Sentinel hospital surveillance was instituted in Australia to detect the presence of pandemic group A Streptococcus strains causing scarlet fever. Genomic and phylogenetic analyses indicated the presence of an Australian GAS emm12 scarlet fever isolate related to United Kingdom outbreak strains. National surveillance to monitor this pandemic is recommended

Barnett, Timothy C

Beatson, Scott A

Brouwer, Stephan

Cork, Amanda J

Davies, Mark R

Dougan, Gordon

Forde, Brian M

Grimwood, Keith

Irwin, Adam D

Maloney, Sam

McIntyre, Liam

Nizet, Victor

Richter, Johanna

Roberts, Leah W

Sundac, Lana

Walker, Mark J

Worthing, Kate A

You, Yuanhai

Yuen, Kwok Y

Zhang, Jianzhong

English

Apollo (Cambridge)

 © The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com. Detection of epidemic scarlet fever group A Streptococcus in Australia  Mark J. Walker Ph.D.1,*, Stephan Brouwer Ph.D.1, Brian M. Forde Ph.D.1, Kate A. Worthing Ph.D.2, Liam McIntyre M.Sc.2, Lana Sundac M.D.3, Sam Maloney M.D.3, Leah W. Roberts B.Sc.1, Timothy C. Barnett Ph.D.1, Johanna Richter B.Sc.1, Amanda J. Cork Ph.D1, Adam D. Irwin M.D.4,5, Yuanhai You Ph.D.6, Jianzhong Zhang Ph.D.6, Gordon Dougan Ph.D.7, KY Yuen M.D.8,9,10, Victor Nizet M.D.11, Scott A. Beatson Ph.D.1, Keith Grimwood M.D.12,13, Mark R. Davies Ph.D.2  1Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, Australia; 2Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC, Australia; 3Pathology Queensland, Gold Coast Laboratory, Gold Coast, QLD, Australia; 4University of Queensland Centre for Clinical Research, Brisbane, QLD, Australia; 5Queensland Children’s Hospital, Brisbane, QLD, Australia; 6State Key Laboratory of Infectious Disease Prevention and Control, Collaborative Innovation, Center for Diagnosis and Treatment of Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China; 7Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom; 8Department of Microbiology, 9Research Centre of Infection and Immunology, 10State Key Laboratory for Emerging Infectious Diseases, The University of Hong Kong, Hong Kong Special Administrative Region, China; 11Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, CA, United States of America; 12Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD, Australia; 13Departments of Infectious Diseases and Pediatrics, Gold Coast Health, Gold Coast, QLD, Australia.  *Corresponding author: Professor Mark J. Walker, School of Chemistry and Molecular Biosciences, The University of Queensland, Cooper Road, St Lucia, QLD, 4072, Australia, Tel: 0061-7-33461623, E-mail: mark.walker@uq.edu.au   Downloaded from https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciz099/5306630 by University of Cambridge user on 15 February 2019 2  Abstract  Sentinel hospital surveillance was instituted in Australia to detect the presence of pandemic group A Streptococcus strains causing scarlet fever. Genomic and phylogenetic analyses indicated the presence of an Australian GAS emm12 scarlet fever isolate related to UK outbreak strains. National surveillance to monitor this pandemic is recommended.    Downloaded from https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciz099/5306630 by University of Cambridge user on 15 February 2019 3  Manuscript  Epidemic scarlet fever caused by the Gram-positive bacterial pathogen Streptococcus pyogenes (group A Streptococcus; GAS) resulted in significant childhood disease in the 19th and early 20th centuries, gradually abating in parallel with improved living conditions, enhanced standards of care, and the advent of antibiotics. By the beginning of this millennium, scarlet fever was considered a disease of negligible concern [1]. From 2011, epidemic scarlet fever has been reported in Hong Kong [2, 3], mainland China [4, 5] and in the United Kingdom since 2014 [6-8] (Figure S1). GAS isolates from these outbreaks have been multiclonal, encompassing several GAS emm types including emm1, emm12 (UK, Hong Kong, mainland China), emm3 and emm4 (UK), and frequently encoding superantigens SpeA, SpeC and SSA. Scarlet fever is a notifiable disease in Hong Kong, mainland China and the UK. However, many national public health systems, including that of Australia, do not require scarlet fever case notification, making global tracking of epidemic strains intrinsically difficult. In 2016 we established a sentinel hospital surveillance (described in Supplementary Information) to monitor the importation of GAS isolates causing epidemic scarlet fever into Australia. GAS isolates from eight confirmed cases of scarlet fever (between 2016 and 2017) were selected for further analysis (Figure S2, Supplementary Table 1; Supplementary Information). The GAS emm sequence type was determined and isolates were screened by PCR for the presence of genes encoding superantigens ssa, speC, speA, and the erythromycin resistance gene ermB (recently associated with scarlet fever isolates from Hong Kong and mainland China) (described in Supplementary Information). This preliminary PCR analysis identified the atypical presence of the ssa gene [9] in an Australian emm12 GAS isolate designated SP1336 causing scarlet fever (Figure S2C, Supplementary Table 1, Supplementary Information).  