Review Article | Published:

The genomic signatures of Shigella evolution, adaptation and geographical spread

Nature Reviews Microbiology volume 14, pages 235250 (2016) | Download Citation

Abstract

Shigella spp. are some of the key pathogens responsible for the global burden of diarrhoeal disease. These facultative intracellular bacteria belong to the family Enterobacteriaceae, together with other intestinal pathogens, such as Escherichia coli and Salmonella spp. The genus Shigella comprises four different species, each consisting of several serogroups, all of which show phenotypic similarity, including invasive pathogenicity. DNA sequencing suggests that this similarity results from the convergent evolution of different Shigella spp. founders. Here, we review the evolutionary relationships between Shigella spp. and E . coli, and we highlight how the genomic plasticity of these bacteria and their acquisition of a distinctive virulence plasmid have enabled the development of such highly specialized pathogens. Furthermore, we discuss the insights that genotyping and whole-genome sequencing have provided into the phylogenetics and intercontinental spread of Shigella spp.

Key points

  • All available genome data indicate that the various Shigella spp.have arisen from different ancestral Escherichia coli isolates on several independent occasions.

  • The acquisition of plasmids that encode virulence genes into numerous ancestral Shigella spp. were pivotal in their evolution as human pathogens. The possession and adaptation of these plasmids has shaped the current Shigella spp.

  • Convergent evolution, through the acquisition of mobile elements and loss of gene function, enabled Shigella spp. to become restricted to humans and exquisitely adapted to interact with the human intestinal mucosa.

  • The shift in dominance from Shigella flexneri to Shigella sonnei in economically transitioning nations warrants more in-depth studies of the evolution and epidemiology of these species.

  • There is a correlation between the global dissemination of Shigella spp. clones and acquisition of resistance to multiple antimicrobials. An antimicrobial-resistance phenotype is likely to be advantageous for the bacteria, as it would promote post-symptomatic shedding by the host and would sustain short-term transmission.

  • In comparison to S. sonnei and S. flexneri, comparatively little is currently understood about Shigella dysenteriae and Shigella boydii; this needs to be addressed to reveal the full evolutionary landscape of the genus.

  • Future laboratory research should be combined with genomics to address the survival, transmission and evolution of Shigella spp. in the environment, specifically focusing on how the environmental lifestyle can affect disease epidemiology and global public health.

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References

  1. 1.

    World Health Organization. World Health Statistics 2014. (WHO, 2014).

  2. 2.

    et al. Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000. Lancet 379, 2151–2161 (2012).

  3. 3.

    , , , & Diarrhea incidence in low- and middle-income countries in 1990 and 2010: a systematic review. BMC Publ. Health 12, 220 (2012).

  4. 4.

    et al. The Global Enteric Multicenter Study (GEMS) of diarrheal disease in infants and young children in developing countries: epidemiologic and clinical methods of the case/control study. Clin. Infect. Dis. 55 (Suppl. 4), S232–S245 (2012).

  5. 5.

    et al. Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS): a prospective, case–control study. Lancet 382, 209–222 (2013).

  6. 6.

    et al. Global burden of Shigella infections: implications for vaccine development and implementation of control strategies. Bull. World Health Organ. 77, 651–666 (1999).

  7. 7.

    , , & Decrease in shigellosis-related deaths without Shigella spp.-specific interventions, Asia. Emerg. Infect. Dis. 16, 1718–1723 (2010).

  8. 8.

    et al. A multicentre study of Shigella diarrhoea in six Asian countries: disease burden, clinical manifestations, and microbiology. PLoS Med. 3, e353 (2006).

  9. 9.

    & Diarrheagenic Escherichia coli. Clin. Microbiol. Rev. 11, 142–201 (1998).

  10. 10.

    & Molecular mechanisms of Escherichia coli pathogenicity. Nat. Rev. Microbiol. 8, 26–38 (2010).

  11. 11.

    et al. Recent advances in understanding enteric pathogenic Escherichia coli. Clin. Microbiol. Rev. 26, 822–880 (2013).

  12. 12.

    & Infective dose of foodborne pathogens in volunteers: a review. J. Food Saf. 21, 49–68 (2001).

  13. 13.

    Ueber den erreger der dysenterie in Japan. Zentralbl. Bakteriol. Mikrobiol. 23, 599–600 (1898).

  14. 14.

    , , & Dr. Kiyoshi Shiga: discoverer of the dysentery Bacillus. Clin. Infect. Dis. 29, 1303–1306 (1999).

  15. 15.

    On the etiology of tropical dysentery. Philadelphia Med. J. 6, 414–421 (1900).

  16. 16.

    Shigella species (Shiga enterotoxins) in Medical Toxicology of Natural Substances: Foods, Fungi, Medicinal Herbs, Plants, and Venomous Animals. Ch. 20, 150–155. (Wiley & Sons, 2008).

