Opposite regulation of immune genes in blood and skin highlights tissue-specific dynamics of mpox virus

Mpox re-emerged globally in 2022 with atypical clinical features and efficient human-to-human transmission, which underscores the need to better understand host immune responses. We conducted an integrative transcriptomic analysis of mpox virus (MPXV) infection in nonhuman primates by leveraging RNA-Seq datasets from whole-blood and skin. We applied the Generalized Linear Model with Quasi-Likelihood F-test and Magnitude-Altitude Score (GLMQL-MAS), a method that combines rigorous statistical testing with a ranking metric to identify and prioritize differentially expressed genes (DEGs), and the Cross-Magnitude-Altitude Score (Cross-MAS) gene selection strategy, which integrates results across multiple time points to identify reproducible signatures, to define compact and robust markers of infection. Longitudinal analysis of whole-blood revealed a staged immune trajectory: early induction of interferon-stimulated genes (IFI27, ISG15) was followed by proliferative and hematopoietic programs and later enrichment of adaptive immune signatures, including B cell activation and TNF signaling. A minimal six-gene panel (IFI27, ISG15, MYO7B, HEY1, VASH1, CNTD2) distinguished infected from control animals with 100% accuracy in both training and independent held-out test sets. In contrast, skin transcriptomes showed upregulation of keratinocyte-related genes (KRT10, KRT1, SOSTDC1) and downregulation of immune mediators (IL1B, CXCL8, S100A8, ISG15), which suggests epithelial remodeling with limited local immune activation. Cross-tissue comparisons revealed that under stringent criteria (BH-adjusted p-value < 0.05 and |log₂FC|> 1), only 10 genes were commonly significant between whole-blood and skin, and all (100%) exhibited opposite regulation. When thresholds were relaxed for exploratory purposes (unadjusted p-value < 0.05 and |log₂FC|> 1), 58 common significant immune-related genes were identified from the curated nCounter® Host Response Panel, of which 74.1% were oppositely regulated. Shared immune genes such as ISG15, MX1, IFIT2, and OAS2 were upregulated in blood but suppressed in skin, and Reactome enrichment of discordant genes highlighted interferon and cytokine signaling pathways. These contrasts suggest that MPXV may trigger systemic interferon activation while suppressing local antiviral responses in lesions; however, because they are derived from independent secondary datasets in different species, they should be regarded as hypothesis-generating signals that require confirmation in matched, longitudinal studies.