Downloaded from https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciz099/5306630 by University of Cambridge user on 15 February 2019 4  The complete genome sequence of SP1336 was determined using a multi-platform approach incorporating sequence data derived from short read (Illumina), long read (Pacific Bioscience and Oxford Nanopore) and PCR-derived capillary sequencing. This approach (described in Supplementary Information) resolved ambiguity within the SP1336 genome due to the presence of multiple related prophages that affected the provisional genome assembly. After several rounds of assembly validation, we determined that SP1336 contained a 1,878,827 base pair circular genome (Figure 1, Genbank accession number CP031738).   Phylogenetic analysis of the 248 emm12 genomes relative to benchmark Hong Kong scarlet fever isolate HKU16 [2] revealed general geographical segregation of scarlet fever isolates from Hong Kong and mainland China, and the UK as reported previously (Figure 1C) [4]. SP1336 shared a close evolutionary relationship (17 core genome SNPs) to a sub-clade of isolates from the UK that included clinical scarlet fever isolates. This clade did not share a recent evolutionary history with two other Australian emm12 strains isolated from non-scarlet fever cases in the 1990s, indicating that they have evolved independently. Instead, these data suggest an evolutionary relationship between scarlet fever cases in the UK and this scarlet fever isolate from Australia.  One of the defining clinical features of scarlet fever is the cutaneous rash believed to be driven by potent immunostimulatory toxins such as the GAS streptococcal pyogenic exotoxins. The emergence of major scarlet fever clades in China has been linked to the acquisition of SSA, SpeC and Spd1 encoded prophages [3]. Analysis of the prophage content of the SP1336 genome revealed four prophage elements designated SP1336.1 (harboring the exotoxin SpeC and the DNase, Spd1); SP1336.2 (toxins SpeH and SpeI); SP1336.3 (superantigen SSA); and SP1336.4 (streptodornase, SdaD2) (Figure 1A). This emm12 prophage profile is similar to that Downloaded from https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciz099/5306630 by University of Cambridge user on 15 February 2019 5  found in the ongoing scarlet fever outbreaks in the UK, Hong Kong and mainland China [3, 4]. Comparative analyses of the SP1336.3 and other ssa-harboring prophages from Hong Kong and mainland China, showed that SP1336.3 is ~95% identical at the nucleotide level to the ssa prophage HKU.ssa from the Hong Kong scarlet fever strain HKU360 (Figure 1B) [3]. SP1336.3 also shared a high degree of synteny with SP1336.1 (~90%), itself ~99% nucleotide identity to prophage MGAS10750.1 from a US pharyngitis patient (Figure 1B) [10]. No multidrug resistance genes or transposable elements were identified in the SP1336 isolate, commensurate with the evolutionary-related emm12 UK lineage.  Scarlet fever cases have risen in multiple countries since 2011 (Figure S1) [2-8]. Rather than subsiding, case numbers of scarlet fever have again significantly increased in recent years both in Hong Kong (Figure S1A) and the UK [11]. The burden of this outbreak on healthcare services is substantial with hospital admissions from scarlet fever increasing threefold from baseline at the peak of the outbreak [8]. We have become increasingly concerned about the spread of scarlet fever-inducing GAS to countries where this disease is not notifiable, and thus instigated our own localized notification system in Australia. Here we report the detection of an emm12 GAS strain in Australia that harbors scarlet fever-associated phage-like elements [3, 4] and shares a recent common ancestor to a cluster of scarlet fever isolates from the UK. The presented data highlight the dynamic nature of toxin-harbouring prophages within poly-lysogenic GAS genomes. Furthermore, the maintenance of distinct virulence gene sets (SSA, SpeC, Spd1, SpeH, SpeI) suggests a positive selection for particular toxin combinations within the current scarlet fever pandemic.  Outbreaks of scarlet fever in the UK, Hong Kong and mainland China have been characterized as multiclonal, encompassing multiple emm types [2-4, 6-8]. While northern Asian and UK emm12 Downloaded from https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciz099/5306630 by University of Cambridge user on 15 February 2019 6  scarlet fever isolates are distantly related, these geographically discrete strains have evolved independently into distinct clades [3, 4], excluding the worldwide spread of a single emm12 scarlet fever clone. GAS superantigens SpeA, SpeC and SSA have been associated with scarlet fever isolates in several studies, but this association is not universal [2-4, 6]. The underlying cause of disease resurgence remains unknown. Immune status changes in the human population resulting in increased susceptibility to infection, introduction of genetic elements encoding superantigens into the GAS population, co-infection with an unknown agent that predisposes the host to scarlet fever and environmental change have all been proposed as possible triggers for the observed resurgence in disease [12]. While a single dominant strain fails to explain the recent international upsurge in scarlet fever, the distant identification of a strain associated with the UK outbreak may herald similar outbreaks elsewhere. In national health systems where scarlet fever is not notifiable, sentinel hospital surveillance of the type used in this study to rapidly identify and monitor the dissemination of GAS isolates causing epidemic scarlet fever is warranted. Such surveillance would underpin public health interventions aimed at limiting further propagation.   