  17. 17.

    & A numerical taxonomic study of the genus Shigella. J. Gen. Microbiol. 128, 1933–1957 (1982).

  18. 18.

    Activity of lysine decarboxylase as an aid in the identification of Salmonellae and Shigellae. Am. J. Clin. Pathol. 29, 598–600 (1958).

  19. 19.

    et al. Comparison of the prevalence and changing resistance to nalidixic acid and ciprofloxacin of Shigella between Europe–America and Asia–Africa from 1998 to 2009. Int. J. Antimicrob. Agents 40, 9–17 (2012).

  20. 20.

    et al. Genome dynamics and diversity of Shigella species, the etiologic agents of bacillary dysentery. Nucleic Acids Res. 33, 6445–6458 (2005). A seminal paper aimed at genomic comparison of four Shigella spp.: S. flexneri, S. sonnei, S. dysenteriae and S. boydii. The analysis provides evidence for convergent evolution among Shigella spp., by gene gain and gene loss.

  21. 21.

    et al. The virulence plasmid pWR100 and the repertoire of proteins secreted by the type III secretion apparatus of Shigella flexneri. Mol. Microbiol. 38, 760–771 (2000).

  22. 22.

    et al. Shigella sonnei genome sequencing and phylogenetic analysis indicate recent global dissemination from Europe. Nat. Genet. 44, 1056–1059 (2012). This key investigation reconstructed the phylogenetic structure and geographical spread of S. sonnei on a global scale, emphasizing that the successful introduction of this species from Europe into other distant regions is facilitated by antimicrobial resistance.

  23. 23.

    et al. Genomic analysis of the emergence of 20th century epidemic dysentery. BMC Genomics 15, 355 (2014). The first work to use phylogenomics to understand the evolutionary history of the pandemic S. dysenteriae 1, highlighting the fact that its recent emergence is coupled with independent acquisitions of antimicrobial-resistance genes.

  24. 24.

    et al. Species-wide whole genome sequencing reveals historical global spread and recent local persistence in Shigella flexneri. eLife 4, e07335 (2015). The original whole-genome study on the diversity of S. flexneri globally, showing that serotype switching is common among phylogenetic groups. The study suggests that the long-term success of this species is linked to its local persistence.

  25. 25.

    , , & Molecular evolution of large virulence plasmid in Shigella clones and enteroinvasive Escherichia coli. Infect. Immun. 69, 6303–6309 (2001).

  26. 26.

    , & Multiple independent origins of Shigella clones of Escherichia coli and convergent evolution of many of their characteristics. Proc. Natl Acad. Sci. USA 97, 10567–10572 (2000). The first article to demonstrate the multiple origins of Shigella spp. from E. coli, on the basis of a phylogenetic analysis of eight housekeeping genes.

  27. 27.

    et al. Revisiting the molecular evolutionary history of Shigella spp. J. Mol. Evol. 64, 71–79 (2007).

  28. 28.

    et al. Evolutionary genetics of a new pathogenic Escherichia species: Escherichia albertii and related Shigella boydii strains. J. Bacteriol. 187, 619–628 (2005).

  29. 29.

    , & Comparison of O-antigen gene clusters of Escherichia coli (Shigella) sonnei and Plesiomonas shigelloides O17: sonnei gained its current plasmid-borne O-antigen genes from P. shigelloides in a recent event. Infect. Immun. 68, 6056–6061 (2000).

  30. 30.

    & Whole-genome phylogeny of Escherichia coli/Shigella group by feature frequency profiles (FFPs). Proc. Natl Acad. Sci. USA 108, 8329–8334 (2011).

  31. 31.

    et al. Organised genome dynamics in the Escherichia coli species results in highly diverse adaptive paths. PLoS Genet. 5, e1000344 (2009).

  32. 32.

    , , & Estimating variation within the genes and inferring the phylogeny of 186 sequenced diverse Escherichia coli genomes. BMC Genomics 13, 577 (2012).

  33. 33.

    & A phylogenomic analysis of Escherichia coli / Shigella group: implications of genomic features associated with pathogenicity and ecological adaptation. BMC Evol. Biol. 12, 174 (2012).

  34. 34.

    et al. Defining the phylogenomics of Shigella species: a pathway to diagnostics. J. Clin. Microbiol. 53, 951–960 (2015). This paper utilizes the most complete collection of Shigella and E. coli isolates for phylogenomic analysis, the results of which both consolidate the evidence for there being multiple origins of Shigella spp. from E. coli, and point to reliable genetic markers for differentiating major Shigella clades.

  35. 35.

    & Differentiation between Shigella, enteroinvasive Escherichia coli (EIEC) and noninvasive Escherichia coli. Eur. J. Clin. Microbiol. Infect. Dis. 31, 899–904 (2012).

