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Enhanced Invasiveness of Bovine-Derived Neonatal Sequence Type 17 Group B Streptococcus Is Independent of Capsular Serotype

  1. Nicola Jones1,
  2. Karen A. Oliver1,
  3. Joanne Barry1,
  4. Rosalind M. Harding3,
  5. Naiel Bisharat1,
  6. Brian G. Spratt4,
  7. Tim Peto2,
  8. Derrick W. Crook1, and
  9. Oxford Group B Streptococcus Consortium
  1. 1Infectious Disease and Microbiology, Oxford
  2. 2Nuffield Department of Medicine, John Radcliffe Hospital, Oxford
  3. 3Department of Statistics, University of Oxford, Oxford
  4. 4Department of Infectious Disease Epidemiology, Faculty of Medicine, Imperial College, St. Mary's Hospital, London, United Kingdom
  1. Reprints or correspondence: Dr. Nicola Jones, Nuffield Dept. for Clinical Laboratory Sciences, Level 7 Dept. of Microbiology, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom (nicola.jones{at}ndcls.ox.ac.uk).
 
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Abstract

Background. A defined geographical area (Oxford, United Kingdom) was investigated for the role of group B Streptococcus (GBS) as a human pathogen.

Methods. GBS carriage in pregnant women and invasive disease in neonates and adults >60 years of age was studied over a 3-year period. Multilocus sequence typing and capsular serotyping were used to study 369 isolates of GBS from carriage in pregnant women (n = 190) and invasive disease in neonates (n = 109) and adults >60 years of age (n = 70).

Results. A total of 20.3% of pregnant women carried GBS. Invasive GBS disease occurred at a rate of 0.9 cases per 1000 live births and 11 cases per 100,000 population >60 years of age per annum. Four sequence types (STs) (ST-17, ST-19, ST-23, and ST-1) that were identified with use of multilocus sequence typing accounted for >50% of carried and invasive strains. A single sequence type (ST-17), previously shown to be phylogenetically of bovine origin, was significantly associated with increased invasiveness in neonates (P = .00002), and this was independent of capsular serotype III. In contrast, among adults >60 years of age, no STs exhibited increased invasiveness, compared with STs carried in pregnant women.

Conclusions. Enhanced invasiveness associated with ST-17 is specific to neonates and is independent of capsular serotype.

Group B Streptococcus (GBS), also known as Streptococcus agalactiae, is commonly carried asymptomatically in the bowel and genitourinary tract of healthy adults [1]. In recent years, it has become the leading infectious cause of neonatal morbidity and mortality and neonatal meningitis in Europe [2, 3] and North America [4]. GBS infection has also been described as an emerging infection among older adults [5, 6], particularly those with chronic medical conditions, including diabetes mellitus, liver cirrhosis, and malignancy [4].

There is a type-specific polysaccharide capsule on the GBS surface [7]. Nine capsular types have been characterized (IA, IB, and II–VIII) and have been traditionally used to distinguish between strains. It has been recognized that serotype-specific capsular polysaccharides are essential for pathogenesis and that type III is prevalent among invasive strains [8].

The presence of terminal sialic acid residues on GBS type III polysaccharide is believed to inhibit the activation of the alternative complement pathway, thereby conferring resistance to phagocytosis in the nonimmune plasma and contributing to virulence [9, 10]. An oligosaccharide motif that is present on the GBS surface is very similar to the sialyl Lewis antigen and related epitopes on human glycolipids and glycoproteins and may represent molecular mimicry [11].

Preliminary work on GBS multilocus sequence typing (MLST) using a global collection of isolates [12] has shown that capsular serotype does not strictly follow sequence type (ST) and that a single bovine-derived ST (ST-17) appears to be overrepresented in neonatal disease [13]. It is unclear whether ST-17 is also overrepresented in adult disease.

To better investigate the enhanced invasiveness of this GBS ST-17 lineage, a large and representative collection of invasive and carried GBS isolates obtained over the same time period and from a geographically well-defined human population is required. Here, the findings of an investigation of the epidemiology and population biology of GBS infection in a single geographical area of the United Kingdom during 2000–2003 are reported. GBS isolates collected from subjects with GBS carriage, from neonates with invasive disease, and from adults with invasive disease were included in the study. Isolates of GBS were characterized by capsular serotyping and MLST.

This study is unique in that it reports a survey of GBS isolates in a geographically defined area and encompasses asymptomatic carriage of GBS in pregnant women and the burden of GBS disease in 2 groups at high risk for GBS infection (i.e., neonates and adults >60 years of age). The previous finding of an overrepresentation of ST-17 among neonatal invasive isolates is confirmed and is shown to be specific to the neonatal age group.

