Project Summary Viruses have imposed a significant global burden of morbidity and mortality for millennia. Just in the last century, highly pathogenic RNA viruses such as influenza A, HIV and SARS-CoV-2 resulted in devastating pandemics that directly impacted millions of individuals and altered socioeconomic dynamics worldwide. Fueled by major advances in sequencing during the last decades, the emerging field of archeovirology has begun identifying viruses that severely impacted humans prior to the 20th century. To this day, however, the pathogens responsible for important past epidemics are still unknown and there are significant gaps remaining in the evolutionary history of certain viral families, especially for RNA viruses. Using a highly collaborative and innovative approach to overcome intrinsic limitations in the identification of viral genomes from human remains, this proposal will uncover the viral diversity that existed during periods of notable epidemic outbreaks and expand our knowledge of the origins and evolution of highly pathogenic viruses. In particular, this proposal seeks to identify and characterize genomes from centuries-old RNA viruses, a goal that so far has remained elusive. Using well-established ancient DNA techniques, forensic proteomics, and improved RNA isolation methodologies, our team will reconstruct viral genomes from human remains of deadly epidemics in early colonial Mexico and preserved lung specimens from pathology collections corresponding to the industrial revolution in Great Britain. Guided by archeological and historical documentation in these two distinct historical contexts, this work will identify viruses that existed in the past ~500 years, study their origin and evolutionary relationships to modern viruses, and characterize the evolution of viral protein function in relation to their human hosts. Together, this proposal will generate a comprehensive characterization of the properties of past viral infections that will not only lead to the identification of viruses responsible for epidemics that profoundly altered human history but will also uncover evolutionary adaptations between past and present viruses and define the origins of highly pathogenic RNA viruses, providing key molecular information to prepare against the (re)emergence of highly virulent viruses in the future.

Project Narrative While the emerging field of archeovirology has enabled the characterization of viral infections that profoundly altered human history, important technical limitations remain that restrict its potential to uncover the evolutionary history of highly pathogenic viral families, especially RNA viruses. Using a multidisciplinary and innovative approach, this proposal will identify viruses that existed in the past ~500 years, understand the origin and evolution of important human pathogens, and reveal functional variation that contribute to their pathogenesis. The results of this proposal will shed light on the etiology of past disease outbreaks and epidemics, estimate when those viruses were introduced into human populations, and develop strategies to better prepare against future viral pandemics.