The homolactic and catalase-deficient pathogen Streptococcus pneumoniae is not only tolerant to oxygen but requires the activity of its NADH oxidase, Nox, to develop optimal virulence and competence for genetic transformation. In this work, we show that the global regulator RegR is also involved in these traits. Genetic dissection revealed that RegR regulates competence and the expression of virulence factors, including hyaluronidase. In bacteria grown in vitro, RegR represses hyaluronidase. At neutral pH, it increases adherence to A549 epithelial cells, and at alkaline pH, it acts upstream of the CiaRH two-component signaling system to activate competence. These phenotypes are not associated with changes in antibiotic resistance, central metabolism, and carbohydrate utilization. Although the RegR 0 (where 0 indicates the loss of the protein) mutation is sufficient to attenuate experimental virulence of strain 23477 in mice, the introduction of an additional hyl 0 (where 0 indicates the loss of function) mutation in the RegR 0 strain 23302 dramatically reduces its virulence. This indicates that residual virulence of the RegR 0 Hyl ؉ derivative is due to hyaluronidase and supports the dual role of RegR in virulence. This LacI/GalR regulator, not essential for in vitro growth in rich media, is indeed involved in the adaptive response of the pneumococcus via its control of competence, adherence, and virulence.Genetic transformability is one of the major attributes of the human pathogen Streptococcus pneumoniae. In vitro, this property appears as a consequence of a sequence of events leading to competence development in cultures growing exponentially, under aerobiosis. Competence and virulence are highly regulated, and there is increasing evidence linking the two phenomena at the genetic level. For instance, the ComD histidine kinase, the target for the competence-stimulating peptide encoded by comC (13,23,24,37), is required for virulence (28). Transcription of the comCDE operon is negatively controlled by the two-component system CiaRH (18), which is also involved in virulence (47). In addition, the virulence factor LytA, a choline binding protein showing autolytic activity (8,20), belongs to a late competence operon (32). Clearly, virulence expression depends on events involved in the competence signaling pathway. Furthermore, mutational alteration of cation transporters and metabolic enzymes decreases both competence and virulence. For instance, mutations affecting the transport of calcium have consequences on competence development, LytA-dependent autolysis, and virulence (4, 48, 49). The ABC transporters encoded by psa (and adc), involved in the uptake of Mn 2ϩ (and possibly Zn 2ϩ ), are important for growth and competence (15), and the psaA product is an essential virulence factor (10). Mutations of LicD2 and of Nox lead to the alteration of both competence and virulence expression (2, 28, 51, 52). For competence, the NADH oxidase Nox influences the pattern of ComCDE expression and transformability in culture...
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