Pattern recognition receptors and divergent disease severity in zoonotic viral infections.

Zoonotic viruses continue to emerge unpredictably, cross species barriers, and inflict major health, economic, and ecological burdens. Recent outbreaks of SARS-CoV-2, H5N1 avian influenza virus (AIV), monkeypox, and Zika virus underscore the unpredictability of viral emergence and the urgent need to understand host-pathogen interactions. This review focuses on how innate immune sensing via pattern recognition receptors (PRRs) shapes disease severity across different species. While PRRs initiate antiviral defenses (interferons, ISGs), inflammatory cytokines, and programmed cell death, host outcomes diverge widely, shaped by genetic variation in PRR pathways and their regulators. Dysregulated inflammatory responses and inflammatory cell death can contribute substantially to severe disease independently of viral load, as demonstrated in influenza and coronavirus infections. Viral effectors that suppress or alter PRR signaling can show species-specific efficacy, and these mismatches can be critical determinants of disease when viruses jump hosts. Using avian influenza as an example, we highlight how disease outcomes vary with viral strain, host species, response timing, and tissue context. Overall, we propose that differential disease severity across host species reflects the balance among PRR-mediated resistance, the efficiency of viral immune evasion in the relevant host, and innate disease-tolerance mechanisms that limit tissue damage. Understanding these dynamics could enhance our ability to predict zoonotic emergence and mitigate the impact of viral pandemics.