Spatial Immune Model of Alveolar Lung Infection (SIMALI) Identifies Structural Determinants of Lung Inflammation.

Inflammation and lung damage in response to respiratory viral infection is a major cause of morbidity and mortality. How specialized lung alveolar structures contribute to variation in inflammatory lung damage observed in patients is a gap in current knowledge. Filling this gap is important for understanding how respiratory infections can lead to persistent and chronic sequelae after acute viral infection, including post-acute sequelae of COVID-19, or "long COVID". Few computational models have incorporated the spatial complexity of alveolar sacs, key sites where infection and inflammation damage lung function. We propose a novel computational model, SIMALI, which represents a sample of the lung's alveolar space as a structured 3D lattice of alveoli composed of air and epithelial cells surrounded by structural lung tissue through which virus and inflammation diffuse. SIMALI extends a previous agent-based model by adding key structural components of the lung, including physiological percentages of infectable cells and differential diffusion of virus through air and lung tissue. SIMALI's simulation predictions are validated against the spatial-temporal growth of lung lesions from Computed Tomography (CT) scans of patients with SARS-CoV-2 infection. By combining parameters validated in a prior study with alveolar structure, the model accurately predicts the typical growth of lung inflammation observed in patient CT scans. SIMALI demonstrates how the spatial architecture of alveolar sacs and the distribution of infectable cell types in the lung constrain the spread of virus and inflammation. Furthermore, SIMALI simulations show how the initial deposition of foci of viral infection distributed across alveolar sacs is an important mechanistic cause of variation in lung damage due to inflammation. The spatial SIMALI model demonstrates a key role for the structure of the alveolar space in driving inflammatory responses. Lung alveolar structure, combined with variation in immune response and the amount and location of initial viral deposition in the lung, all contribute to the highly variable damage to lung recapitulating variation observed across patients with SARS-CoV-2 infection.