Receptor binding and antibody neutralization escape of emerging RNA viruses

Abstract

Emerging RNA viruses present a continued threat to humans around the globe. Recent threats, such as the Ebola virus outbreak in 2013, Zika virus epidemic in 2014, and the ongoing severe acute respiratory coronavirus 2 (SARS-CoV-2) pandemic, have demonstrated the capacity of RNA viruses for rapid proliferation and widespread devastation. With an error-prone RNA- dependent RNA polymerase, RNA viruses can rapidly evolve, leading to high levels of diversity, rapid immune evasion, and increased likelihood of a species jump. Viral host cell receptors serve as a determinant of viral tropism and pathogenesis. Foreknowledge of these receptors coupled with systems that produce and assess effective therapeutics and vaccines can lead to a more rapid response to RNA viruses as they evolve and re-emerge, as well as to the inevitable emergence of RNA viruses humans have yet to encounter. In the work presented in this dissertation, we first identify an evolutionary conserved class of lipoprotein receptors as cellular receptors for three alphaviruses. Alphaviruses are emerging global pathogens transmitted by mosquitos. Despite their epidemic potential, there are currently no vaccines or treatments licensed for any alphavirus. Their use of lipoprotein receptors in part explains how this family of viruses can achieve such a broad species tropism and sheds light on the pathogenesis of each virus. We then examine a different family of RNA viruses, coronaviruses, and identify a class of neutralizing antibodies commonly produced in response to SARS-CoV-2 infection. We identify means through which SARS-CoV-2 can escape neutralization by this class of antibodies and as antibodies currently being used as therapeutics. Finally, we demonstrate that through continued evolution of its receptor binding domains, the SARS-CoV-2 spike protein may continue to evade antibodies produced in response to both natural infection and vaccination. Because of its central role in mediating viral entry, the receptor binding site is an obvious target for antibody therapeutics and vaccine design. Nonetheless, given the constant selective pressures it faces, therapeutic design can face challenges as RNA viruses quickly adapt and escape. Understanding all the pressures at play on viral envelope proteins that inevitably contribute to virus/host adaption, including optimized receptor engagement and continued escape from the host immune response, is vital to pandemic preparedness against the next emerging RNA virus we may face.