. Streptococcus agalactiae (group B Streptococcus; GBS) is a leading cause of invasive infections such as pneumonia, sepsis, and meningitis in neonates. GBS is also an emerging cause of disease among the immunocompromised and elderly. Regulation of virulence determinants and factors important for survival within the host most likely occurs as GBS transitions through different host environments during the progression of disease. However, the regulatory mechanisms in GBS governing its survival within the host and virulence have not been extensively studied. While some pathogens such as Staphylococcus aureus, Streptococcus pyogenes, and Clostridium perfringens are armed with a wide variety of toxins and other molecules that damage the host, it is not apparent that GBS elaborates a large repertoire of `classical' virulence factors. Despite it paucity of virulence factors, GBS can be highly lethal to individuals with immature or poorly functioning immune systems. GBS grows rapidly within the host during acute stages of infection. We posit that ability to acquire nutrients is extremely important to the virulence of GBS. Unlike other pathogens that can synthesize their own nutrients, GBS is fastidious and must scavenge many amino acids and other metabolites from its host. We have discovered that a novel transcriptional regulator, MtaR, is essential for virulence, growth under low-methionine conditions, and transport of methionine. We have identified a gene cluster (the metQ1 region) that is dependent on MtaR for expression and may encode the methionine transport system. The central hypothesis of this proposal is that MtaR-controlled genes permit growth under low-methionine conditions and are important for GBS virulence. Test of the central hypothesis will be conducted through two Specific Aims. 1) Determine the contribution of the metQ1 region to methionine transport, methionine-dependent growth, and virulence. 2) Globally identify genes under the control of MtaR and genes necessary for methionine-dependent growth. Taken together, results from these aims will determine the contribution of methionine transport to GBS virulence and will identify genes that are under the control of MtaR, whether the control is direct or indirect. In addition to the testing our specific hypothesis, completion of the aims may uncover new links between MtaR, virulence, and metabolism. ? ? This proposal seeks to identify properties of a pathogenic bacterium, group B streptococcus, that allow it to cause disease. ? ? ? ?
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