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Methods

Assembly of Collections

Invasive isolates. GBS strains isolated from normally sterile sites were collected prospectively from March 2000 to September 2003 from neonates (n = 109), children (n = 7), adults ⩽60 years of age (n = 84), and adults >60 years of age (n = 70). The study sites were the Oxford Radcliffe Hospitals (Oxford, United Kingdom) and adjacent hospitals in the Oxford GBS consortium. The area of study included 6 counties in the southeast of England (Oxfordshire, Wiltshire, Bedfordshire, Berkshire, Buckinghamshire, and Northamptonshire) with a total population of ∼3 million people. No cases from outside the region were observed in the study.

Carried isolates. A prospective GBS carriage study was performed in the 2 antenatal departments of Oxfordshire (Oxford and Banbury Hospitals; source population, 605,488) during 2001–2003. Vaginorectal swabs collected from women in the final trimester of pregnancy (from week 34 of gestation onwards) were cultured for GBS [14], and the resultant GBS isolates formed the collection of carried strains. These samples were obtained with full ethics committee approval.

Enhanced Surveillance

Incidence rates for invasive GBS were calculated for the subset of strains assembled prospectively from the Oxfordshire area only. The population estimates from the Oxfordshire 2001 census (available at http://www.statistics.gov.uk) were used.

ORs for Invasive Disease

ORs and their 95% CIs were calculated as described elsewhere [15]. An OR of 1.0 indicates that a clone was equally likely to be associated with invasive disease as with carriage, whereas a ratio >1.0 or <1.0 indicates that the strain was associated with invasive disease or carriage, respectively. The OR and 95% CIs were calculated using the χ2, Yates corrected, or Fisher's exact tests (Epi Info 2002, available from the Centers for Disease Control and Prevention [16]) when appropriate. To allow for multiple comparisons for individual comparisons, a P value of <.005 was considered to be significant.

Identification of GBS

Isolates were grown on 5% horse blood agar and were identified as GBS according to the following criteria: β-haemolysis on blood agar (1% of strains were nonhaemolytic), Gram stain with microscopic examination showing gram-positive cocci in pairs or short chains, a negative reaction with catalase reagent, and Lancefield grouping with serotype B (Oxoid). Isolates of GBS were kept frozen at -80°C in Tryptone-soy broth with 10% glycerol.

Characterization of Isolates

The following 3 groups of isolates were further characterized with use of MLST: isolates associated with asymptomatic carriage in pregnant women, invasive isolates obtained from neonates, and invasive isolates obtained from adults >60 years of age. Capsular serotyping with use of latex agglutination was undertaken on carried isolates from pregnant women and invasive isolates obtained from neonates according to methods described elsewhere [17].

Methods for DNA extraction and MLST allele and ST assignment. For each isolate, ∼500-bp fragments of 7 housekeeping genes were amplified with use of PCR and sequenced as described elsewhere [12]. The studied genes were alcohol dehydrogenase, phenylalanyl tRNA synthetase, amino acid transporter protein, glutamine synthetase, serine dehydratase, glucose kinase, and transketolase. Each different sequence was assigned a novel allele number, and the combination of the 7 allele numbers provided the allelic profile of the isolate. Each different allelic profile was assigned a novel ST. Alleles were assigned using the GBS MLST Web site (available at: http://pubmlst.org/sagalactiae/); the sequences of new alleles were deposited at this Web site.

Computational analyses. DNA sequences were assembled from chromatograms with use of the Staden suite of computer programs [18]. Concatenated sequences of the 7 MLST loci were assembled as described elsewhere [13] and analyzed with use of the unweighted pair-group method of arithmetic means algorithm from Molecular Evolutionary Genetic Analyses software, version 2.1 [19].

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Results

Carriage study. A total of 748 women were recruited over a 2-year period (2001–2003) as part of the Oxfordshire carriage study; of these, 159 women (21.3%) were vaginorectal carriers of GBS. An additional 31 GBS isolates collected from routine antenatal vaginal swabs from pregnant women from the same region during the same period made up the collection (n = 190) for MLST analysis.

Epidemiology of invasive disease. A total of 109 isolates of GBS were obtained from neonates, of whom 55 (50.5%) were female. Onset of neonatal disease occurred early (<7 days after birth) in 64 (58.7%) of the cases. A total of 70 GBS isolates were collected from adults >60 years of age. Blood cultures were the most common sourse of GBS isolates (table 1).

Table 1
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Table 1

Sources of cultures positive for group B Streptococcus (GBS) in neonates and adults >60 years of age with invasive GBS disease.