Downloaded from https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciz099/5306630 by University of Cambridge user on 15 February 2019 7  Acknowledgments The authors thank Dr Shane George who provided information from the Emergency Department Information System.   Funding This work was supported by the National Health and Medical Research Council of Australia; the Wellcome Trust, UK; Chinese Center For Disease Control And Prevention; the Department of Health Consultancy Service for Enhancing Laboratory Surveillance of Emerging Infectious Diseases, Research Capability on Antimicrobial Resistance, and the Queen Mary Hospital Charitable Trust, Hong Kong  Conflict of interest statement The authors declare no conflicts of interest. Downloaded from https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciz099/5306630 by University of Cambridge user on 15 February 2019 8  References 1. Morens DM, Folkers GK, Fauci AS. The challenge of emerging and re-emerging infectious diseases. Nature 2004; 430(6996): 242-9. 2. Tse H, Bao JYJ, Davies MR, et al. Molecular characterization of the 2011 Hong Kong scarlet fever outbreak. J Infect Dis 2012; 206(3): 341-51. 3. Davies MR, Holden MT, Coupland P, et al. Emergence of scarlet fever Streptococcus pyogenes emm12 clones in Hong Kong is associated with toxin acquisition and multidrug resistance. Nat Genet 2015; 47(1): 84-7. 4. You Y, Davies MR, Protani M, McIntyre L, Walker MJ, Zhang J. Scarlet fever epidemic in China caused by Streptococcus pyogenes serotype M12: epidemiologic and molecular analysis. EBioMedicine 2018; 28: 128-35. 5. Liu Y, Chan TC, Yap LW, et al. Resurgence of scarlet fever in China: a 13-year population-based surveillance study. Lancet Infect Dis 2018; 18(8): 903-12. 6. Turner CE, Pyzio M, Song B, et al. Scarlet fever upsurge in England and molecular-genetic analysis in North-West London, 2014. Emerg Infect Dis 2016; 22(6): 1075-8. 7. Chalker V, Jironkin A, Coelho J, et al. Genome analysis following a national increase in scarlet fever in England 2014. BMC Genomics 2017; 18(1): 224. 8. Lamagni T, Guy R, Chand M, et al. Resurgence of scarlet fever in England, 2014-16: a population-based surveillance study. Lancet Infect Dis 2018; 18(2): 180-7. 9. Commons R, Rogers S, Gooding T, et al. Superantigen genes in group A streptococcal isolates and their relationship with emm types. J Med Microbiol 2008; 57(Pt 10): 1238-46. Downloaded from https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciz099/5306630 by University of Cambridge user on 15 February 2019 9  10. Beres SB, Musser JM. Contribution of exogenous genetic elements to the group A Streptococcus metagenome. PLoS One 2007; 2(8): e800. 11. Public Health England. Group A streptococcal infections: third report on seasonal activity, 2017 to 2018. Health Protection Report 2018; 12(13). 12. Walker MJ, Brouwer S. Scarlet fever makes a comeback. Lancet Infect Dis 2018; 18(2): 128-9. Downloaded from https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciz099/5306630 by University of Cambridge user on 15 February 2019 10  Figure legends  Figure 1. Population genomics of the Australia scarlet fever strain SP1336. (A) Genome ring of the SP1336 emm12 GAS genome showing (from inner ring); GC skew, GC plot, position and name of prophage elements (red blocks), and location and orientation of coding sequences. (B) Genomic organization of SP1336.3 and SP1336.1 relative to their closest genetic relatives; HKU.ssa (from an emm12 Hong Kong scarlet fever strain HKU360 [3]) and MGAS10750 (from an emm4 pharyngitis isolate from the USA [10]) respectively. Nucleotide sequence diversity is scaled from 100% (black) to 80% (yellow). (C) Midpoint-rooted maximum-likelihood phylogenetic tree of 248 emm12 GAS strains built on 2,633 polymorphic sites within the non-recombinogenic core genome relative to the HKU16 reference isolate [2]. Clinical association and country of isolation is displayed next to the tree in addition to the relative distribution of selected virulence genes, and antimicrobial resistance genes and ssa carrying prophages (HKU.vir [2]), HKU.ssa [3] and SP1336.3) within the emm12 population (black shading refers to gene carriage). Phylogenetic branch relating to the Australian scarlet fever isolate SP1336 is coloured in green and indicated by an arrow for visual aid.  Downloaded from https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciz099/5306630 by University of Cambridge user on 15 February 2019 11   Downloaded from https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciz099/5306630 by University of Cambridge user on 15 February 2019

