Species- and Strain-Specific Control of a Complex, Flexible Regulon by Bordetella BvgAS

Abstract

؊ -and Bvg i -phase genes diverged substantially between species; regulation of metabolic, transporter, and motility loci indicated an increased capacity in B. bronchiseptica, compared to B. pertussis, for ex vivo adaptation. Strain comparisons also demonstrated variation in gene expression patterns within species. Among the genes with the greatest variability in patterns of expression, predicted promoter sequences were nearly identical. Our data suggest that the complement of transcriptional regulators is largely responsible for transcriptional diversity. In support of this hypothesis, many putative transcriptional regulators that were Bvg regulated in B. bronchiseptica were deleted, inactivated, or unregulated by BvgAS in B. pertussis. We propose the concept of a "flexible regulon." This flexible regulon may prove to be important for pathogen evolution and the diversification of host range specificity.

Differential regulation of type III secretion and virulence genes in Bordetella pertussis and Bordetella bronchiseptica by a secreted anti-σ factor

“…First, ΔbtrA strains display high level, BtrSdependent expression of flagellar and chemotaxis genes in cluster 1, which were previously assumed to be exclusively expressed in the Bvg-phase (4,42). A regulatory scheme that can account for these observations is shown in Fig.…”

“…4B), BtrA control could be uncoupled in a single step by mutation of a predicted BtrS-activated negative regulator. Indeed, our previously reported comparative microarray analysis showed that numerous transcriptional regulators that are expressed and BvgAS-regulated in B. bronchiseptica are missing, not transcribed, or present as pseudogenes in B. pertussis (4).…”

“…This transition also correlates with a systematic pattern of transcriptional diversity in the BvgAS virulence regulon that we hypothesized was due to functional alterations in regulatory factors that control clusters of loci in a hierarchical network (4). In B. bronchiseptica and B. pertussis, the transmembrane BvgS histidine kinase and BvgA response regulator coordinate expression of nearly all known colonization and virulence genes, an array of transcriptional regulators, and numerous genes of unknown function (3)(4)(5)(6). BvgAS establishes a spectrum of phenotypic phases in response to environmental cues, functioning as a rheostat that controls the infectious cycle (7,8).…”

“…The Bvg + phase is characterized by high level BvgAS activity, expression of virulence factors [including pertussis toxin (9), adenylate cyclase toxin (10,11), filamentous hemagglutinin (12), fimbriae (13), the Bordetella secretion complex (Bsc) type III secretion system (T3SS Bsc ) (14)(15)(16)], and the ability to survive and replicate on respiratory epithelia (17). In the Bvg phase, the BvgAS phosphorelay is quiescent, Bvg + phase genes are silent, and "virulence-repressed genes" are maximally transcribed (4,17,18). These genes include flagella and motility loci in B. bronchiseptica and genes with unknown function in B. pertussis.…”

“…As a result of their close evolutionary relationship, comparative studies exploiting the experimental tractability of B. bronchiseptica are relevant for understanding B. pertussis (3,4,7,16,(23)(24)(25). B. bronchiseptica isolates from diverse hosts, including humans, readily display T3SS activity in vitro (20).…”