Brucella melitensis, B. neotomaeandB. ovisElicit Common and Distinctive Macrophage Defense Transcriptional Responses

Abstract

Brucella spp. establish an intracellular replicative niche in macrophages, while macrophages attempt to eliminate the bacteria by innate defense mechanisms. Brucella spp. possess similar genomes yet exhibit different macrophage infections. Few B. melitensis and B. neotomae enter macrophages with intracellular adaptation occurring over 4-8 hr. Conversely, B. ovis are readily ingested by macrophages and exhibit a persistent plateau of infection. Evaluating early macrophage interaction with Brucella spp. allows discovery of host entry and intracellular translocation mechanisms. Microarray analysis of macrophage transcriptional response following a 4 hr infection by different Brucella spp. revealed common macrophage genes altered in expression compared to uninfected macrophages. Macrophage infection with three different Brucella spp. provokes a common innate immune theme with increased transcript levels of chemokines and defense response genes and decreased transcript levels of GTPase signaling and cytoskeletal function that may affect trafficking of Brucella containing vesicles. For example, transcript levels of genes associated with chemotaxis (IL-1β, MIP-1α), cytokine regulation (Socs3) and defense (Fas, Tnf) were increased, while transcript levels of genes associated with vesicular trafficking (Rab3d) and lysosomal associated enzymes (prosaposin) were decreased. Genes with altered macrophage transcript levels among Brucella spp. infections may correlate with species specific host defenses and intracellular survival strategies. Depending on the infecting Brucella species, gene ontology categorization identified genes differentially involved in cell growth and maintenance, endopeptidase inhibitor activity and Gprotein mediated signaling. Examples of decreased gene expression in B. melitensis infection but not other Brucella spp. were growth arrest (Gas2), immunoglobulin receptor (FcγrI) and chemokine receptor (Cxcr4) genes, suggesting opposing effects on intracellular functions.

Key Role of Toll-Like Receptor 2 in the Inflammatory Response and Major Histocompatibility Complex Class II Downregulation in Brucella abortus-Infected Alveolar Macrophages

“…IL-12 was secreted by B. abortus-infected PM, in agreement with previous studies (40), but its production by infected AM was comparatively low and delayed. The monocyte chemoattractant MCP-1 has been shown to be induced by Brucella infection in the murine macrophagic cell line RAW 264.7 and microglia cells (46,47). In the present study, MCP-1 was produced early (24 h p.i.)…”

Transcriptome analysis of HeLa cells response to Brucella melitensis infection: a molecular approach to understand the role of the mucosal epithelium in the onset of the Brucella pathogenesis

“…Previous studies have described the molecular response of professional phagocytic cells at different time points after Brucella infection [13, 18–21]. Eskra et al .…”

“…and Covert et al found quite similar number of genes up- and down-regulated in a murine macrophage cell line infected with different Brucella species at 4 h p.i. [18, 19]. In general, genes associated with immune and inflammatory response were up-regulated, and genes involved in cell cycle/cell division/proliferation and differentiation, intracellular trafficking and metabolism were down-regulated.…”

Digital gene expression analysis of transcriptomes in lipopolysaccharide-induced acute respiratory distress syndrome

“…As reported in previous studies, Schlafen genes (Slfns), including Slfn1, Slfn2, Slfn4, Slfn5, and Slfn8, are upregulated by LPS [39][40][41][42][43] . Slfns were first discovered in mice by Schwarz et al in 1998 [39] as a multigene family whose members were differentially expressed during thymocyte maturation and T-cell activation.…”