Abstract
The healthy state of an organism is constantly threatened by external cues. Due to the daily inhalation of hundreds of particles and pathogens, the immune system needs to constantly accomplish the task of pathogen clearance in order to maintain this healthy state. However, infection dynamics are highly influenced by the peculiar anatomy of the human lung. Lung alveoli that are packed in alveolar sacs are interconnected by so called Pores of Kohn. Mainly due to the lack of in vivo methods, the role of Pores of Kohn in the mammalian lung is still under debate and partly contradicting hypotheses remain to be investigated. Although it was shown by electron microscopy that Pores of Kohn may serve as passageways for immune cells, their impact on the infection dynamics in the lung is still unknown under in vivo conditions. In the present study, we apply a hybrid agent-based infection model to quantitatively compare three different scenarios and discuss the importance of Pores of Kohn during infections of Aspergillus fumigatus. A. fumigatus is an airborne opportunistic fungus with rising incidences causing severe infections in immunocompromised patients that are associated with high mortality rates. Our hybrid agent-based model incorporates immune cell dynamics of alveolar macrophages – the resident phagocytes in the lung – as well as molecular dynamics of diffusing chemokines that attract alveolar macrophages to the site of infection. Consequently, this model allows a quantitative comparison of three different scenarios and to study the importance of Pores of Kohn. This enables us to demonstrate how passaging of alveolar macrophages and chemokine diffusion affect A. fumigatus infection dynamics. We show that Pores of Kohn alter important infection clearance mechanisms, such as the spatial distribution of macrophages and the effect of chemokine signaling. However, despite these differences, a lack of passageways for alveolar macrophages does impede infection clearance only to a minor extend. Furthermore, we quantify the importance of recruited macrophages in comparison to resident macrophages.
Highlights
External cues constantly threaten the healthy state of organisms
In the present study we investigated the impact of Pores of Kohn (PoK) on the infection dynamics during A. fumigatus lung infection
In Section “PoK+/+ Shows Highest Infection Clearance Compared to PoK+/− and PoK−/−” we investigate the infection clearance in the three scenarios for various chemokine parameters and how this depends on the position of the conidium in the alveolus
Summary
External cues constantly threaten the healthy state of organisms. Due to the daily inhalation of hundreds of particles and pathogens the immune system needs to constantly accomplish the task of pathogen clearance in the lung in order to maintain and restore a healthy state. Alveolar macrophages (AM) – i.e., resident phagocytes in the lung – were observed inside a PoK supporting the postulated role of PoK as inter-alveolar cellular communication channels. The important role of PoK for ventilation is widely accepted (Namati et al, 2008), the exact function of PoK in the lung is still not fully understood and experimental evidence supports partially contradicting hypotheses. If PoK are regulators of air pressure and open and close at a typical human respiration rate of approximately 3–5 s (Barrett et al, 2012), how can they serve as entry/exit points for immune cells, such as AM, which migrate at a much lower pace? If PoK are regulators of air pressure and open and close at a typical human respiration rate of approximately 3–5 s (Barrett et al, 2012), how can they serve as entry/exit points for immune cells, such as AM, which migrate at a much lower pace? How do PoK allow for collateral ventilation when covered with surfactant (Oldham and Moss, 1989)? In case AM are routinely migrating between neighboring alveoli through PoK, how does this affect the dynamics of infection processes?
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