Understanding the regulation of Group B Streptococcal virulence factors

Abstract

Bacterial infections remain a significant threat to the health of newborns and adults. Group B Streptococci (GBS) are Gram-positive bacteria that are common asymptomatic colonizers of healthy adults. However, this opportunistic organism can also subvert suboptimal host defenses to cause severe invasive disease and tissue damage. The increasing emergence of antibiotic-resistant GBS raises more concerns for sustained measures in treatment of the disease. A number of factors that are important for virulence of GBS have been identified. This review summarizes the functions of some well-characterized virulence factors, with an emphasis on how GBS regulates their expression. Regulatory and signaling molecules are attractive drug targets in the treatment of bacterial infections. Consequently, understanding signaling responses of GBS is essential for elucidation of pathogenesis of GBS infection and for the identification of novel therapeutic agents.

Figure 1. Lifecycle of Group B Streptococci as a neonatal pathogen

(A) GBS reside as a commensal in genital and lower gastrointestinal tracts of women. (B) GBS can infiltrate the intrauterine compartment in pregnant mothers who are asymptomatic carriers. (C) Newborn aspirate GBS in utero or during birth. (D) GBS invades the neonatal lung causing pneumonia. (E) From the lung, GBS gains access into the bloodstream of the neonate causing sepsis and invades multiple neonatal organs including the heart (F) GBS penetrates the blood–brain barrier causing meningitis. GBS: Group B Streptococci.

Figure 2. Regulation of factors important for Group B Streptococci disease pathogenesis

Two-component system (TCS) comprising the response regulators CovR, RgfA, CiaR and DltR, and their cognate sensor histidine kinases CovS, RgfC, CiaH and DltS, regulate the transcription of toxins and other factors that contribute to GBS virulence. These include the pore-forming toxins and factors that promote adherence, immune evasion and resistance to host defences. The genes regulated by 13 other TCS that are conserved in GBS serotypes are not known. Apart from TCS, GBS encodes signaling enzymes commonly found in eukaryotes, such as a serine threonine kinase Stk1 and its cognate phosphatase Stp1 that also regulates the expression of pore-forming toxins. Of the six standalone regulators, the function of only three (MtaR, RovS and RogB) have been examined. The genome sequence indicates that GBS encodes up to 107 regulatory molecules; the function of only a few are known. β-H/C: β-hemolysin/cytolysin; AMP: Antimicrobial peptide; C5ase: C5a peptidase; CAMP: Christie Atkins Munch Peterson; FbsA: Fibrinogen-binding protein A; GBS: Group B Streptococci LTA: Lipotechoic acid; Met: Methionine; Sia-CPS: Sialic acid capsular polysaccharide; SodA: Superoxide dismutase.