J. Mol. Microbiol. Biotechnol. (2002) 4(3): 197–203. JMMB Symposium Regulatory Factors of Bordetella pertussis Affecting Virulence Gene Expression Jochen Ko¨ nig, Andreas Bock, Anne-Laure Perraud, 1989). Phenotypic modulation depends on the activity Thilo M. Fuchs, Dagmar Beier, and Roy Gross* of the histidine kinase BvgS which is an environmental sensor located in the cytoplasmic membrane. Under Lehrstuhl fu¨ rMikrobiologie, Theodor-Boveri-Institut the appropriate conditions, the BvgS protein autophos- fu¨ rBiowissenschaften, Universita¨ tWu¨ rzburg, D- phorylates at a histidine residue in its transmitter 97074 Wu¨ rzburg, Germany domain and, subsequently, the phosphate is trans- ferred to an aspartic acid in the receiver domain of the BvgA response regulator. BvgA-P is then able to activate transcription from the virulence gene promo- Abstract ters leading to expression of several adhesins and toxins (Table 1) (Rappuoli, 1994). Most pathogenic bacteria encounter changing The BvgAS system differs from typical two-com- growth conditions during their infectious cycle ponent systems, because BvgS contains additional and, accordingly, have to modulate gene expres- phosphorylation sites outside of its transmitter: In fact, sion to enable the efficient colonization of different an obligate multistep His-Asp-His-Asp phosphorelay environments outside or within their host organ- occurs that involves the BvgS transmitter, receiver and isms. In Bordetella pertussis the transcription of HPt domains (Figure 1) (Arico et al., 1989; Perraud most virulence factors including several toxins et al., 1999; Uhl and Miller, 1994,1996). The high and adhesins is regulated coordinately by the energy phosphohistidine present in the C-terminal HPt BvgAS two-component system. The molecular domain is the exclusive phosphate source for BvgA characterization of the BvgAS system revealed (Perraud et al., 1998). Furthermore, transcomplemen- that it belongs to the small group of unorthodox tation of mutant sensor proteins by the separate two-component systems applying an obligate mul- expression of individual signalling domains demon- tistep phosphorelay. Moreover, despite the coordi- strated that the phosphorelay in the BvgS histidine nated control of the virulence regulon, subtle kinase involves BvgS homodimers (Beier et al., 1995, differences in the regulation of individual virulence 1996). BvgA also forms homodimers, but, in contrast to genes were observed which led to the identifica- several other response regulators such as FixJ, there is tion of sophisticated mechanisms possibly no evidence for any influence of phosphorylation on its engaged in fine tuning of virulence gene expres- oligomerisation state (Bock, Rippe and Gross, sion. unpublished; Perraud et al., 2000). This shows that activation of BvgA by phosphorylation does not Coordinate Regulation of the Bvg-Regulon involve its dimerization (Perraud et al., 2000; Bock et al., 2001). It has been known for a long time that the expression of Little is known about the mechanisms of signal per- virulence properties of B. pertussis,theetiological ception and the control of the histidine kinase activity agent of whooping cough, is unstable. In fact, avirulent present in the transmitter domain of two-component so-called phase variants may arise with high fre- sensor proteins. However, like in other sensor proteins quency. Moreover, the virulent phenotype depends on the linker region of BvgS connecting the transmitter environmental conditions and is reversibly affected by domain with the membrane spanning region and the changes in the temperature and by several chemical periplasmic domain appears to be crucial, because compounds, a phenomenon termed phenotypic mod- point mutations in this linker can either cause the ulation.For example, the virulence regulon is only inactivation of BvgS or constitutive kinase activity expressed at body but not at room temperature. Both (Beier et al., 1996; Manetti et al., 1994; Miller et al., phenomena – phase variation and phenotypic modula- 1992). Interestingly, the BvgS linker region was tion –were shown to involve the BvgAS two-component recently shown by sequence similarity to contain a system (Arico et al., 1989; Cotter and DiRita, 2000; PAS domain which should be affected by these point Gross and Rappuoli, 1988,1989; Weiss and Falkow, mutations (Taylor and Zhulin, 1999). This may indicate 1984). Phase variation leads to a spontaneous and that the BvgS protein via its PAS domain is also able to usually irreversible loss of virulence gene expression perceive oxygen and/or the energy state of the due to mutations, frequently short deletions, in the bacteria. The preception of such stimuli would be in bvgAS gene locus (Monack et al., 1989; Stibitz et al., agreement with the fact, that also housekeeping functions including the cytochrome composition of the *For correspondence. Email [email protected]; terminal oxidase of the respiratory chain are Bvg- Tel. (931) 888 4403; Fax. (931) 888 4402. regulated (Cotter and DiRita, 2000). # 2002 Horizon Scientific Press Further Reading Caister Academic Press is a leading academic publisher of advanced texts in microbiology, molecular biology and medical research. 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Selected virulence factors of B. pertussis encoded by genes activated by the BvgAS two-component system. to several other bacterial phosphorelay systems including the ArcAB and EvgAS systems of E. coli. Factors Activity/Function The ArcAB system controls the aerobic modulation regulon and the EvgAS system controls expression of Pertussis Toxin (PTX) ADP-ribosylation of G-proteins adrugeffluxpump(Katoet al., 2000; Sawers 1999). In Adenylate cyclase toxin (CYA) Invasive adenylate cyclase general, the interaction of the histidine kinase and its and hemolysin cognate response regulator occurs with high specifi- Dermonecrotic toxin (DNT) Transglutaminase city, although in some particular two-component Filamentous hemagglutinin (FHA) Adhesion and colonization systems or under artificial conditions a cross-talk