Accession Number:

ADA625935

Title:

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

Descriptive Note:

Final rept. Oct 2012-Sep 2015

Corporate Author:

HENRY M JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE WRIGHT-PATTERSON AFB OH

Report Date:

2015-09-01

Pagination or Media Count:

37.0

Abstract:

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 cells 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 ATRTEM8 or CMG2 ANTR12 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, BL6, 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 BALBC 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.

Subject Categories:

  • Anatomy and Physiology
  • Medicine and Medical Research
  • Microbiology

Distribution Statement:

APPROVED FOR PUBLIC RELEASE