Spatiotemporal Dynamics of Complement C5a Production within Bacterial Extracellular Polymeric Substance

Abstract

Opsonization and anaphylatoxin production are early events in the innate response to bacterial pathogens. Opsonization alone is frequently not lethal and production of anaphy-latoxins, especially C5a, allows for recruitment of cellular defenses. Complement biochemistry is extensively studied and computational models have been reported previously. However, a critical feature of complement-mediated attack is its spatial dependence: diffusion of mediators into and away from a bacterium is central to understanding C5a generation. Spatial dependence is especially important in biofilms, where diffusion limitation is crucial to bacterial counterdefense. Here we develop a model of opsonization and C5a production in the presence of a common blood-borne pathogen, Staphylococcus epidermidis. Our results indicate that when complement attacks a single cell, diffusion into the extracellular polymeric substance (EPS) is complete within 10 ms and that production of C5a peaks over the next 15 min. When longer diffusion lengths (as in an EPS-rich biofilm) are incorporated, diffusion limitation appears such that the intensity and duration of C5a production is increased. However, the amount of C5a produced under several likely clinical scenarios where single cells or sparse biofilms are present is below the k_D of the C5a receptor suggesting that complement activation by a single bacterium may be difficult to detect when diffusion is taken into account.