Abstract
Group B Streptococcus (GBS), a common commensal of the female genital tract, is the leading cause of invasive infections in neonates. Expression of major GBS virulence factors, such as the hemolysin operon cyl, is regulated directly at the transcriptional level by the CovSR two-component system. Using a random genetic approach, we identified a multi-spanning transmembrane protein, Abx1, essential for the production of the GBS hemolysin. Despite its similarity to eukaryotic CaaX proteases, the Abx1 function is not involved in a post-translational modification of the GBS hemolysin. Instead, we demonstrate that Abx1 regulates transcription of several virulence genes, including those comprising the hemolysin operon, by a CovSR-dependent mechanism. By combining genetic analyses, transcriptome profiling, and site-directed mutagenesis, we showed that Abx1 is a regulator of the histidine kinase CovS. Overexpression of Abx1 is sufficient to activate virulence gene expression through CovS, overcoming the need for an additional signal. Conversely, the absence of Abx1 has the opposite effect on virulence gene expression consistent with CovS locked in a kinase-competent state. Using a bacterial two-hybrid system, direct interaction between Abx1 and CovS was mapped specifically to CovS domains involved in signal processing. We demonstrate that the CovSR two-component system is the core of a signaling pathway integrating the regulation of CovS by Abx1 in addition to the regulation of CovR by the serine/threonine kinase Stk1. In conclusion, our study reports a regulatory function for Abx1, a member of a large protein family with a characteristic Abi-domain, which forms a signaling complex with the histidine kinase CovS in GBS.
Highlights
In addition to defining the genetic network controlling virulence gene expression in Group B Streptococcus (GBS), we provide the first report of a cellular regulator of histidine protein kinase (HK) activity belonging to the large family of bacterial Abi-domain proteins
We extended this approach with approx. 2,500 new Himar1 mutants screened for hemolytic activity on blood agar plates and for pigmentation on Granada agar, a specific medium that stabilizes the GBS pigment [42]
Studies of two-component system (TCS) signaling in cellular context have identified a great variety of additional TCS partners, targeting either the HK or the RR [31,32]
Summary
The signals dictating the switch from commensalism to virulence are mainly unknown. Deciphering the molecular events that govern the transition between commensalism and virulence will contribute to understanding and controlling infections due to opportunistic pathogens. Streptococcus agalactiae (Group B Streptococcus, GBS) is a commensal bacterium of the adult gastro-intestinal tract and is present asymptomatically in the vaginal flora of 10–30% of healthy women [3]. GBS is the leading cause of invasive infections in neonates (pneumonia, septicaemia, and meningitis) and a serious cause of mortality or morbidity in adults with underlying diseases [4,5,6]. The ability of GBS to cause infections is multifactorial [7]. The main virulenceassociated GBS proteins identified to date are secreted or surface components, including the ß-hemolysin/cytolysin and specific adhesins [7,8,9,10]
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