With use of data from Oxford hospitals alone, there were a total of 155 cases of invasive GBS disease. The distribution of cases according to age and the incidence rates of invasive GBS infection for specific age groups were calculated using census figures for the population of Oxfordshire (figure 1). Disease incidence was highest among neonates and adults >60 years of age. Live birth cohort figures for the period September 2000–December 2003 at the Oxford hospitals were used to calculate the incidence of neonatal GBS infection; this was determined to be 0.94 cases per 1000 live births overall, with 0.63 cases of early-onset infection per 1000 live births and 0.31 cases of late-onset infection (i.e., infection occurring 7–90 days after birth) per 1000 live births.

Figure 1
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Figure 1

Incidence of invasive group B streptococcal disease in Oxfordshire, United Kingdom, 2000–2003. Bars, total number of cases; line, age-adjusted annual incidence rate; whiskers, 95% CIs.

MLST and capsular serotyping. A total of 369 GBS isolates were available for MLST. Of these, 190 were obtained from pregnant women with asymptomatic carriage, 109 were obtained from patients with invasive neonatal disease, and 70 were obtained from adults with invasive disease who were >60 years of age.

MLST identified 60 STs among the 369 isolates (table 2). There were 38 STs among the isolates associated with asymptomatic carriage, 29 STs among the isolates from neonates with invasive disease, and 27 STs among the isolates from adults with invasive disease who were >60 years of age. The most prevalent STs among the isolates from pregnant women with asymptomatic carriage and adults >60 years of age with invasive disease were ST-23, ST-19, and ST-1. In contrast, isolates from neonates with invasive disease were ST-17 in 30.3% of cases, with ST-1 (15.6%), ST-23 (11.9%), and ST-19 (11.0%) occurring less frequently.

Table 2
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Table 2

Multilocus sequence typing (ST) characterization of group B Streptococcus (GBS) isolates from patients with invasive GBS disease and GBS carriage.

Examination of capsular serotype (table 3) for isolates from pregnant women with asymptomatic carriage and neonates with invasive disease revealed that, among the more-common STs, only ST-17 was homogeneous; all 52 isolates of ST-17 were capsular serotype III. ST-23 was predominantly associated with capsular serotype IA (found in 47 [94%] of 50 strains), ST-1 was predominantly associated with serotype V (39 [78%] of 50), ST-8 was predominantly associated with serotype IB (15 [88%] of 17), and ST-19 was predominantly associated with serotype III (37 [92.5%] of 40).

Table 3
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Table 3

Capsular serotypes according to sequence type (ST) of group B Streptococcus (GBS) isolates from asymptomatic pregnant women and neonates with invasive GBS disease.

The concatenated sequences of the STs were used to construct a tree with the unweighted pair-group method of arithmetic means clustering algorithm (Molecular Evolutionary Genetic Analyses software, version 2.1 [19]), shown in figure 2. The STs were grouped into previously defined clonal complexes by analysis using the Based upon Related Sequence Types (BURST) algorithm [12]; these clonal complexes include ST-1 complex, ST-6 complex, ST-10 complex, ST-17 complex, ST-19 complex, and ST-23 complex. The relationships observed here did not differ from those already described for the GBS population as determined by MLST.

Figure 2
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Figure 2

Unweighted pair-group method of arithmetic means (UPGMA) tree showing genetic relationships between 60 sequence types (STs) of group B Streptococcus, isolated from patients with asymptomatic carriage and from neonates and adults >60 years of age with invasive disease. Clonal complexes are indicated by brackets.

Calculation of invasiveness ratios. The ORs were calculated for STs with a total of >10 representatives (i.e., ST-1, ST-8, ST-12, ST-17, ST-19, and ST-23). The ORs for neonatal invasive disease are shown in table 4. Overall, for the 6 STs with >10 isolates, there was evidence of a difference in the ST distribution between invasive and carried strains (χ26, 23.5; P = .001). For all but 1 of the STs, the OR for disease did not differ significantly from 1.0. The exception was ST-17, which was associated with an OR of 3.9 (95% CI, 2.0–7.7; P = .00002). There was no evidence of any difference between the distribution of ST types between early-onset and late-onset neonatal disease (χ26, 8.9; P = .2). Also, there was no convincing evidence of any difference between the invasiveness of ST-17 in cases of early-onset and late-onset disease (OR, 0.46; 95% CI, 0.18–1.14; χ21, 3.43; P = .064). There was no significant difference in the ORs of the STs (including ST-17) associated with invasive disease in adults >60 years of age (table 5).