  36. 36.

    et al. Molecular evolutionary relationships of enteroinvasive Escherichia coli and Shigella spp. Infect. Immun. 72, 5080–5088 (2004).

  37. 37.

    & Molecular pathogenesis of Shigella spp.: controlling host cell signaling, invasion, and death by type III secretion. Clin. Microbiol. Rev. 21, 134–156 (2008). This extensive review details the molecular pathogenesis of Shigella spp.

  38. 38.

    et al. Complete DNA sequence and analysis of the large virulence plasmid of Shigella flexneri complete DNA sequence and analysis of the large virulence plasmid of Shigella flexneri. Infect. Immun. 69, 3271–3285 (2001). Together with reference 21, this report describes the first sequence analysis of the Shigella virulence plasmid, highlighting the rich repertoire of virulence factors encoded by this plasmid.

  39. 39.

    et al. The complete sequence and analysis of the large virulence plasmid pSS of Shigella sonnei. Plasmid 54, 149–159 (2005).

  40. 40.

    , & Genetic relatedness of the basic replicon of the virulence plasmid in shigellae and enteroinvasive Escherichia coli. Microb. Pathog. 5, 267–274 (1988).

  41. 41.

    & Escherichia coli in disguise: molecular origins of Shigella. Microbes Infect. 4, 1125–1132 (2002).

  42. 42.

    et al. The sigA gene which is borne on the she pathogenicity island of Shigella flexneri 2a encodes an exported cytopathic protease involved in intestinal fluid accumulation. Infect. Immun. 68, 2457–2463 (2000).

  43. 43.

    , & Pathogenicity islands of Shigella. Curr. Top. Microbiol. Immunol. 264, 49–65 (2002).

  44. 44.

    , , , & Ferric dicitrate transport system (Fec) of Shigella flexneri 2a YSH6000 is encoded on a novel pathogenicity island carrying multiple antibiotic resistance genes. Infect. Immun. 69, 6012–6021 (2001).

  45. 45.

    , , & The aerobactin iron transport system genes in Shigella flexneri are present within a pathogenicity island. Mol. Microbiol. 33, 63–73 (1999).

  46. 46.

    et al. Genetics and virulence association of the Shigella flexneri Sit iron transport system. Infect. Immun. 77, 1992–1999 (2009).

  47. 47.

    et al. Short report: emergence of Shiga toxin 1 genes within Shigella dysenteriae type 4 isolates from travelers returning from the Island of Hispañola. Am. J. Trop. Med. Hyg. 76, 1163–1165 (2007).

  48. 48.

    et al. Clinical isolates of Shiga toxin 1a-producing Shigella flexneri with an epidemiological link to recent travel to Hispañiola. Emerg. Infect. Dis. 20, 1669–1677 (2014).

  49. 49.

    et al. Prevalence of Shiga toxin-producing Shigella species isolated from French travellers returning from the Caribbean: an emerging pathogen with international implications. Clin. Microbiol. Infect. 21, 765.e9–765.e14 (2015).

  50. 50.

    et al. Stx-producing Shigella species from patients in Haiti: an emerging pathogen with the potential for global spread. Open Forum Infect. Dis. 2, ofv134 (2015).

  51. 51.

    , & Bacterial insertion sequences: their genomic impact and diversity. FEMS Microbiol. Rev. 38, 865–891 (2014).

  52. 52.

    & Distant horizontal gene transfer is rare for multiple families of prokaryotic insertion sequences. Mol. Genet. Genom. 280, 397–408 (2008).

  53. 53.

    & The nature and dynamics of bacterial genomes. Science 311, 1730–1733 (2006).

  54. 54.

    et al. The decaying genome of Mycobacterium leprae. Lepr. Rev. 72, 387–398 (2001).

  55. 55.

    et al. Genome sequence of Yersinia pestis, the causative agent of plague. Nature 413, 523–527 (2001).

  56. 56.

    et al. High-throughput sequencing provides insights into genome variation and evolution in Salmonella Typhi. Nat. Genet. 40, 987–993 (2008).

  57. 57.

    , & Gene decay in Shigella as an incipient stage of host-adaptation. PLoS ONE 6, e27754 (2011).

  58. 58.

    , , , & Distinct mutations led to inactivation of type 1 fimbriae expression in Shigella spp. PLoS ONE 10, e0121785 (2015).

  59. 59.

    , & Bacterial flagellins: mediators of pathogenicity and host immune responses in mucosa. Trends Microbiol. 12, 509–517 (2004).

  60. 60.

    et al. Genome-scale metabolic reconstructions of multiple Escherichia coli strains highlight strain-specific adaptations to nutritional environments. Proc. Natl Acad. Sci. USA 110, 20338–20343 (2013).

