Two studies of anthrax: I. Altered gene expression in anthrax-infected mice. II. Mathematical modeling of the anthrax infection process.

摘要

This dissertation reports the results of two studies---one experimental and one theoretical---on the development of anthrax in mammals.;The experimental study is based on the analysis of altered gene expression in DBA mice infected with anthrax Sterne strain spores. Standard bioinformatics methods are applied to expression data acquired with cDNA microarrays. Genes whose expression levels are significantly affected by anthrax are identified, and their potential roles in the progression of the disease are discussed.;The experiments differ in several particulars from prior microarray studies of anthrax: (1) the study was done in vivo on live animals, not on cell lines; (2) heterogeneous tissues, including multiple cell types, were examined; (3) the work examined the later period of infection, from 24 to 72 hours, not just the first 6 hours.;Screening according to both biological and statistical criteria identified 33 up-regulated genes and 20-down regulated genes in liver, lung and spleen. 45 of the 53 are known genes which could be assigned to functional categories, two of which appear to be related to the progression of anthrax and its mechanisms of lethality. One group of five genes related to the immune system of the host was found to be regulated in a direction contributing to the suppression of the immune response. A second group of eight genes was found to be related to the control of endothelial barrier integrity. Altered expression of those genes suggests disrupted balance of endothelial barrier control, and may be related to the hemorrhage and hypotension observed in the late stages of anthrax.;The theoretical study develops mathematical models of the anthrax infection process. Models include growth of bacteria and toxins, kinetics of binding of toxins to cell surface receptors, effects of monoclonal antibodies in countering toxin proteins, and interactions with the phagocytes of the innate immune system.;Separate pharmacodynamic/pharmacokinetic models are developed to study the effects of antibiotics on the growth and clearance of anthrax bacteria. The effects of different doses and dose schedules are modeled.