Table 4
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Table 4

Calculation of invasiveness of group B Streptococcus (GBS) sequence types (STs) of isolates from neonates with invasive GBS disease (neonatal disease isolates), compared with STs of isolates from pregnant women with asymptomatic GBS carriage (carriage isolates).

Table 5
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Table 5

Calculation of invasiveness of group B Streptococcus (GBS) sequence types (STs) of isolates from adults >60 years of age with invasive GBS disease (adult disease isolates), compared with STs of isolates from pregnant women with asymptomatic GBS carriage (carriage isolates).

Capsular serotype was significantly associated with invasiveness in neonates (P = .0001; table 6), but when ST-17 was removed from the analysis, capsular serotype was no longer significantly associated with invasive disease in neonates (P = .08; table 6). This strongly suggests that invasiveness is independent of capsular serotype III.

Table 6
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Table 6

Correlation between capsular serotype and invasiveness for strains of group B Streptococcus (GBS) isolated from neonates with invasive GBS disease, compared with strains isolated from pregnant women with asymptomatic GBS carriage.

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Discussion

Enhanced invasiveness of GBS, as demonstrated in this study, is specific to the neonatal age group, is linked to a specific bovine-derived ST (ST-17), and is independent of capsular serotype. Neonates are believed to acquire infection from their colonized mothers [20–22]. A comparison of the prevalence of each ST of GBS in vaginorectal swabs of pregnant women in Oxfordshire with the STs causing neonatal invasive disease in the same region, therefore, allows us to identify genotypes that are significantly more likely than others to cause invasive disease. It could be argued that it is better to use isolates recovered from patients with early neonatal disease than isolates of strains carried by pregnant woman in calculating the invasive potential of GBS genotypes, because almost all cases of invasive disease are caused by strains traced to maternal carriage at the time of birth. Nonetheless, maternal carriage is also a major risk factor for late-onset disease in neonates [22]. Furthermore, no evidence for a difference in invasiveness of ST-17 between early-onset and late-onset invasive GBS disease in neonates could be found in this study, suggesting that ST-17 is a more invasive lineage for both categories of neonatal GBS disease.

A recently published population-based study from Israel has findings similar to those reported here—namely, that study found that ST-17 was uniquely associated with enhanced invasiveness in neonates [23]. Davies et al. [24], in a smaller study that was restricted in design to serotype III and early-onset invasive GBS disease, found little difference between the invasive postential of ST-17 and that of ST-19 in neonates. However, they did not compare ST-17 with all other serotypes and genotypes. We have reanalyzed our data, the data from the study from Israel [23], and the data from Davies et al. [24] for the subset of ST-17 and ST-19 GBS, and we calculated their invasive ratios. For the current study, the OR was 2.05 (95% CI, 0.96–4.36); for the study from Israel [23], the OR was 3.93 (95% CI, 1.12–13.75); and for the study from Alberta [24], the OR was 1.15 (95% CI, 0.43–3.09). The overall Mantel-Hanzel pooled OR was 1.95 (95% CI, 1.14–3.31; P = .014), and there was no evidence of heterogeneity between the studies (χ22, 2.31; P = .32). The findings of this overall comparative analysis are consistent with the enhanced invasiveness of ST-17 rather than of the serotype III phenotype.

Our study adds to the body of evidence supporting the finding that strains of serotype III consist of >1 genetic lineage and demonstrates that pathogenicity in GBS is caused by factors other than the type III capsule alone. The overrepresentation of ST-17 among isolates from neonates with invasive disease is detected worldwide [12]. This suggests that this clone has spread widely and is a “global” neonatal invasive clone. Intriguingly, a phylogenetic analysis has previously shown this clone to be derived from the bovine population of GBS [13]. This suggests that there has been acquisition of this more-invasive human neonatal GBS clone from cattle.

The finding that serotype identity does not indicate close genetic relatedness in GBS was reported by Musser et al. [25] in 1989. In particular, 2 distinct evolutionary divisions of serotype III strains that differed in virulence were inferred from multilocus enzyme electrophoresis (MLEE) [25] and by restriction digest pattern (RDP) typing [26]. The more-virulent lineages (ET-1 by MLEE and RDP type III-3) were each distinct and are equivalent to ST-17, as has been shown elsewhere [12]. Intriguingly, each investigation found enhanced expression by these types (equivalent to ST-17) of either extracellular neuraminidase [25] or capsular sialic acid [26]. In each case, they suggested that this phenotype may have accounted for the enhanced virulence of this lineage. This has not been independently demonstrated since these studies were published. However, the findings of these studies are consistent with ST-17 possessing properties that uniquely favour its invasiveness, as suggested in our study. Given the possible involvement of gene expression, the role of a gene regulator specific to the ST-17 lineage becomes a possible explanatory genetic factor for its enhanced invasiveness. Such global gene regulation of virulence and pathogenic factors is increasingly recognized as having a role in bacterial pathogenesis [27].