  61. 61.

    , , , & 'Black holes' and bacterial pathogenicity: a large genomic deletion that enhances the virulence of Shigella spp. and enteroinvasive Escherichia coli. Proc. Natl Acad. Sci. USA 95, 3943–3948 (1998).

  62. 62.

    et al. nadA and nadB of Shigella flexneri 5a are antivirulence loci responsible for the synthesis of quinolinate, a small molecule inhibitor of Shigella pathogenicity. Microbiology 153, 2363–2372 (2007).

  63. 63.

    et al. Shedding of genes that interfere with the pathogenic lifestyle: the Shigella model. Res. Microbiol. 163, 399–406 (2012).

  64. 64.

    et al. The absence of a surface protease, OmpT, determines the intercellular spreading ability of Shigella: the relationship between the ompT and kcpA loci. Mol. Microbiol. 9, 459–468 (1993).

  65. 65.

    et al. A novel anti-virulence gene revealed by proteomic analysis in Shigella flexneri 2a. Proteome Sci. 8, 30 (2010).

  66. 66.

    et al. A new piece of the Shigella pathogenicity puzzle: spermidine accumulation by silencing of the speG gene. PLoS ONE 6, e27226 (2011).

  67. 67.

    , & Reduced selection leads to accelerated gene loss in Shigella. Genome Biol. 8, R164 (2007).

  68. 68.

    , & The temporal dynamics of slightly deleterious mutations in Escherichia coli and Shigella spp. Mol. Biol. Evol. 26, 345–355 (2009).

  69. 69.

    et al. A changing picture of shigellosis in southern Vietnam: shifting species dominance, antimicrobial susceptibility and clinical presentation. BMC Infect. Dis. 9, 204 (2009).

  70. 70.

    et al. Changing trends in the prevalence of Shigella species: emergence of multi-drug resistant Shigella sonnei biotype g in Bangladesh. PLoS ONE 8, e82601 (2013).

  71. 71.

    et al. Shigella from humans in Thailand during 1993 to 2006: spatial-time trends in species and serotype distribution. Foodborne Pathog. Dis. 5, 773–784 (2008).

  72. 72.

    , , , & Epidemiology and evolution of genotype and antimicrobial resistance of an imported Shigella sonnei clone circulating in central Taiwan. Diagn. Microbiol. Infect. Dis. 58, 469–475 (2007).

  73. 73.

    et al. Foodborne outbreaks of shigellosis in the USA, 1998–2008. Epidemiol. Infect. 141, 233–241 (2013).

  74. 74.

    et al. Treatment of bacillary dysentery in Vietnamese children: two doses of ofloxacin versus 5-days nalidixic acid. Trans. R. Soc. Trop. Med. Hyg. 94, 323–326 (2000).

  75. 75.

    et al. Tracking the establishment of local endemic populations of an emergent enteric pathogen. Proc. Natl Acad. Sci. USA 110, 17522–17527 (2013). The first study to detail the microevolution of S. sonnei in a developing region in high resolution, pointing out that antimicrobial resistance is a crucial factor for understanding the clonal expansion of this species.

  76. 76.

    et al. The sudden dominance of blaCTX–M harbouring plasmids in Shigella spp. circulating southern Vietnam. PLoS Negl. Trop. Dis. 4, e702 (2010).

  77. 77.

    & Possible transfer of plasmid mediated third generation cephalosporin resistance between Escherichia coli and Shigella sonnei in the human gut. Infect. Genet. Evol. 30, 15–18 (2015).

  78. 78.

    et al. Optimization of virulence functions through glucosylation of Shigella LPS. Science 307, 1313–1317 (2005).

  79. 79.

    & Serotype-converting bacteriophages and O-antigen modification in Shigella flexneri. Trends Microbiol. 8, 17–23 (2000).

  80. 80.

    , & Cloning and analysis of the glucosyl transferase gene encoding type I antigen in Shigella flexneri. FEMS Microbiol. Lett. 156, 133–139 (1997).

  81. 81.

    et al. Isolation and genomic characterization of SfI, a serotype-converting bacteriophage of Shigella flexneri. BMC Microbiol. 13, 39 (2013).

  82. 82.

    , & Mechanism of bacteriophage SfII-mediated serotype conversion in Shigella flexneri. Mol. Microbiol. 26, 939–950 (1997).

  83. 83.

    , & The oac gene encoding a lipopolysaccharide O-antigen acetylase maps adjacent to the integrase-encoding gene on the genome of Shigella flexneri bacteriophage Sf6. Gene 107, 43–52 (1991).

  84. 84.

    , & Isolation, characterization and comparative genomics of bacteriophage SfIV: a novel serotype converting phage from Shigella flexneri. BMC Genomics 14, 677 (2013).

  85. 85.

