Host-Pathogen Coupled Networks: Model for Bacillus Anthracis Interaction with Host Macrophages.

摘要

Macrophages are key in establishing Bacillus anthracis (BA) infection via spore germination, and providing transportation to the regional lymph nodes where vegetative BA bacteria synthesize protective antigen (PA), lethal factor (LF), and edema factor (EF) for release into circulation. PA binds to anthrax toxin receptors on the endosomal membrane to form oligomeric pores that mediate transport of LF (and EF) into the cytosol, where it accumulates, causing macrophage death and the release of accumulated toxins and bacteria. We describe an in silico quantitative model of cytosolic LF attacking the host cell's mitogen-activated protein kinase (MAPK) signaling pathway that includes the time-course of LF accumulation in the cytosol, and LF-mediated cleavage of MAPK kinases in terms of a second order rate constant. Cytosolic LF accumulation is determined by external LF and PA concentrations via a composite Hill-type equation. Additional key parameters include total numbers of macrophage ATR/TEM8 or CMG2 (ANTR1/2) receptors for pore formation by PA; LF flux into cytosol through each such pore; binding affinities of PA (to surface receptors) and LF (to pores); and cytosolic LF half-life. Sensitivity analysis shows that LF half-life is critical to the sensitivity of AKR, BL/6, DBA and human macrophages to LF (with their viability half-lives of 48 to 72 hours in vitro), but not the RAW264.7, J774A.1 or BALB/C macrophages having shorter half-lives of 1-3 hours, where macrophage viability is primarily determined by LF influx into the cytosol. The model forms a link between multi-cellular organismlevel infection models, and sub-cellular molecular pathway models.