants that cannot fold successfully are removed from the population, even if they could otherwise confer a beneficial adaptive function. Recent work has revealed that the composition and activities of the host cell’s protein folding and quality control machinery (the proteostasis network) play a central role in defining the amino acid sequence space accessible to rapidly evolving RNA viral proteins. This phenomenon has so far largely been explored using proteostasis modulation itself as the selection pressure. It is not yet clear whether host cell chaperones are directly – by enhancing viral protein folding – impacting the ability of viruses to adapt to and escape from external selection pressures stemming from the host’s adaptive immune system, antiviral drugs, or other factors. Using influenza as a model system, this proposal integrates state-of-the-art chemical biology, genetic, biochemical, biophysical, and computational methods to comprehensively evaluate and elucidate, at the molecular-level, the emerging and complex interplay between host proteostasis and viral adaptation in the context of diverse selection pressures. Aim 1 focuses on the mechanism by which hijacked host chaperones promote influenza escape from innate immune system factors, establishing biophysical origins of host chaperone-dependence in influenza nucleoprotein evolution and elucidating whether and how the virus can readily adapt to challenging host proteo- stasis environments. Aim 2 establishes how the composition and activities of the host cell’s endoplasmic reticulum proteostasis network impact the ability of influenza hemagglutinin, the primary target of influenza-neutralizing antibodies, to escape selection pressure from the adaptive immune system. Aim 3 operates on a broader scale to understand how host proteostasis networks impact genome-wide mutational tolerance and influenza error catastrophe, a phenomenon in which increasing viral mutation rates past a certain threshold causes population extinction. Experimental findings from all these Aims are integrated with protein biophysical studies and computational modeling to illuminate molecular origins of host proteostasis-dependent viral adaptation. This work is expected to establish host proteostasis as a defining force that shapes viral adaptation, particularly in the context of highly relevant selection pressures. Beyond fundamental elucidation of viral evolution, findings will greatly enhance understanding of the factors involved in viral adaptation to host selection pressures and, in the longer-term, improve the ability to accurately predict viral evolution. Discoveries are also expected to highlight the potential of therapeutic adjuvants targeting host chaperones to enable treatment regimens to which viruses cannot easily evolve resistance. Contributions will impact fields ranging from basic virology and vaccine and antiviral drug development to evolutionary biology and protein folding biophysics.
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