    , , , & Molecular characterization of the genes involved in O-antigen modification, attachment, integration and excision in Shigella flexneri bacteriophage SfV. Gene 195, 217–227 (1997).

  86. 86.

    , & Functional analysis of the O antigen glucosylation gene cluster of Shigella flexneri bacteriophage SfX. Microbiology 145, 1263–1273 (1999).

  87. 87.

    & Structural and immunochemical studies of the lipopolysaccharide from a new provisional serotype of Shigella flexneri. Eur. J. Biochem. 176, 471–476 (1988).

  88. 88.

    , & Identification of newly recognized serotype 1c as the most prevalent Shigella flexneri serotype in northern rural Vietnam. Epidemiol. Infect. 136, 1134–1140 (2008).

  89. 89.

    et al. Emergence of a novel Shigella flexneri serotype 1d in China. Diagn. Microbiol. Infect. Dis. 74, 316–319 (2012).

  90. 90.

    et al. Emergence of a new multidrug-resistant serotype X variant in an epidemic clone of Shigella flexneri. J. Clin. Microbiol. 48, 419–426 (2010).

  91. 91.

    et al. Emergence of a novel Shigella flexneri serotype 4s strain that evolved from a serotype X variant in China. J. Clin. Microbiol. 49, 1148–1150 (2011).

  92. 92.

    et al. A novel glucosyltransferase involved in O-antigen modification of Shigella flexneri serotype 1c. J. Bacteriol. 191, 6612–6617 (2009).

  93. 93.

    et al. Identification and characterization of a novel Shigella flexneri serotype Yv in China. PLoS ONE 8, e70238 (2013).

  94. 94.

    et al. Genomic portrait of the evolution and epidemic spread of a recently emerged multidrug-resistant Shigella flexneri clone in China. J. Clin. Microbiol. 52, 1119–1126 (2014).

  95. 95.

    , , , & Molecular evolution of typical enteropathogenic Escherichia coli: clonal analysis by multilocus sequence typing and virulence gene allelic profiling. J. Bacteriol. 189, 342–350 (2007).

  96. 96.

    et al. Standardization of pulsed-field gel electrophoresis protocols for the subtyping of Escherichia coli O157:H7, Salmonella, and Shigella for PulseNet. Foodborne Pathog. Dis. 3, 59–67 (2006).

  97. 97.

    et al. Sex and virulence in Escherichia coli: an evolutionary perspective. Mol. Microbiol. 60, 1136–1151 (2006).

  98. 98.

    et al. Multilocus sequence typing analysis of Shigella flexneri isolates collected in Asian countries. J. Med. Microbiol. 56, 1460–1466 (2007).

  99. 99.

    et al. Ongoing outbreak of Shigella flexneri serotype 3a in men who have sex with men in England and Wales, data from 2009–2011. Euro Surveill. 17, 20137 (2012).

  100. 100.

    & Shifting dominance of Shigella species in men who have sex with men. Epidemiol. Infect. 140, 2082–2086 (2012).

  101. 101.

    et al. Intercontinental dissemination of azithromycin-resistant shigellosis through sexual transmission: a cross-sectional study. Lancet Infect. Dis. 15, 913–921 (2015).

  102. 102.

    , & Gastrointestinal and extra-intestinal manifestations of childhood shigellosis in a region where all four species of Shigella are endemic. PLoS ONE 8, e64097 (2013).

  103. 103.

    et al. Structure of the Shigella dysenteriae haem transport locus and its phylogenetic distribution in enteric bacteria. Mol. Microbiol. 28, 1139–1152 (1998).

  104. 104.

    , , , & RNA-mediated thermoregulation of iron-acquisition genes in Shigella dysenteriae and pathogenic Escherichia coli. PLoS ONE 8, e63781 (2013).

  105. 105.

    et al. In vivo versus in vitro protein abundance analysis of Shigella dysenteriae type 1 reveals changes in the expression of proteins involved in virulence, stress and energy metabolism. BMC Microbiol. 11, 147 (2011).

  106. 106.

    et al. Shigella dysenteriae serotype 1 in west Africa: intervention strategy for an outbreak in Sierra Leone. Lancet 362, 705–706 (2003).

  107. 107.

    et al. Evolutionary history of Salmonella Typhi. Science 314, 1301–1304 (2006).

  108. 108.

    , , , & Fourteen years of shigellosis in Dhaka: an epidemiological analysis. Int. J. Epidemiol. 14, 607–613 (1985).

  109. 109.

    et al. Epidemiological features of a newly described serotype of Shigella boydii. Epidemiol. Infect. 132, 579–583 (2004).

  110. 110.

    et al. Identification and characterization of Shigella boydii 20 serovar nov., a new and emerging Shigella serotype. J. Med. Microbiol. 54, 741–748 (2005).

