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Volume 23, Number 1—January 2017
Letter

Group B Streptococcal Toxic Shock Syndrome and covR/S Mutations Revisited

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Abstract

Gene mutations in the virulence regulator CovR/S of group A Streptococcus play a substantial role in the pathogenesis of streptococcal toxic shock syndrome. We screened 25 group B Streptococcus (GBS) isolates obtained from patients with streptococcal toxic shock syndrome and found only 1 GBS clone harboring this kind of mutation.

Streptococcal toxic shock syndrome (STSS) is typically caused by Streptococcus pyogenes (group A Streptococcus [GAS]) (1). Major investigations on host-pathogen interactions have been performed to determine why some persons experience uncomplicated pharyngitis, but STSS develops in others. On a molecular level, mutations in covS (a sensor gene of the major virulence regulator CovR/S) have been frequently associated with invasive GAS disease (2). In 2009, we reported a case of STSS caused by S. agalactiae (group B Streptococcus [GBS]) and covS mutation (3). Here, we reassess those findings in a larger collection of GBS isolates causing STSS.

We tested 26 GBS isolates from 25 patients (22 adults, 3 children) (Table) that were pooled from 3 countries; the United States (22 strains collected 2004–2005), Germany (1 strain, 2006), and Switzerland (2 strains, 2005). For 1 of the 2 case-patients from Switzerland, 2 isolates (same clone) were available for mutation analyses (patient 23 [4]). The isolate from our previously published case report (Sweden, 2005 [3]) served as a control strain for molecular analyses; the corresponding case-patient was included in the demographic analyses (i.e., 26 patients: 23 adults, 3 children). The median age of the included adult patients was 59 years (interquartile range 45.5–68 years); mortality rate was 35% (8/23). The ages of the 3 children were 0, 30, and 60 days (1 death).

We used standard molecular biology techniques for nucleic acid preparation and analysis. We performed molecular typing by multilocus sequence typing (MLST) as described (5) and capsular typing by using latex agglutination and PCR serotype determination (6) (Table). To analyze the cov gene locus, we amplified the genes covS and covR by PCR (Technical Appendix Table). Resulting PCR products underwent DNA sequencing with internal cov primers on an ABI PRISM 310 Genetic Analyzer (Applied Biosystems, Weiterstadt, Germany).

Nucleotide sequence analysis showed that, in 1 of the strains (from patient 18), both genes, the sensor histidine kinase covS and the response regulator covR, had mutated. In covR, at nucleotide position 242, cytosine was replaced by thymine, leading to an amino acid exchange from alanine to valine. In addition, the covS gene of this strain showed a 1-bp deletion of adenine at position 895 of the gene, causing a frame shift and leading to a truncated CovS with a stop codon at nucleotide position 926 of the gene. In the control strain that harbored a 3-bp deletion, our previously published finding was confirmed (3). In the remaining strains, cov alleles matched the gene sequences of completely sequenced GBS strains in the GenBank database (NEM316, 2603V/R, 909A).

During the past few decades, the overall incidence of invasive GBS infections has increased substantially. This trend is particularly noticeable in the elderly and in persons with co-morbid conditions (7). Our results regarding age distribution of patients, mortality rate, and frequencies of different GBS serotypes are in line with results of previous studies. Twelve (52%) of 23 patients were >59 years old. The mortality rate for group B STSS (>30%) was similar to that reported for group A STSS (1). In a previous case series, which included 13 patients with group B STSS, the mortality rate was 23% (3/13) (8). Three-quarter of our strains (19/26 strains) were attributed to serotype V or Ia/Ib. Large epidemiologic studies have frequently implicated serotype s Ia/Ib, III, and V GBS isolates in the etiology of invasive disease in adults (9). Apart from sequence type (ST) 1 and ST23 (15/26 strains), the distribution of MLSTs among the GBS isolates was heterogeneous. The highly virulent GBS lineage ST17 was found in only 2 patients (1 adult and 1 child).

The role of covR/S mutations in the switch from colonization to invasion has been demonstrated for GAS in a mouse model (2). Consistent with these findings, GAS strains isolated from STSS patients frequently carry mutations in this operon (10). Similarly, a 3-bp deletion in the covR gene was detected in a GBS strain that caused STSS and necrotizing fasciitis (3). However, our investigations on a larger collection of GBS isolates did not confirm a high cov mutation rate. Only 1 of 25 GBS clones demonstrated a mutation. From 1 patient, a colonizing and invasive isolate (same clone) was available (4); that isolate showed no mutation in covR/S.

