title: Systems biology approach predicts antibody signature associated with Brucella melitensis infection in humans.
abstract: A complete understanding of the factors that determine selection of antigens recognized by the humoral immune response following infectious agent challenge is lacking. Here we illustrate a systems biology approach to identify the antibody signature associated with Brucella melitensis (Bm) infection in humans and predict proteomic features of serodiagnostic antigens. By taking advantage of a full proteome microarray expressing previously cloned 1406 and newly cloned 1640 Bm genes, we were able to identify 122 immunodominant antigens and 33 serodiagnostic antigens. The reactive antigens were then classified according to annotated functional features (COGs), computationally predicted features (e.g., subcellular localization, physical properties), and protein expression estimated by mass spectrometry (MS). Enrichment analyses indicated that membrane association and secretion were significant enriching features of the reactive antigens, as were proteins predicted to have a signal peptide, a single transmembrane domain, and outer membrane or periplasmic location. These features accounted for 67% of the serodiagnostic antigens. An overlay of the seroreactive antigen set with proteomic data sets generated by MS identified an additional 24%, suggesting that protein expression in bacteria is an additional determinant in the induction of Brucella-specific antibodies. This analysis indicates that one-third of the proteome contains enriching features that account for 91% of the antigens recognized, and after B. melitensis infection the immune system develops significant antibody titers against 10% of the proteins with these enriching features. This systems biology approach provides an empirical basis for understanding the breadth and specificity of the immune response to B. melitensis and a new framework for comparing the humoral responses against other microorganisms.
authors.affiliation: Department of Medicine, Division of Infectious Diseases, University of California, Irvine, California 92697, United States.
authors.forename: Li
authors.initials: L
authors.lastname: Liang
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Tan
authors.forename: Silvia
authors.initials: S
authors.lastname: Juarez
authors.forename: Homarh
authors.initials: H
authors.lastname: Villaverde
authors.forename: Jozelyn
authors.initials: J
authors.lastname: Pablo
authors.forename: Rie
authors.initials: R
authors.lastname: Nakajima-Sasaki
authors.forename: Eduardo
authors.initials: E
authors.lastname: Gotuzzo
authors.forename: Mayuko
authors.initials: M
authors.lastname: Saito
authors.forename: Gary
authors.initials: G
authors.lastname: Hermanson
authors.forename: Douglas
authors.initials: D
authors.lastname: Molina
authors.forename: Scott
authors.initials: S
authors.lastname: Felgner
authors.forename: W John W
authors.initials: WJ
authors.lastname: Morrow
authors.forename: Xiaowu
authors.initials: X
authors.lastname: Liang
authors.forename: Robert H
authors.initials: RH
authors.lastname: Gilman
authors.forename: D Huw
authors.initials: DH
authors.lastname: Davies
authors.forename: Renée M
authors.initials: RM
authors.lastname: Tsolis
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Vinetz
authors.forename: Philip L
authors.initials: PL
authors.lastname: Felgner
mesh_terms: D000906:Antibodies / Q000737:chemistry; D001426:Bacterial Proteins / Q000737:chemistry; D017347:Brucella melitensis / Q000378:metabolism*; D002006:Brucellosis / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007107:Immune System; D008070:Lipopolysaccharides / Q000737:chemistry; D013058:Mass Spectrometry / Q000379:methods; D016366:Open Reading Frames; D040081:Protein Array Analysis; D040901:Proteomics / Q000379:methods; D015203:Reproducibility of Results; D049490:Systems Biology
chemical_list: D000906:Antibodies; D001426:Bacterial Proteins; D008070:Lipopolysaccharides