  111. 111.

    et al. Analysis of a temporal cluster of Shigella boydii isolates in Mpumalanga, South Africa, November to December 2007. J. Infect. Dev. Ctries 3, 65–70 (2009).

  112. 112.

    et al. Genetic diversity and antibiotic resistance in Shigella dysenteriae and Shigella boydii strains isolated from children aged <5 years in Egypt. Epidemiol. Infect. 140, 299–310 (2012).

  113. 113.

    et al. Shigella isolates from the global enteric multicenter study inform vaccine development. Clin. Infect. Dis. 59, 933–941 (2014). Using data from the largest prospective paediatric diarrhoea study, this paper provides an up-to-date description for the prevalence of different Shigella spp. in developing countries.

  114. 114.

    , , & Emergence of a novel Shiga toxin-producing Escherichia coli O serogroup cross-reacting with Shigella boydii type 10. J. Clin. Microbiol. 49, 3678–3680 (2011).

  115. 115.

    et al. Evidence of interspecies O antigen gene cluster transfer between Shigella boydii 15 and Escherichia fergusonii. Apmis 120, 959–966 (2012).

  116. 116.

    & Effect of mutations in Shigella flexneri chromosomal and plasmid-encoded lipopolysaccharide genes on invasion and serum resistance. Mol. Microbiol. 24, 779–791 (1997).

  117. 117.

    , & Genetic modulation of Shigella flexneri 2a lipopolysaccharide O antigen modal chain length reveals that it has been optimized for virulence. Microbiology 149, 925–939 (2003).

  118. 118.

    et al. An O antigen capsule modulates bacterial pathogenesis in Shigella sonnei. PLoS Pathog. 11, e1004749 (2015).

  119. 119.

    , , , & IcsA is a Shigella flexneri adhesin regulated by the type III secretion system and required for pathogenesis. Cell Host Microbe 15, 435–445 (2014).

  120. 120.

    et al. The multivalent adhesion molecule SSO1327 plays a key role in Shigella sonnei pathogenesis. Mol. Microbiol. 99, 658–673 (2016).

  121. 121.

    et al. Parallel independent evolution of pathogenicity within the genus Yersinia. Proc. Natl Acad. Sci. USA 111, 6768–6773 (2014).

  122. 122.

    et al. Broadly protective Shigella vaccine based on type III secretion apparatus proteins. Infect. Immun. 80, 1222–1231 (2012).

  123. 123.

    et al. Intradermal delivery of Shigella IpaB and IpaD type III secretion proteins: kinetics of cell recruitment and antigen uptake, mucosal and systemic immunity, and protection across serotypes. J. Immunol. 192, 1630–1640 (2014).

  124. 124.

    et al. Shigella IpaB and IpaD displayed on L. lactis bacterium-like particles induce protective immunity in adult and infant mice. Immunol. Cell Biol. 93, 641–652 (2015).

  125. 125.

    & Tips and tricks about Shigella invasion of epithelial cells. Curr. Opin. Microbiol. 16, 32–37 (2013).

  126. 126.

    et al. Infection of rabbit Peyer's patches by Shigella flexneri: effect of adhesive or invasive bacterial phenotypes on follicle-associated epithelium. Infect. Immun. 64, 2752–2764 (1996).

  127. 127.

    , & Shigella flexneri induces apoptosis in infected macrophages. Nature 358, 167–169 (1992).

  128. 128.

    et al. Shigella-induced apoptosis is dependent on caspase-1 which binds to IpaB. J. Biol. Chem. 273, 32895–32900 (1998).

  129. 129.

    , , , & Initial steps of Shigella infection depend on the cholesterol/sphingolipid raft-mediated CD44–IpaB interaction. EMBO J. 21, 4449–4457 (2002).

  130. 130.

    et al. CD44 binds to the Shigella IpaB protein and participates in bacterial invasion of epithelial cells. Cell. Microbiol. 2, 19–33 (2000).

  131. 131.

    , & Interaction of Ipa proteins of Shigella flexneri with α5β1 integrin promotes entry of the bacteria into mammalian cells. J. Exp. Med. 183, 991–999 (1996).

  132. 132.

    et al. The IpaC carboxyterminal effector domain mediates Src-dependent actin polymerization during Shigella invasion of epithelial cells. PLoS Pathog. 5, e1000271 (2009).

  133. 133.

    et al. Shigella IpgB1 promotes bacterial entry through the ELMO–Dock180 machinery. Nat. Cell Biol. 9, 121–128 (2007).

  134. 134.

    et al. Conversion of PtdIns(4,5)P2 into PtdIns(5)P by the S. flexneri effector IpgD reorganizes host cell morphology. EMBO J. 21, 5069–5078 (2002).

  135. 135.

