Whole Body Deep Tissue Characterization of the Human Virome

SUMMARY/ABSTRACT The virome is heterogenous and widely distributed across the whole body. Given the challenges of obtaining deeper tissues from healthy individuals, however, it is unknown how these viruses persist across various anatomical, histological, and cellular environments or how host immune and inflammatory responses differ across these compartments in response to infection. Thus, it is essential for the Human Virome Project (HVP) to include studies of deeper tissues in the general (healthy) population. To address these critical knowledge gaps, we will leverage our unique longitudinal POstmortemSystematic InvesTigation of Sudden Cardiac Death (POST SCD) Study, a prospective postmortem study of consecutive victims of out-of-hospital sudden death in San Francisco County which has thus far collected extensive tissue samples from numerous tissues including brain, lymph nodes, liver, spleen, gut, heart, pulmonary vasculature, lung parenchyma, pancreas, and bone marrow from >1,000 SCD victims. We also leverage our ongoing prospective tissue biopsy program through the UCSF LIINC study to collect blood, PBMC, gut tissue, lymph node aspirates and bone marrow in people with prior COVID-19. The unique, direct access to human represents an unprecedented opportunity to examine the human virome across organ systems in a broad survey of ambulatory adults to uncover mechanisms that facilitate viral persistence but also may lead to immune dysregulation or subclinical inflammation. This highly innovative project involves in situ hybridization, cutting-edge tissue-based transcriptomic/proteomic profiling, metagenomics virome sequencing, and ultra-high multiplexed immuno-histochemical platforms. Our aims are to: (1) Test the hypothesis that the human tissue virome in otherwise healthy persons is heterogeneously distributed in various anatomical and immune-privileged regions, across the lifespan, and by sex assigned at birth. We will accomplish this by determining the anatomical, histological, and cellular tropism of the human virome in adults in relatively good health dying suddenly out-of-hospital. (2) Test the hypothesis that the tissue virome is dependent on host gene, protein and immune responses across tissues that facilitate persistence. We further hypothesize that the virome requires escape from or adaptation to innate and adaptive immune responses which allow viral persistence, but also may lead to immune modulation or sub-clinical tissue inflammation. (3) Establish an innovative pilot research grant award program to support collaborative, cutting edge research involving tissue-based studies to foster interest and development in novel ways to characterize the virome and impact on host responses across the whole body, a key component of the Human Virome Project.