Our results should be interpreted with caution because the absolute number of included patients is small, and the cases were pooled from various centers. Nonetheless, Ikebe et al. found covR/S mutations in 76 (46.3%) of 164 GAS strains causing STSS and in only 1.7% of 59 strains without invasive disease (10). In light of these results, the low frequency of mutations found in our collection is surprising. Yet, the association with covR/S mutations and GBS TSS in a case report has been shown previously and confirmed here. However, GBS harbors multiple 2-component systems and stand-alone regulators. Our findings indicate that different virulence regulators may be involved in the pathogenesis of fulminant GBS disease.

Dr. Sendi is an attending physician and lecturer in infectious diseases at Bern University Hospital and University of Bern, Switzerland. His research interests are group B Streptococcus in nonpregnant adults and infections of the locomotor apparatus.

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Acknowledgment

We thank the Active Bacterial Core surveillance collective, including Bernard Beall and the Streptococcus Laboratory, Respiratory Diseases Branch, Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA, for generously providing GBS strains. We also are grateful to Stefanie Mauerer and Beatrice Reinisch for expert technical assistance.

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Parham Sendi1, Muad Abd el Hay1, Claudia M. Brandt, and Barbara SpellerbergComments to Author 

Author affiliations: University of Bern, Bern, Switzerland (P. Sendi); University of Ulm, Ulm, Germany (M. Abd el Hay, B. Spellerberg); Johann Wolfgang Goethe University, Frankfurt, Germany (C. Brandt)

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References

  1. Stevens  DL, Tanner  MH, Winship  J, Swarts  R, Ries  KM, Schlievert  PM, et al. Severe group A streptococcal infections associated with a toxic shock-like syndrome and scarlet fever toxin A. N Engl J Med. 1989;321:17. DOIPubMed
  2. Walker  MJ, Hollands  A, Sanderson-Smith  ML, Cole  JN, Kirk  JK, Henningham  A, et al. DNase Sda1 provides selection pressure for a switch to invasive group A streptococcal infection. Nat Med. 2007;13:9815. DOIPubMed
  3. Sendi  P, Johansson  L, Dahesh  S, Van-Sorge  NM, Darenberg  J, Norgren  M, et al. Bacterial phenotype variants in group B streptococcal toxic shock syndrome. Emerg Infect Dis. 2009;15:22332. DOIPubMed
  4. Sendi  P, Graber  P, Johansson  L, Norrby-Teglund  A, Zimmerli  W. Streptococcus agalactiae in relapsing cellulitis. Clin Infect Dis. 2007;44:11412. DOIPubMed
  5. Jones  N, Bohnsack  JF, Takahashi  S, Oliver  KA, Chan  MS, Kunst  F, et al. Multilocus sequence typing system for group B streptococcus. J Clin Microbiol. 2003;41:25306. DOIPubMed
  6. Poyart  C, Tazi  A, Réglier-Poupet  H, Billoët  A, Tavares  N, Raymond  J, et al. Multiplex PCR assay for rapid and accurate capsular typing of group B streptococci. J Clin Microbiol. 2007;45:19858. DOIPubMed
  7. Ballard  MS, Schønheyder  HC, Knudsen  JD, Lyytikäinen  O, Dryden  M, Kennedy  KJ, et al.; International Bacteremia Surveillance Collaborative. The changing epidemiology of group B streptococcus bloodstream infection: a multi-national population-based assessment. Infect Dis (Lond). 2016;48:38691. DOIPubMed
  8. Al Akhrass  F, Abdallah  L, Berger  S, Hanna  R, Reynolds  N, Thompson  S, et al. Streptococcus agalactiae toxic shock-like syndrome: two case reports and review of the literature. Medicine (Baltimore). 2013;92:104. DOIPubMed
  9. Lambertsen  LM, Ingels  H, Schønheyder  HC, Hoffmann  S; Danish Streptococcal Surveillance Collaboration Group 2011. Nationwide laboratory-based surveillance of invasive beta-haemolytic streptococci in Denmark from 2005 to 2011. Clin Microbiol Infect. 2014;20:O21623. DOIPubMed
  10. Ikebe  T, Ato  M, Matsumura  T, Hasegawa  H, Sata  T, Kobayashi  K, et al. Highly frequent mutations in negative regulators of multiple virulence genes in group A streptococcal toxic shock syndrome isolates. PLoS Pathog. 2010;6:e1000832. DOIPubMed

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Cite This Article

DOI: 10.3201/eid2301.161063

1These authors contributed equally to this article.

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Table of Contents – Volume 23, Number 1—January 2017

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Barbara Spellerberg, Institute of Medical Microbiology and Hygiene, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany

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Page created: December 16, 2016
Page updated: December 16, 2016
Page reviewed: December 16, 2016
The conclusions, findings, and opinions expressed by authors contributing to this journal do not necessarily reflect the official position of the U.S. Department of Health and Human Services, the Public Health Service, the Centers for Disease Control and Prevention, or the authors' affiliated institutions. Use of trade names is for identification only and does not imply endorsement by any of the groups named above.
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