Streptococcus agalactiae (group B Streptococcus [GBS]) is an important cause of invasive infection in newborns, maternal women, and older individuals with underlying chronic illnesses. GBS has many mechanisms to adapt and survive in its host, and these mechanisms are often controlled via two-component signal transduction systems. In GBS, more than 20 distinct two-component systems (TCSs) have been classified to date, consisting of canonical TCSs as well as orphan and atypical sensors and regulators. These signal transducing systems are necessary for metabolic regulation, resistance to antibiotics and antimicrobials, pathogenesis, and adhesion to the mucosal surfaces to colonize the host. This minireview discusses the structures of these TCSs in GBS as well as how selected systems regulate essential cellular processes such as survival and colonization. GBS contains almost double the number of TCSs compared to the closely related Streptococcus pyogenes and Streptococcus pneumoniae, and while research on GBS TCSs has been increasing in recent years, no comprehensive reviews of these TCSs exist, making this review especially relevant.
Group A streptococcus (GAS) produces millions of infections worldwide, including mild mucosal infections, postinfection sequelae, and life-threatening invasive diseases. During infection, GAS readily acquires nutritional iron from host heme and hemoproteins. Here, we identified a new heme importer, named SiaFGH, and investigated its role in GAS pathophysiology. The SiaFGH proteins belong to a group of transporters with an unknown ligand from the recently described family of energy coupling factors (ECFs). A siaFGH deletion mutant exhibited high streptonigrin resistance compared to the parental strain, suggesting that iron ions or an iron complex is the likely ligand. Iron uptake and inductively coupled plasma mass spectrometry (ICP-MS) studies showed that the loss of siaFGH did not impact GAS import of ferric or ferrous iron, but the mutant was impaired in using hemoglobin iron for growth. Analysis of cells growing on hemoglobin iron revealed a substantial decrease in the cellular heme content in the mutant compared to the complemented strain. The induction of the siaFGH genes in trans resulted in the induction of heme uptake. The siaFGH mutant exhibited a significant impairment in murine models of mucosal colonization and systemic infection. Together, the data show that SiaFGH is a new type of heme importer that is key for GAS use of host hemoproteins and that this system is imperative for bacterial colonization and invasive infection. IMPORTANCE ECF systems are new transporters that take up various vitamins, cobalt, or nickel with a high affinity. Here, we establish the GAS SiaFGH proteins as a new ECF module that imports heme and demonstrate its importance in virulence. SiaFGH is the first heme ECF system described in bacteria. We identified homologous systems in the genomes of related pathogens from the Firmicutes phylum. Notably, GAS and other pathogens that use a SiaFGH-type importer rely on host hemoproteins for a source of iron during infection. Hence, recognizing the function of this noncanonical ABC transporter in heme acquisition and the critical role that it plays in disease has broad implications.
4-hour in vitro growth curves of a type III group B streptococcus (GBS) and Escherichia coli were examined in sterile term human amniotic fluid specimens. Both bacterial strains proliferated despite ratios of phosphate to elemental zinc in the range reportedly inhibitory for E. coli. After 4 h of incubation, despite comparable inocula, GBS numbers exceeded those of E. coli by 10-fold to 100-fold. The strikingly rapid growth of some GBS strains in amniotic fluid may represent yet another factor responsible for perinatal GBS infection of the human neonate.
Group A Streptococcus (GAS) is a major pathogen that causes simple and invasive infections. GAS requires iron for metabolic processes and pathogenesis, and heme is its preferred iron source. We previously described the iron-regulated hupZ in GAS, showing that a recombinant HupZ-His6 protein binds and degrades heme. The His6 tag was later implicated in heme iron coordination by HupZ-His6. Hence, we tested several recombinant HupZ proteins, including a tag-free protein, for heme binding and degradation in vitro. We established that HupZ binds heme but without coordinating the heme iron. Heme-HupZ readily accepted exogenous imidazole as its axial heme ligand, prompting degradation. Furthermore, HupZ bound a fragment of heme c (whose iron is coordinated by the cytochrome histidine residue) and exhibited limited degradation. GAS, however, did not grow on a heme c fragment as an iron source. Heterologous HupZ expression in Lactococcus lactis increased heme b iron use. A GAS hupZ mutant showed reduced growth when using hemoglobin as an iron source, increased sensitivity to heme toxicity, and decreased fitness in a murine model for vaginal colonization. Together, the data demonstrate that HupZ contributes to heme metabolism and host survival, likely as a heme chaperone. HupZ is structurally similar to the recently described heme c-degrading enzyme, Pden_1323, suggesting that the GAS HupZ might be divergent to play a new role in heme metabolism.
Neonatal GBS disease is a major cause of morbidity and mortality, and maternal vaginal colonization is the leading risk factor for the disease. Colonization prevention would greatly impact the rates of disease transmission, but vaccine development has stalled as capsular polysaccharide vaccines have low immunogenicity in vivo. While these vaccines are still in development, the addition of a protein conjugate may prove fruitful in increasing immunogenicity and strain coverage across GBS serotypes.
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