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Group B Streptococcus: Virulence factors and pathogenic mechanisms

Group B Streptococcus: Virulence factors and pathogenic mechanisms
Author:
Lawrence C Madoff, MD
Section Editor:
Daniel J Sexton, MD
Deputy Editor:
Milana Bogorodskaya, MD
Literature review current through: Apr 2022. | This topic last updated: Oct 04, 2019.

INTRODUCTION — Group B Streptococcus (GBS; Streptococcus agalactiae) is a gram-positive coccus that frequently colonizes the human genital and gastrointestinal tracts [1,2]. It is an important cause of infection in three populations:

Neonates – GBS infection is acquired in utero by ascending infection or during passage through the vagina. Neonatal disease is categorized by the age at onset into early- and late-onset infection. Early-onset most commonly presents at or within 12 hours of birth but, by definition, can occur through day six of life. The most common manifestations are bacteremia without a focus, sepsis, pneumonia, and/or meningitis. Late-onset infection occurs after day six and up to 90 days of life. It most often presents as bacteremia without a focus (65 percent of cases) but meningitis (32 percent) and focal infections also occur. Late-onset infections most frequently are caused by serotype III GBS. (See "Group B streptococcal infection in neonates and young infants".)

Pregnant women – GBS is a frequent cause of urinary tract infection (usually asymptomatic bacteriuria), chorioamnionitis, postpartum endometritis, and peripartum bacteremia. (See "Group B streptococcal infection in pregnant individuals".)

Nonpregnant adults – GBS is increasingly recognized as a cause of sepsis, soft tissue infections, and other focal infections in nonpregnant adults. These infections occur predominantly in those with chronic underlying medical conditions, such as diabetes mellitus, malignancy especially breast cancer, and liver disease. However, GBS also can cause infection in healthy patients over the age of 65 years. (See "Group B streptococcal infections in nonpregnant adults".)

The microbiology of GBS will be reviewed here. GBS infection and treatment in neonates and young infants, pregnant women, and nonpregnant adults and prevention strategies through chemoprophylaxis and vaccination are discussed separately. (See "Group B streptococcal infections in nonpregnant adults" and "Group B streptococcal infection in neonates and young infants" and "Group B streptococcal infection in pregnant individuals" and "Prevention of early-onset group B streptococcal disease in neonates" and "Vaccines for the prevention of group B streptococcal disease".)

MICROBIOLOGY — Streptococcus agalactiae, the sole member of Lancefield group B, forms small 3 to 4 mm, grey-white colonies that have a narrow zone of beta hemolysis on blood agar [1,3,4]. Lancefield identified the group B antigen, a cell wall-associated carbohydrate that distinguishes GBS from other streptococcal species [4].

Clinical microbiology — GBS is identified in the clinical laboratory by its characteristic narrow zone of beta hemolysis; by its elaboration of CAMP factor, a phospholipase which enhances the hemolysis caused by beta lysins of many Staphylococcus aureus strains; and by biochemical characteristics, including lack of hydrolysis of bile esculin agar and hydrolysis of hippurate [1,2]. Commercial kits with antisera that recognize the group B antigen are used to confirm the identity of isolates.

Molecular methods such as real-time polymerase chain reaction are also used for rapid identification of GBS and are available commercially [5]. Whole genome sequencing may facilitate determination of serotype and antimicrobial resistance [6].

Virulence factors — GBS produces many extracellular substances, some of which have a role either in virulence or as protective antigens [1]. The best characterized are the capsular polysaccharides, which confer serotype specificity to GBS [7-9]. These complex carbohydrates are composed of approximately 150 repeating oligosaccharide subunits [10-13]. The 10 capsular serotypes (Ia, Ib, II, III, IV, V, VI, VII, VIII, and IX) currently recognized differ in their arrangements of monosaccharides within the oligosaccharide repeating units. However, each subunit contains a mono-, di-, or trisaccharide side chain terminating in an N-acetylneuraminic acid (sialic acid) residue.

The capsule confers virulence to the organism, at least in part, by inhibiting the deposition of complement components on the surface of the organism in the absence of serotype-specific antibody. The sialic acid moiety is critical to this function. Antibodies to capsular polysaccharide confer protection against invasive disease, at least in neonates and young infants [14]. Subsequent data suggest a role for GBS capsular sialic acid moieties in molecular mimicry of host structures. Capsular residues bind neutrophil Siglec-9 resulting in impaired neutrophil and platelet response [15,16]. Structural biology methods identified a linear, sialic acid-dependent, functional protective epitope within the type III polysaccharide recognized by a monoclonal antibody, which may be important for vaccine development [17].

The invasion associated gene (iagA), which encodes a glycosyltransferase and produces a cell membrane anchor for lipoteichoic acid, plays a role in bacterial invasion of the blood-brain barrier. In a mouse model of hematogenous meningitis, animals challenged with a GBS iagA mutant developed bacteremia comparable to mice challenged with wild-type GBS organisms, but had significantly lower mortality (20 versus 90 percent) and a decreased incidence of meningitis [18].

