Decoding the mechanophysiology for inhaled onset of smallpox with model-based implications for mpox spread

Orthopoxviruses can transmit via inhalation of virus-laden airborne particulates, with the initial infection triggered along the respiratory pathway. Understanding the flow physics of inhaled aerosols and droplets within the respiratory tract is crucial for improving transmission mitigation strategies and elucidating disease pathology. Here, we introduce an experimentally-validated physiological fluid dynamics model simulating inhaled onset of smallpox caused by the variola virus of Orthopoxvirus genus. Using high-fidelity Large Eddy Simulations, we modeled airflow and particulate motion within anatomical airway domains reconstructed from medical imaging. By integrating these simulations with viral concentration and individual immune factors, we estimated critical exposure durations for infection onset to be between 1 − 19 hours, aligning with existing smallpox literature. To formalize the broader applicability of this framework, we extended our analysis to mpox virus, a circulating pathogen from same genus. For mpox, the mechanophysiological computations indicate a critical exposure window of 24 − 40 hours; however, this can vary significantly—from as short as 8 hours to as long as 127 hours—depending on virion concentration fluctuations within inhaled particulates, assuming happenstance of viral evolution. Predictably longer than the critical exposure durations for smallpox, the mpox findings still strongly suggest the possibility for airborne inhaled transmission during prolonged proximity.