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Examples are influenza A viruses (IAV) and coronaviruses (CoV). When emerging IAV and CoV spill over to humans, they adapt to evade immune responses and optimize their replication and spread in human cells. In IAV, adaptation occurs in all viral proteins, including the viral ribonucleoprotein (RNP) complex. RNPs consist of a copy of the viral RNA polymerase, a double-helical coil of nucleoprotein, and one of the eight segments of the IAV RNA genome. The RNA segments and their transcripts are partially structured to coordinate the packaging of the viral genome and modulate viral mRNA translation. In addition, RNA structures can affect the efficiency of viral RNA synthesis and the activation of host innate immune response. Here, we investigated if RNA structures that modulate IAV replication processivity, so-called template loops (t-loops), vary during the adaptation of pandemic and emerging IAV to humans. Using cell culture-based replication assays and in silico sequence analyses, we find that the sensitivity of the IAV H3N2 RNA polymerase to t-loops increased between isolates from 1968 and 2017, whereas the total free energy of t-loops in the IAV H3N2 genome was reduced. This reduction is particularly prominent in the PB1 gene. In H1N1 IAV, we find two separate reductions in t-loop free energy, one following the 1918 pandemic and one following the 2009 pandemic. No destabilization of t-loops is observed in the influenza B virus genome, whereas analysis of SARS-CoV-2 isolates reveals destabilization of viral RNA structures. Overall, we propose that a loss of free energy in the RNA genome of emerging respiratory RNA viruses may contribute to the adaption of these viruses to the human population.<\/jats:p>","DOI":"10.1093\/ve\/vead056","type":"journal-article","created":{"date-parts":[[2023,9,9]],"date-time":"2023-09-09T11:51:05Z","timestamp":1694260265000},"source":"Crossref","is-referenced-by-count":15,"title":["Evolution of\u00a0transient RNA structure\u2013RNA polymerase interactions in\u00a0respiratory RNA virus genomes"],"prefix":"10.1093","volume":"9","author":[{"given":"Charlotte V","family":"Rigby","sequence":"first","affiliation":[{"name":"Lewis Thomas Laboratory, Department of Molecular Biology, Princeton University , Washington Road, Princeton, NJ 08544, USA"},{"name":"Department of Pathology, Addenbrooke\u2019s Hospital, University of Cambridge , Hills Road, Cambridge CB2 2QQ, UK"},{"name":"Addenbrooke\u2019s Hospital, Public Health England , Hills Road, Cambridge CB2 2QQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly R","family":"Sabsay","sequence":"additional","affiliation":[{"name":"Lewis Thomas Laboratory, Department of Molecular Biology, Princeton University , Washington Road, Princeton, NJ 08544, USA"},{"name":"Carl Icahn Laboratory, Lewis-Sigler Institute, Princeton University , South Drive, Princeton, NJ 08544, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karishma","family":"Bisht","sequence":"additional","affiliation":[{"name":"Lewis Thomas Laboratory, Department of Molecular Biology, Princeton University , Washington Road, Princeton, NJ 08544, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4248-6008","authenticated-orcid":false,"given":"Dirk","family":"Eggink","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Amsterdam UMC , Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamid","family":"Jalal","sequence":"additional","affiliation":[{"name":"Addenbrooke\u2019s Hospital, Public Health England , Hills Road, Cambridge CB2 2QQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5129-3953","authenticated-orcid":false,"given":"Aartjan J W","family":"te Velthuis","sequence":"additional","affiliation":[{"name":"Lewis Thomas Laboratory, Department of Molecular Biology, Princeton University , Washington Road, Princeton, NJ 08544, USA"},{"name":"Center for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM) , Antonie van Leeuwenhoeklaan 9, Bilthoven 3721 MA, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,8,26]]},"reference":[{"key":"2023090911505188100_R1","doi-asserted-by":"crossref","DOI":"10.1186\/s12967-023-03996-w","article-title":"Global Landscape of\u00a0SARS-CoV-2 Mutations and\u00a0Conserved Regions","volume":"21","author":"Abbasian","year":"2023","journal-title":"Journal of Translational Medicine"},{"key":"2023090911505188100_R2","doi-asserted-by":"crossref","DOI":"10.3390\/v13040537","article-title":"Key Factors that Enable the Pandemic Potential of\u00a0RNA Viruses and\u00a0Inter-Species Transmission: A Systematic Review","volume":"13","author":"Alvarez-Munoz","year":"2021","journal-title":"Viruses"},{"key":"2023090911505188100_R3","doi-asserted-by":"crossref","DOI":"10.1186\/s12985-019-1271-0","article-title":"Changes in\u00a0RNA Secondary Structure Affect NS1 Protein Expression during Early Stage Influenza Virus 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