    , , , & Novel vinculin binding site of the IpaA invasin of Shigella. J. Biol. Chem. 286, 23214–23221 (2011).

  136. 136.

    et al. Shigella deliver an effector protein to trigger host microtubule destabilization, which promotes Rac1 activity and efficient bacterial internalization. EMBO J. 21, 2923–2935 (2002).

  137. 137.

    et al. ATP-mediated Erk1/2 activation stimulates bacterial capture by filopodia, which precedes Shigella invasion of epithelial cells. Cell Host Microbe 9, 508–519 (2011).

  138. 138.

    et al. Shigella flexneri IpaH7.8 facilitates escape of virulent bacteria from the endocytic vacuoles of mouse and human macrophages. Infect. Immun. 68, 3608–3619 (2000).

  139. 139.

    , & Characterization of the interaction of single tryptophan containing mutants of IpaC from Shigella flexneri with phospholipid membranes. Biochemistry 45, 626–636 (2006).

  140. 140.

    , & Activation of the CDC42 effector N-WASP by the Shigella flexneri IcsA protein promotes actin nucleation by Arp2/3 complex and bacterial actin-based motility. J. Cell Biol. 146, 1319–1332 (1999).

  141. 141.

    et al. A bacterial effector targets Mad2L2, an APC inhibitor, to modulate host cell cycling. Cell 130, 611–623 (2007).

  142. 142.

    et al. PtdIns5P activates the host cell PI3-kinase/Akt pathway during Shigella flexneri infection. EMBO J. 25, 1024–1034 (2006).

  143. 143.

    et al. Bacteria hijack integrin-linked kinase to stabilize focal adhesions and block cell detachment. Nature 459, 578–582 (2009).

  144. 144.

    et al. Shigella effector IpaB-induced cholesterol relocation disrupts the Golgi complex and recycling network to inhibit host cell secretion. Cell Host Microbe 12, 381–389 (2012).

  145. 145.

    et al. Structurally distinct bacterial TBC-like GAPs link Arf GTPase to Rab1 inactivation to counteract host defenses. Cell 150, 1029–1041 (2012).

  146. 146.

    , , , & Effect of Shigella enterotoxin 1 (ShET1) on rabbit intestine in vitro and in vivo. Gut 40, 505–511 (1997).

  147. 147.

    et al. Identification and cloning of a novel plasmid-encoded enterotoxin of enteroinvasive Escherichia coli and Shigella strains. Infect. Immun. 63, 4721–4728 (1995).

  148. 148.

    et al. Chromosomal and plasmid-encoded factors of Shigella flexneri induce secretogenic activity ex vivo. PLoS ONE 7, e49980 (2012).

  149. 149.

    et al. Shigella deploy multiple countermeasures against host innate immune responses. Curr. Opin. Microbiol. 14, 16–23 (2011).

  150. 150.

    et al. Caspase-1 activation of IL-1β and IL-18 are essential for Shigella flexneri-induced inflammation. Immunity 12, 581–590 (2000).

  151. 151.

    & Interleukin-8 controls bacterial transepithelial translocation at the cost of epithelial destruction in experimental shigellosis. Infect. Immun. 67, 1471–1480 (1999).

  152. 152.

    et al. The Shigella flexneri effector OspG interferes with innate immune responses by targeting ubiquitin-conjugating enzymes. Proc. Natl Acad. Sci. USA 102, 14046–14051 (2005).

  153. 153.

    et al. An injected bacterial effector targets chromatin access for transcription factor NF-κB to alter transcription of host genes involved in immune responses. Nat. Immunol. 8, 47–56 (2007).

  154. 154.

    et al. The type III effectors NleE and NleB from enteropathogenic E. coli and OspZ from Shigella block nuclear translocation of NF-κB p65. PLoS Pathog. 6, e1000898 (2010).

  155. 155.

    , , & New insights into the crosstalk between Shigella and T lymphocytes. Trends Microbiol. 22, 192–198 (2014).

  156. 156.

    et al. The Shigella flexneri type three secretion system effector IpgD inhibits T cell migration by manipulating host phosphoinositide metabolism. Cell Host Microbe 9, 263–272 (2011).

  157. 157.

    et al. Shigella impairs T lymphocyte dynamics in vivo. Proc. Natl Acad. Sci. USA 110, 4458–4463 (2013).

  158. 158.

    et al. B lymphocytes undergo TLR2-dependent apoptosis upon Shigella infection. J. Exp. Med. 211, 1215–1229 (2014).

  159. 159.

    , & Involvement of a plasmid in the invasive ability of Shigella flexneri. Infect. Immun. 35, 852–860 (1982).

  160. 160.

    , & Shigella sonnei plasmids: evidence that a large plasmid is necessary for virulence. Infect. Immun. 34, 75–83 (1981). This is the first study to demonstrate that the large plasmid is necessary for virulence in Shigella spp.

