Past viral infections can shape inter-individual variability in anti-viral TLR responses

Viral infections can shape adaptive immunity, but whether they also influence innate immune responses later in life remains incompletely characterized. Here, we profiled serum from 12 healthy adults using VirScan, a high-throughput serological assay that infers prior viral exposures by mapping antiviral antibody reactivity across a broad range of viral epitopes. We paired this with ex vivo stimulation of TLR3 and TLR7/8 antiviral pathways and tested whether post-stimulation inflammatory responses are associated with prior viral exposures. At the antibody level, we observed consistent immunodominance at the protein level across individuals, alongside substantial variability at the epitope level. At the functional level, prior exposure to HSV-1, HSV-2, and norovirus was associated with differential production of CCL4, MCP-2, and TNF following TLR7/8 stimulation, respectively. This pilot study establishes a framework for integrating broad viral serology with functional immune profiling to investigate links between lifetime exposures and immune variability. Our results suggest that past viral infections, including acute infections, can contribute to variation in innate immune responses later in life. Larger studies will be required to validate these associations, establish causality, and determine the underlying mechanisms.