The Oro-Respiratory-Gut Virome Axis Over Space and Time - Overall - Abstract The human virome is vast, differs among human individuals, and changes over the human lifespan. While the virome influences human health in diverse ways, true understanding of its impact is limited by incomplete characterization of the human virome composition. The goal of the Penn Virome Characterization Center (VCC), titled “The Oro-Respiratory-Gut Virome Axis Over Space and Time”, is to define the human virome and its dynamics in priority body sites in generally healthy individuals without acute illnesses, reflecting typical US populations across diverse lifespan and community participants. Our program will provide key insights into virome composition, richness and complexity, and produce extensive data and methodologies for future studies of disease associations. We will focus on key body sites identified by the NIH Human Virome Program as priority targets, including Oral/Dental, Gut (fecal), Respiratory Tract (upper and lower) and Blood. Our collaborative team has published extensively on the microbiome and virome, and in the course of these studies assembled unique cohorts with biobanked specimen repositories suitable for rapid initiation of the Penn VCC program. Most of our sampling is from an urban setting in the mid-Atlantic region, so that African Americans are particularly well represented. To achieve our goals, the Penn VCC will: (a) Take advantage of rich in hand biobanks of human samples for rapid efficient analysis, and enroll and phenotype new subjects to obtain longitudinal oro-respiratory-gut-blood specimens, from existing cohorts of healthy children, adolescents, adults and elderly individuals; (b) Comprehensively describe and quantify virome populations from distinct oro-respiratory-gut-blood sites, including viruses of humans, bacteria, and human eukaryotic commensals, and implement methods for molecular identification of host cells for novel viruses and characterization of viral DNA modification; (e) Define the commonalities and differences of virome communities across oro-respiratory-gut biogeography and blood over time within individuals and between age groups; (f) Protect participants, investigators, and NIH by ensuring adherence to ethical norms and regulatory requirements, while conducting rigorous legal and qualitative research that addresses unanswered questions raised by human virome research that will inform future policy and research practice via our Ethical, Legal, and Social Implications Core; (g) Ensure harmonization and integration with other VCCs of the Human Virome Program, and establish open sharing of data to maximize research value; (h) Support collaborative research among HVP investigators using specimens, data, and novel insights generated through the VCC; and (i) Ensure representation of traditionally under-studied populations as research participants, and enhance diversity and inclusion within the virology, microbiome and computational biology research communities.