Modeling Inhalation-Driven Orthopoxvirus Infection: Mechanophysiological Insights into Smallpox and Mpox Exposure

Airborne transmission of Orthopoxviruses occurs via inhalation of virus-ferried particulates that initiate infection along the respiratory tract. Understanding how air moves through the airways and the deposition of these particles is crucial for explaining how such viruses spread and trigger infection. Here, we present a physics-based, experimentally validated computational framework that simulates the inhalation-driven onset of smallpox infection by the variola virus. High-resolution Large Eddy Simulations in anatomically realistic airway models reconstructed from medical imaging achieve the coupled air and particle transport under normal breathing rate. Integrating flow physics with virological and host-response data, the model estimates smallpox exposure period between 1–19 hours, consistent with historical evidence. Extending this mechanophysiological framework to the mpox virus suggests a longer exposure duration of 24–40 hours, varying widely (8–127 hours) with virion load and potential viral evolution. Although mpox is less efficient in airborne transmission than smallpox, longer exposure in confined spaces may still cause infection. Utilization of this anatomically resolved fluid-dynamic framework for assessing respiratory transmission potential in emerging Orthopoxviruses.