For a particular strain of serotype III GBS that has been strongly associated with neonatal meningitis after the first week of life, a surface-anchored protein called hypervirulent GBS adhesin (HvgA) is thought to mediate its hypervirulence [19]. Expression of HvgA promotes adherence to the intestinal epithelium and cells that form the blood-brain barrier. When GBS expressing HvgA are inoculated into mice, the bacteria can be detected in their meninges, brain parenchyma, and cerebral vasculature. In contrast, lower numbers of GBS are found at these sites in mice infected with HvgA deletion mutants.

The two-component CovR/S regulatory system controls numerous gene products that impact the virulence of GBS [20]. GBS strains lacking CovR/S, which acts as a hemolysin repressor, accelerate amniotic barrier failure and penetrate chorioamniotic membranes in a hemolysin-dependent manner [21]. Some hyperhemolytic clinical isolates from women in preterm labor are associated with CovR/S mutations. These isolates have been shown to allow ascending infection and fetal injury. The hemolysin appears to be an ornithine rhamnolipid pigment known as granadaene [22]. Another virulence mechanism for GBS is direct cytotoxicity to host phagocytes.

C proteins and other related surface proteins also are known to be involved in protective immunity and may have a role in virulence [23-26]. As an example, some neonatal isolates contain fewer tandem repeats in the alpha C surface protein than do their corresponding maternal isolate; these organisms, which may be selected for under specific antibody pressure, are less sensitive to killing by specific antibody [25]. On the other hand, in vitro studies show that organisms with larger numbers of repeats generate less antibody response [26]. The following hypothesis can reconcile these seemingly contradictory findings. In nature, GBS has a relatively high number of repeats, which tends to diminish the antibody response; if an antibody response occurs, the organism loses repeats, thereby removing the inciting antigen. In addition, the alpha C protein has been shown to have a role in invasion by GBS into cultured cervical epithelial cells that is related to binding of host glycosaminoglycans [27]. Homologous tandem-repeat containing proteins Rib, R, and Alp occur in many GBS strains [28]. The beta C protein, found in most serotype Ib GBS, binds specifically to human immunoglobulin (Ig)A [24], suggesting a role in virulence. Antibody to this protein is protective in animal models. Both C proteins have been used in experimental vaccines either alone or conjugated to capsular polysaccharides [28].

Pilins, long known for their role in virulence of gram-negative pathogens, have also been demonstrated to occur in group B streptococci and function as adhesins, promote CNS entry, and enhance biofilm formation [29]. Antibodies directed against pilus-islands 1, 2a, and 2b are protective in a murine model of lethal infection [30]. Sialylation of the PilA adhesion has been observed and suggests that this may contribute to stability and host interactions of the pilins [31]. Other substances produced by GBS, which enhance adherence to epithelial cells and extracellular matrix (and thus may enhance vaginal and other mucosal colonization) include serine-rich proteins (Srr1 and Srr2) that bind to host fibrinolytic proteins, alpha-like proteins, and bacterial surface adhesins BsaB, BspA, and BibA [32]. Other constituents that have putative roles in GBS virulence include hemolysins, protease CspA, complement inhibiting protein (CIP), Pbp1a, CAMP factor, plasminogen-binding protein (PbsP), hyaluronate lyase (hyaluronidase), complement factor 5a (C5a) peptidase, nucleases, and lipoteichoic acid. Among these, the best evidence for virulence in human infection is for beta hemolysin [33] and C5a peptidase [1].

Multiple complete genomic sequences for GBS have been published and are available through online databases [34,35]. Complete genomic sequencing of 202 invasive GBS of serotype V belonging to a virulent multilocus sequence type (ST 1) revealed the presence of a novel alpha-like protein [36]. The genomic analysis also suggested that small genetic changes (often at loci encoding capsule biosynthesis proteins, pilus regulation, and 2-component regulators) drove phenotypic diversity and that recombination appeared relatively unimportant. Analysis of genomic data should enable the identification of new vaccine antigens and improve the understanding of pathogenic mechanisms and epidemiology of GBS.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

Beyond the Basics topics (see "Patient education: Group B streptococcus and pregnancy (Beyond the Basics)")

SUMMARY

Group B Streptococcus is an important cause of invasive infection in neonates and pregnant women. It is also an increasingly recognized pathogen in other adults, particularly the elderly and those with underlying medical conditions. (See 'Introduction' above.)

It is the only Streptococcus in the Lancefield group B and is distinguished by its narrow zone of beta hemolysis, elaboration of CAMP factor, hydrolysis of hippurate, and lack of bile esculin agar hydrolysis. (See 'Clinical microbiology' above.)

Virulence factors include the polysaccharide capsule, C-proteins, and pilins, which are also targets of protective antibody responses. The invasion associated gene and, for certain strains, the hypervirulent GBS adhesion protein may be instrumental in the tropism of Group B Streptococcus for the central nervous system. (See 'Virulence factors' above.)

ACKNOWLEDGMENT — The author and editorial staff at UpToDate, Inc. would like to acknowledge Dr. Carol Baker for her contributions to this topic.

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