Detection of Epidemic Scarlet Fever Group A Streptococcus in Australia.

Sentinel hospital surveillance was instituted in Australia to detect the presence of pandemic group A Streptococcus strains causing scarlet fever. Genomic and phylogenetic analyses indicated the presence of an Australian GAS emm12 scarlet fever isolate related to United Kingdom outbreak strains. National surveillance to monitor this pandemic is recommended.</p

Walker, Mark J.

Forde, Brian M.

Worthing, Kate A.

Roberts, Leah W.

Barnett, Timothy C.

Cork, Amanda J.

Irwin, Adam D.

Yuen, Kwok Y.

Beatson, Scott A.

Davies, Mark R.

Queensland University of Technology ePrints Archive

Detection of Epidemic Scarlet Fever Group A Streptococcus in Australia

Sentinel hospital surveillance was instituted in Australia to detect the presence of pandemic group A Streptococcus strains causing scarlet fever. Genomic and phylogenetic analyses indicated the presence of an Australian GAS emm12 scarlet fever isolate related to UK outbreak strains. National surveillance to monitor this pandemic is recommended

Yuen, K. Y.

University of Queensland eSpace

Detection of epidemic scarlet fever group A Streptococcus in Australia

https://www.repository.cam.ac.uk/bitstream/1810/289785/1/ciz099.pdf

Detection of Epidemic Scarlet Fever Group A Streptococcus in Australia.

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