Legionella pneumophila is an intracellular pathogen, ubiquitous in the environment and considered opportunistic. It is the leading cause of legionellosis, which can be present in its nonpneumonic form (Pontiac fever) and acute pneumonic form (Legionnaires`disease -LD). In the soil and aquatic systems, L. pneumophila can invade and survive intracellularly in various protozoans. The ability to proliferate within biofilms provides additional protection from environmental stresses, such as disinfection. Human infection by L. pneumophila occurs after the inhalation or aspiration of aerosols containing the pathogen. Upon infection, alveolar macrophages can be invaded and used by L. pneumophila for replication, resembling the infection of protozoan hosts in the environment. The ability of L. pneumophila to overcome the killing mechanisms of phagocytes depends on the Dot/Icm type IV secretion systema specialized protein translocation system vital for the intracellular survival of the pathogen and for establishing a replicative niche known as the Legionella-containing vacuole. Following host cell lysis, the released bacteria infect other host cells, beginning a new cycle of infection.
In this work, we show how the mechanical properties of the cellular microenvironment modulate the growth of tumour spheroids. Based on the composition of the extracellular matrix, its stiffness and architecture can significantly vary, subsequently influencing cell movement and tumour growth. However, it is still unclear exactly how both of these processes are regulated by the matrix composition. Here, we present a centre-based computational model that describes how collagen density, which modulates the steric hindrance properties of the matrix, governs individual cell migration and, consequently, leads to the formation of multicellular clusters of varying size. The model was calibrated using previously published experimental data, replicating a set of experiments in which cells were seeded in collagen matrices of different collagen densities, hence producing distinct mechanical properties. At an initial stage, we tracked individual cell trajectories and speeds. Subsequently, the formation of multicellular clusters was also analysed by quantifying their size. Overall, the results showed that our model could accurately replicate what was previously seen experimentally. Specifically, we showed that cells seeded in matrices with low collagen density tended to migrate more. Accordingly, cells strayed away from their original cluster and thus promoted the formation of small structures. In contrast, we also showed that high collagen densities hindered cell migration and produced multicellular clusters with increased volume. In conclusion, this model not only establishes a relation between matrix density and individual cell migration but also showcases how migration, or its inhibition, modulates tumour growth.
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