Persistent inflammation and tissue injury may contribute to post-acute COVID-19 syndrome (PACS). However, direct tissue evidence from mildly-infected individuals sampled long after recovery remains exceptionally limited. Here, we performed post-mortem bulk RNA-seq and GeoMx digital spatial profiling of lung, heart, and brain tissues from four individuals who recovered from mild COVID-19 more than 250 days before death from unrelated causes. Samples were collected during the early phase of the national vaccination program, before widespread vaccine uptake and recurrent infection, providing a rare reference cohort for defining tissue responses to SARS-CoV-2 in the absence of major confounding from vaccination and/or reinfection; such a cohort can no longer be prospectively assembled. We observed residual SARS-CoV-2 nucleocapsid antigen within tissues and revealed organ-specific immune alterations. Lung and heart tissues exhibited a coordinated, self-sustaining inflammatory response, whereas brain tissue showed vascular dysfunction and altered neuroimmune homeostasis. These findings showcase the distinct tissue responses following mild infection and provide a spatially resolved view of sub-clinical long-term tissue sequelae. Collectively, our data establish a unique baseline for persistent viral antigen and tissue-specific immune dysregulation underlying PACS.
