MOLECULAR BARRIERS TO THE EMERGENCE OF CORONAVIRUSES IN HUMANS

We hypothesise that certain circulating bat coronaviruses (CoVs) could emerge in human populations with devastating consequences (similar to SARS-CoV-2). However, the existing human CoVs all appear to have emerged via transmission from possible intermediate species, rather than directly from bats, suggesting that specific molecular barriers may hinder direct zoonotic transmission from bats to humans. We therefore aim to identify both the bat CoVs with increased risk of emerging in humans, as well as genome-encoded defences that could constrain CoV cross-species transmission.By combining supervised machine learning with evolutionary and bioinformatic analyses, we will identify bat CoVs with an increased risk of emergence in humans. Six of these 'poised' bat CoVs will then be synthesised, and combined with highly pathogenic human CoVs, and seasonal human CoVs, to create a cross-species CoV test panel, on which we will focus further molecular experimentation.Previous studies have shown that genome-encoded antiviral defences can form powerful barriers to cross-species transmission of viruses, and are often encoded by interferon-stimulated genes (ISGs). We will therefore define the interferome of horseshoe bats (the reservoir of SARS-CoVs) and construct a library of ~150 horseshoe bat ISGs. These bat ISGs, along with our existing ISG libraries (human, macaque, bovine) will then be used to identify ISGs that inhibit any coronaviruses in our cross-species test panel (described above).Subsequent analyses will examine patterns of restriction of the anti-CoV ISGs in potential intermediate species, in order to identify blocks to cross-species transmission. Together, this knowledge should improve our capacity to make predictions about which CoVs are likely to make successful cross-species 'jumps', aiding surveillance of CoVs with pandemic potential. In addition, understanding how ISGs inhibit CoVs could potentially improve our understanding of SARS-CoV-2 pathogenesis.