INTRODUCTION
The study of viral infection dynamics has long relied on both computational models and experimental systems that simplify host tissues into flat, uniform surfaces. While this framework has been useful for capturing broad infection behaviors, it overlooks the reality that respiratory tract tissues are not flat but geometrically complex. The respiratory tract is shaped by tubular, branching structures, with spatial heterogeneity that fundamentally alters infection progression and immune responses. By integrating more realistic tissue architecture into computational models, researchers are now uncovering new insights into viral lineage dynamics and regional variations in infection severity. This shift represents a significant advance in bridging experimental virology with computational biology.
RESPIRATORY TRACT GEOMETRY AND ITS BIOLOGICAL IMPORTANCE
The respiratory tract consists of a branching tubular structure where each generation of airways narrows progressively, leading to the deep alveolar regions. This geometry plays a central role in viral infections because viral particles experience distinct deposition patterns across airway generations. Narrower airways in deeper lung regions are not only harder for the immune system to access but are also associated with severe infection outcomes. Thus, the anatomical design of the respiratory tract is more than structural—it directly influences the spatial and temporal spread of viral infections. Recognizing this has important implications for both experimental systems and computational modelling.
LIMITATIONS OF FLAT TISSUE MODELS
Flat, wide tissue models commonly used in computational and in vitro studies fail to capture the complexity of infection dynamics in the respiratory system. While such models allow for controlled environments, they neglect the tubular branching that drives non-uniform viral spread. As a result, these simplified models may underestimate viral heterogeneity, immune response variability, and lineage evolution. This limitation has hindered translation of in vitro findings to in vivo infection outcomes, particularly in respiratory diseases such as influenza, SARS-CoV-2, and other emerging viral pathogens.
MULTICELLULAR MODELLING WITH REALISTIC GEOMETRY
To address these limitations, researchers are extending multicellular models of viral dynamics by incorporating features of the respiratory tract’s architecture. Such models capture both the tubular nature of airways and the branching structure of airway generations. This realistic approach allows simulation of how infection dynamics differ between upper and lower airways, how viral load changes along the tract, and how immune responses adapt to spatial heterogeneity. Importantly, the models help to explain why deeper infections are often more severe and resistant to immune clearance.
VIRAL LINEAGE DYNAMICS AND IMMUNE HETEROGENEITY
One major advantage of incorporating respiratory tract geometry into models is the ability to study viral lineage dynamics. Infections in deeper lung regions may foster distinct viral subpopulations due to reduced immune surveillance and spatial compartmentalization. Moreover, immune responses are not evenly distributed across the tract, meaning that infection control is highly variable. These factors contribute to within-host viral diversity, potentially influencing transmission, disease severity, and treatment outcomes. Such heterogeneity cannot be fully appreciated using flat in vitro systems.
IMPLICATIONS FOR FUTURE EXPERIMENTAL SYSTEMS
This new modelling framework highlights the need to design experimental systems that better represent the branching architecture of the respiratory tract. Bioreactors, organoids, and microfluidic airway-on-a-chip devices could incorporate tubular and branching geometries to better mimic in vivo conditions. Doing so will enable more accurate evaluation of antiviral drugs, vaccines, and immune therapies in the context of realistic tissue structures. Ultimately, integrating geometry into infection research bridges a key gap between experimental virology and clinical reality, offering new opportunities for translational science.
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