Other than ST-17, the other major STs (ST-23, ST-19, and ST-1 complexes) are not significantly associated with elevated odds of invasive neonatal disease and are likely to be well-adapted strains that have successfully colonized humans and cause invasive disease in a manner similar to opportunistic pathogens. No ST was significantly associated with increased invasiveness in adults >60 years of age, because the distribution of STs commonly identified in cases of asymptomatic carriage among pregnant woman were also those that were most commonly associated with disease among adults >60 years of age. These data are consistent with ST-17 being less invasive in the elderly population than in neonates; however, a very low rate of carriage of ST-17 in the elderly population could confound this inference. Such a low rate of carriage of ST-17 is not supported by the limited carriage data reported in the elderly population [28]. This indicates that serotype III GBS accounts for 12% of isolates and, because ST-17 is 1 of the 2 major serotype III genotypes found among GBS isolates, such very low prevalence of ST-17 in the elderly population is implausible. Nevertheless, a better understanding of differences among GBS isolates found in different age groups is needed, and this understanding would benefit from better studies of GBS carriage and genotypic characterization of the isolates.

The descriptive epidemiological findings of our study provide further support for the findings of previous studies. A total of 21% of women living in the area of Oxford, United Kingdom, are carriers of GBS. This prevalence is similar to the prevalence of GBS seen in studies from the Republic of Ireland [29] and London [30]. The incidence of neonatal GBS infection found in our study (0.94 cases per 1000 live births) is consistent with that found in a recent national study conducted in the United Kingdom, which found a nationwide rate of 0.9 cases per 1000 live births [31]. Older adults are thought to be at particular risk for invasive GBS infection. High rates of infection (11–72 cases per 100,000 population per year) [32, 33] have been described in older age groups, particularly among nursing home residents in North America. The findings of this report suggest that the prevalence of invasive GBS disease among individuals >60 years of age in the United Kingdom is similar to that found in the United States, where the prevalence is ∼11 cases of invasive GBS disease per 100,000 individual >60 years of age per year.

In summary, the population structure of GBS revealed by MLST indicates well-adapted human lineages of GBS, which are commonly isolated from individuals with GBS carriage and which cause disease in neonates and adults >60 years of age in an opportunistic fashion. In addition, a single, globally dispersed clone of GBS (ST-17), which is of bovine origin, has been identified and is significantly associated with enhanced invasiveness in neonates. The increased invasiveness of ST-17 is likely to be due to factors other than capsular serotype III alone. Future work, focusing particularly on ST-17 GBS, presents an opportunity to investigate a host-pathogen interaction that is unique to neonates and to a single lineage of GBS.

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Acknowledgments

We would like to acknowledge the Oxford GBS Consortium (consisting of microbiology departments from hospitals in Aylesbury [Dr. Paul Gillett and Dr. Jean O'Driscoll], Banbury [Dr. Chris Hall], Bedford [Dr. Lorraine Fitch], High Wycombe [Dr. David Waghorn and Dr. Mary Lyons], Kettering [Dr. Ros Cox and Dr. Manjulana Natarajan], Luton, [Dr. Mustafa Atta and Dr. Rohinton Mulla], Milton Keynes [Dr. Biren Das], Northampton [Dr. Minas Minassian and Dr. Tony Bentley], Oxford [Dr. Derrick Crook, Dr. Ian Bowler, Dr. Nicky Jones, Dr. Bridget Atkins, and Dr. Katie Jeffery], Reading [Dr. Andrew Stacey and Dr. Shabnam Iyer], Swindon [Dr. Barbara Kirkpatrick], and Slough [Dr. Albert Lessing and Dr. Mike McIntyre]); midwives from the John Radcliffe and Horton Hospitals, especially Yvonne Jones and Anne Haines; and laboratory and administrative staff at the Nuffield Department of Clinical Laboratory Sciences, especially David Griffiths and Man-Suen Chan, from Paediatric Bioinformatics (Oxford).

Financial support. Action Medical Research (SP3727), the Medical Research Council of the United Kingdom (G84/5455) and the Wellcome Trust (067147/Z/02/Z). G.B.S is a Wellcome Principal Fellow, and D.W.C. was a Wellcome Leave Fellow during this study.

Potential conflicts of interest. All authors: no conflicts.

  • Received September 19, 2005.
  • Accepted November 22, 2005.
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  1. Clin Infect Dis. (2006) 42 (7): 915-924. doi: 10.1086/500324
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