Spatiotemporal modeling quantifies cellular contributions to uptake of Aspergillus fumigatus in the human lung

Abstract The human lung is confronted daily with thousands of microbial invaders reaching the lower respiratory tract. An efficient response by the resident type 1 and type 2 alveolar epithelial cells (AECs) and alveolar macrophages (AMs) cells during the early hours of innate immunity is a prerequisite to maintain a non-inflammatory state, but foremost to rapidly remove harmful substances. One such human-pathogenic invader is the opportunistic fungus Aspergillus fumigatus. If the spherical conidia are not cleared in time, they swell reaching approximately twice of their initial size and germinate to develop hyphae around six hours post-infection. This process of morphological change is crucial as it enables the pathogen to invade the alveolar epithelium and to reach the bloodstream, but also makes it conspicuous for the immune system. During this process, conidia are first in contact with AECs then with migrating AMs, both attempting to internalize and clear the fungus. However, the relative contribution of AMs and AECs to uptake of A. fumigatus remains an open question, especially the capabilities of the barely investigated type 1 AECs. In this study, we present a bottom-up modeling approach to incorporate experimental data on the dynamic increase of the conidial diameter and A. fumigatus uptake by AECs and AMs in a hybrid agent-based model (hABM) for the to-scale simulation of virtual infection scenarios in the human alveolus. By screening a wide range of parameters, we found that type 1 AECs, which cover approximately 95% of the alveolar surface, are likely to have a greater impact on uptake than type 2 AECs. Moreover, the majority of infection scenarios across the regime of tested parameters were cleared through uptake by AMs, whereas the contribution to conidial uptake by AECs was observed to be limited, indicating that their crucial support might mostly consist in mediating chemokine secretion for AM recruitment. Regardless, as the first host cell being confronted with A. fumigatus conidia, our results evidence the large potential impact of type 1 AECs antimicrobial activities, underlining the requirement of increasing experimental efforts on this alveolar constituent.