Diminished Capsule Exacerbates Virulence, Blood–Brain Barrier Penetration, Intracellular Persistence, and Antibiotic Evasion of Hyperhemolytic Group B Streptococci

Abstract

Group B streptococci (GBS) are encapsulated, β-hemolytic bacteria that are a common cause of infections in human newborns and certain adults. Two factors important for GBS virulence are the sialic acid capsular polysaccharide that promotes immune evasion and the hemolytic pigment that induces host cell cytotoxcity. These virulence factors are often oppositely regulated by the CovR/CovS two-component system. Clinical GBS strains exhibiting hyperhemolysis and low capsule due to pathoadaptive covR/S mutations have been isolated from patients. Given the importance of capsule to GBS virulence, we predicted that a decrease or loss of capsule would attenuate the virulence of covR/S mutants. Surprisingly, hyperhemolytic GBS with low or no capsule exhibit increased virulence, intracellular persistence, and blood-brain barrier penetration, which was independent of a Trojan horse mechanism of barrier penetration. Additionally, intracellular persistence enabled both hemolytic and hyperhemolytic GBS to evade antibiotics routinely used to treat these infections. The finding that diminished capsule expression promotes GBS virulence, intracellular persistence, and antibiotic evasion has important implications for sustained antibiotic therapy and efficacy of capsule-based vaccines.

The CovR regulatory network drives the evolution of Group B Streptococcus virulence

“…This non-canonical regulation appears conserved in GBS with clusters of prophages genes showing an opposite regulation in the Δ covR and CovR D53A mutants. The mechanism might involve a competition between non-phosphorylated CovR and a nucleoid-associated protein (NAP), as observed in S. mutans (57, 58), and might also be co-opted to regulate other loci such as the capsule operon which shows strain-specific CovR regulation (59). The regulation of mobile elements by NAPs or by the recruitment of an ancestral regulatory network, such as PhoP/Q or OmpR/EnvZ two-component systems, have been extensively described in Gram-negative bacteria (28, 60).…”

The Double Life of Group B Streptococcus: Asymptomatic Colonizer and Potent Pathogen

“…Additionally, CPS sialic acid binds to host inhibitory Siglecs (Sialic acid-binding immunoglobulin-type lectins), which reduces neutrophil activation and inflammation of the placental membranes [133][134][135], dampens pro-inflammatory signaling in vivo [136], and facilitates bacterial dissemination [136]. Interestingly, diminished CPS expression enhances GBS's ability to invade epithelial and endothelial cells in vitro [137,138], and acapsular, hyper-hemolytic GBS more readily disseminates to peripheral organs and crosses the BBB in vivo [139]. Also, sialoadhesin present in splenic macrophages binds CPS sialic acid and promotes phagocytic uptake, thereby restricting GBS dissemination [140].…”

Virulence Factors of Meningitis-Causing Bacteria: Enabling Brain Entry across the Blood–Brain Barrier

“…The capsular polysaccharide has a protective function in bloodstream survival [46]. However, it was observed to attenuate invasion of the BBB and BCSFB [47,48,49]. This could result from electrostatic repulsion or from the masking of bacterial surface structures [8].…”

“…The necessity of high-level bacteremia indicates that bloodstream survival is an important virulence factor of the pathogen along with the sialylated GBS capsular polysaccharide [108]. Additionally, reduction of capsule expression by GBS was demonstrated to increase virulence and intracellular persistence [49]…”

“…Direct interaction of GBS with the BBB endothelium has been demonstrated, resulting in traversal of the barrier and subsequent infection of the CNS [49,109]. Both direct invasion of the BBB and/or brain invasion as a direct result of increased permeability of the barrier have been observed [4].…”