Effective management of Chronic Wasting Disease (CWD) is necessary for North American deer herd sustainability, but efforts are hampered by limits of available disease detection methods and incomplete understanding of host susceptibility and CWD transmission. In alignment with the research priorities of the CWD Alliance, we propose an intersectional study to advance early detection methods for both CWD and host factors indicative of high CWD risk using non-invasive samples. Our objectives are fourfold: 1) Identify and ecotype CWD prions in fecal samples collected from white-tailed deer (Odocoileus virginianus), 2) Compare prion protein genotypes of white-tailed deer per CWD ecotype, 3) Characterize the commensal gut microbiome of white-tailed deer with CWD, and 4) Integrate objectives 1-3 to link host and pathogen factors in disease susceptibility. We will thereby expand CWD surveillance methods to include sensitive detection of CWD in non-invasively collected samples (ex. fecal samples collected by hunters), by improving early detection of at-risk individuals and populations. To meet these objectives, we will perform real-time quaking-induced conversion (RT-QuIC) to identify presence of CWD prions in fecal samples and classify prion ecotype with western blotting. We will classify the prion protein genotype at 8 loci associated with host susceptibility to CWD using second generation sequencing. Gut microbial communities will be characterized with 16s rRNA gene sequencing methods. Expected outcomes for delivery in one year include advancement of CWD testing, identification of host factors associated with CWD susceptibility and transmission, and evaluation of the viability of fecal samples as a CWD screening tool.