SARS-CoV-2 viral RNA disseminates to hamster toes and associates with localized IFN-I production: mechanistic footprints of an abortive COVID-19 infection in pandemic-associated pernio

SARS-CoV-2 infection generates a systemic immune response mediated by type I interferons. Pernio is a rare cutaneous manifestation of disorders characterized by excessive IFN-I signaling. Pernio increased in incidence during the pandemic but lacks direct evidence of SARS-CoV-2. We characterized clinical pernio samples and mechanistic feasibility in a rodent model which phenocopies human SARS-CoV-2 infection. Golden hamsters infected with SARS-CoV-2 experienced rapid dissemination of viral RNA to both lungs and toes. Interferon responses at both sites coincided with detection of viral RNA, which cleared within 10 days post-infection. Live virus could not be detected at acral sites. In two cohorts of clinical biopsies of affected skin, we detected SARS-CoV-2 RNA in 20-30% of cases, plasmacytoid dendritic cell activation, and a robust IFN-I response across all samples. Our data suggest footprints from SARS-CoV-2 exposure in a subset of cases that can produce a sustained localized IFN-I response-- even in the absence of serconversion. Overall design: Hamsters were intranasally infected with 1000 PFU of SARS-CoV-2 (Washington strain) and sacrificed at 3 days-post infection (dpi). Hamsters were intracardially perfused with 60 mL PBS, and toes were harvested into Trizol. RNA was extracted from toes, poly-A enriched, and sequenced for transcriptional analysis. Human PBMC samples were taken from a group of control donors as well as donors affected by pandemic associated pernio (PAP), alternatively known as COVID-associated pernio (CAP) or COVID toes, at various points post-presentation in clinic. These PBMCs were frozen following isolation using Ficoll gradient. PBMCs were thawed, and then RNA was isolated and sequenced for transcriptional analysis. RNA-seq data was aligned to the Mesocricetus Auratus MesAur1.0 genome or GRCH38 Homo Sapiens genome as appropriate using Salmon. Salmon output files were further analyzed for differential expression via DESeq2 where necessary.