title: Systems biology analysis of Brucella infected Peyer's patch reveals rapid invasion with modest transient perturbations of the host transcriptome.
abstract: Brucella melitensis causes the most severe and acute symptoms of all Brucella species in human beings and infects hosts primarily through the oral route. The epithelium covering domed villi of jejunal-ileal Peyer's patches is an important site of entry for several pathogens, including Brucella. Here, we use the calf ligated ileal loop model to study temporal in vivo Brucella-infected host molecular and morphological responses. Our results document Brucella bacteremia occurring within 30 min after intraluminal inoculation of the ileum without histopathologic traces of lesions. Based on a system biology Dynamic Bayesian Network modeling approach (DBN) of microarray data, a very early transient perturbation of the host enteric transcriptome was associated with the initial host response to Brucella contact that is rapidly averted allowing invasion and dissemination. A detailed analysis revealed active expression of Syndecan 2, Integrin alpha L and Integrin beta 2 genes, which may favor initial Brucella adhesion. Also, two intestinal barrier-related pathways (Tight Junction and Trefoil Factors Initiated Mucosal Healing) were significantly repressed in the early stage of infection, suggesting subversion of mucosal epithelial barrier function to facilitate Brucella transepithelial migration. Simultaneously, the strong activation of the innate immune response pathways would suggest that the host mounts an appropriate protective immune response; however, the expression of the two key genes that encode innate immunity anti-Brucella cytokines such as TNF-α and IL12p40 were not significantly changed throughout the study. Furthermore, the defective expression of Toll-Like Receptor Signaling pathways may partially explain the lack of proinflammatory cytokine production and consequently the absence of morphologically detectable inflammation at the site of infection. Cumulatively, our results indicate that the in vivo pathogenesis of the early infectious process of Brucella is primarily accomplished by compromising the mucosal immune barrier and subverting critical immune response mechanisms.
authors.affiliation: Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, United States of America.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Rossetti
authors.affiliation: Seralogix, Limited Liability Corporation, Austin, Texas, United States of America.
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Drake
authors.affiliation: Seralogix, Limited Liability Corporation, Austin, Texas, United States of America.
authors.forename: Prasad
authors.initials: P
authors.lastname: Siddavatam
authors.affiliation: Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, United States of America.
authors.forename: Sara D
authors.initials: SD
authors.lastname: Lawhon
authors.affiliation: Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, United States of America.
authors.forename: Jairo E S
authors.initials: JE
authors.lastname: Nunes
authors.affiliation: Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, United States of America.
authors.forename: Tamara
authors.initials: T
authors.lastname: Gull
authors.affiliation: Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, United States of America.
authors.forename: Sangeeta
authors.initials: S
authors.lastname: Khare
authors.affiliation: Department of Animal Sciences, University of Illinois, Urbana, Illinois, United States of America.
authors.forename: Robin E
authors.initials: RE
authors.lastname: Everts
authors.affiliation: Department of Animal Sciences, University of Illinois, Urbana, Illinois, United States of America.
authors.forename: Harris A
authors.initials: HA
authors.lastname: Lewin
authors.affiliation: Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, United States of America.
authors.forename: Leslie Garry
authors.initials: LG
authors.lastname: Adams
mesh_terms: D000818:Animals; D001422:Bacterial Adhesion; D001499:Bayes Theorem; D017347:Brucella melitensis / Q000276:immunology / Q000472:pathogenicity*; D002006:Brucellosis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D002417:Cattle; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D007082:Ileum / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D057131:Immune Evasion; D007113:Immunity, Innate; D018928:Immunity, Mucosal; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D008297:Male; D058977:Molecular Sequence Annotation; D010581:Peyer's Patches / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D015398:Signal Transduction; D049490:Systems Biology; D059467:Transcriptome / Q000276:immunology*