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Discovery of Infectious Disease Biomarkers in Murine Anthrax Model Using Mass Spectrometry of the Low-Molecular-Mass Serum Proteome

Aarthi Narayanan, Weidong Zhou, Mark Ross, Jane Tang, Lance Liotta, Emanuel Petricoin, Fatah Kashanchi, Charles Bailey and Serguei Popov

A novel mass spectrometry (MS)-based approach to the identification of host-derived biomarkers (BMs) in the circulating low-molecular-mass (LMM) fraction ( <25 kDa) of blood proteome was tested in a murine model . DBA2/J mice were challenged intraperitonially with spores of either the toxigenic B. anthracis Sterne strain (pXO1 + , pXO2 - ) that is virulent in DBA/2 mice or the nontoxigenic, non-virulent delta Sterne strain (pXO 1 - , pXO2 - ). Serum samples were obtained at multiple time points and seperated by continuous flow denaturing gel electrophoresis followed by Coomassie staining to i so- late the LMM archive for subsequent MS identificati on. Peptide fragments derived from more than 200 protei ns displayed low-variance differential abundances betw een lethal and non-lethal challenges. Several proteins from the MS analysis were subjected to secondary verific a- tion by western blots. Serum abundances of 6 prote ins (carbonic anhydrase 2, adenylate kinase 1, peroxyre doxin 2, UMP-CMP kinase, Ras-related C3 botulinum substra te 1, and destrin) from a total of 10 tested proteins were strongly coincident with established anthrax diseas e and mortality thus making them potential candidates for host- derived anthrax disease associated BMs. These BMs were demonstrated to be “elastic” in that their abu ndance levels in sera of doxycycline-treated mice responde d to the therapeutic intervention thus making them usefu l tools for monitoring efficacies of existing and novel tre atment regimens.