Viral infections such as SARS-CoV-2, HIV, and EBV can alter nonsense-mediated decay and impact cellular processes unique to an individual's genome

Throughout the last few years, understanding the physiological mechanisms to viral infections has highlighted individuals' unique outcomes. While SARS-CoV-2 and other pathogens can cause hospitalization and mortality, some individuals remain asymptomatic, and others will suffer from years of altered diverse physiological pathways (such as long COVID). Our team, through transcriptomics, has built a hypothesis that many of the individual-level responses are due to the interaction of a virus with a process known as nonsense-mediated decays (NMD) and how suppression of NMD interacts with an individual's genomic variants to drive diverse physiological response. This hypothesis has been built on nearly five hundred clinical transcriptomes of infants with RSV infection, newborns with genomic disorders, kids with multiple organ dysfunction syndrome, and adults with hospitalized COVID-19 paired with >16,000 publicly deposited blood transcriptomes of broad pathologies. Several virus interactions with human genomics have been observed within our work. First, a patient with EBV had an acute activation of viral-induced genetics through suppression of NMD, resulting in elevated RNASEH2B dominant-negative human protein resulting in Hemophagocytic lymphohistiocytosis (HLH), a mechanism of a rare transient disorders. Second, we have observed multiple individuals with viral infections that resulted in either the activation or suppression of interferon cascades correlated to common variant alleles altered by NMD changes, such as ISG15 and cytokines. Third, we show that several of these cytokine modulation genetics can elevate the risk of NMD-regulated Neutrophile Extracellular Trap (NET) production associated with long-term endocrine and hemodynamic modulation. Finally, we show that when a virus suppresses NMD (SARS-CoV-2, HIV, EBV), multiple individuals with latent infections can have an elevation of the dormant virus transcripts, including EBV and Torque teno virus. Thus, individuals can have multiple viruses activated that change physiological outcomes simultaneously. Overall, it is essential to physiology and medicine to refine each individual's precision and unique outcomes based on the complex interaction of a virus with NMD and genomic variants to modify cellular, systems, and inflammatory responses. This research was funded by the Gerber Foundation, National Institutes of Health (K01ES025435 and R01AI171984), Michigan Department of Health and Human Services, and Michigan State University. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.