  161. 161.

    & Characterization of the stable maintenance of the Shigella flexneri plasmid pHS-2. Plasmid 36, 183–190 (1996).

  162. 162.

    & Association between reactive arthritis and antecedent infection with Shigella flexneri carrying a 2-MD plasmid and encoding an HLA-B27 mimetic epitope. Arthritis Rheum. 36, 1387–1391 (1993).

  163. 163.

    Shigella induced reactive arthritis. Ann. Rheum. Dis. 64, 517–518 (2005).

  164. 164.

    , , & Reactive arthritis attributable to Shigella infection: a clinical and epidemiological nationwide study. Ann. Rheum. Dis. 64, 594–598 (2005).

  165. 165.

    , , , & Activity spectrum of colicins produced by Shigella sonnei and genetic mechanism of colicin resistance in conspecific S. sonnei strains and Escherichia coli. Antimicrob. Agents Chemother. 59, 152–158 (2015).

  166. 166.

    et al. The introduction and establishment of fluoroquinolone resistant Shigella sonnei into Bhutan. Microb. Genom. (2015).

  167. 167.

    et al. Epidemiologic patterns of acute diarrhea and endemic Shigella infections in children in a poor periurban setting in Santiago, Chile. Am. J. Epidemiol. 134, 614–627 (1991).

  168. 168.

    et al. Strategy for cross-protection among Shigella flexneri serotypes. Infect. Immun. 67, 782–788 (1999).

  169. 169.

    The emergence and spread of dysentery. Nat. Genet. 44, 964–965 (2012).

  170. 170.

    , L, , & Clinical trials of Shigella vaccines: two steps forward and one step back on a long, hard road. Nat. Rev. Microbiol. 5, 540–553 (2007).

  171. 171.

    , & Progress and pitfalls in Shigella vaccine research. Nat. Rev. Gastroenterol. Hepatol. 10, 245–255 (2013).

  172. 172.

    An assessment of enterotoxigenic Escherichia coli and Shigella vaccine candidates for infants and children. Vaccine 33, 954–965 (2015). A comprehensive and up-to-date review evaluating the current approaches for a Shigella spp. vaccine.

  173. 173.

    et al. Characterization of a novel fusion protein from IpaB and IpaD of Shigella spp. and its potential as a pan-Shigella vaccine. Infect. Immun. 81, 4470–4477 (2013).

  174. 174.

    et al. Safety and immunogenicity of an intranasal Shigella flexneri 2a Invaplex 50 vaccine. Vaccine 29, 7009–7019 (2011).

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Acknowledgements

H.C.T., D.P.T. and N.R.T. are funded by the Wellcome Trust (grant 098051); K.E.H is funded by the Australian National Health and Medical Research Council (NHMRC); and S.B. is a Sir Henry Dale Fellow, funded by the Wellcome Trust and the Royal Society (grant 100087/Z/12/Z).

Author information

Affiliations

  1. The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, 764 Vo Van Kiet, Quan 5, Ho Chi Minh City, Vietnam.

    • Hao Chung The
    • , Duy Pham Thanh
    •  & Stephen Baker
  2. Centre for Systems Genomics, University of Melbourne.

    • Kathryn E. Holt
  3. Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria 3052, Australia.

    • Kathryn E. Holt
  4. Bacterial Genomics, The Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.

    • Nicholas R. Thomson
  5. Centre for Tropical Medicine and Global Health, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7FZ, UK.

    • Nicholas R. Thomson
    •  & Stephen Baker
  6. Department of Pathogen and Molecular Biology, The London School of Hygiene and Tropical Medicine, Keppel St, London WC1E 7HT, UK.

    • Stephen Baker

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Stephen Baker.

Glossary

Disability adjusted life years

(DALY). A measure of overall disease burden, expressed as the cumulative number of years lost owing to ill health, disability or early death.

Pathovars

Groups of bacterial strains that have similar characteristics and are differentiated at the subspecies level on the basis of their distinctive pathogenicity in one or more hosts.

Lysine decarboxylation

(LDC). A reaction that is used in a biochemical test to determine the ability of a microorganism to use lysine as a source of carbon for growth. In a positive LDC test, lysine is metabolized into the amine cadaverine through the activity of the enzyme lysine decarboxylase.

Microfold cell

(M cell). A specialized epithelial cell type found in the follicle-associated epithelium of the gastrointestinal tract. Their function is to transport macromolecules and microorganisms across the epithelial barriers to the immune cells, thus inducing mucosal immunity.

Transcytosis

The selective vesicular transport of macromolecules from one side of the cell to the other while maintaining the unique compositions of these vesicular environments.

O antigen

A repeating glycan polymer attached to the outer core in lipopolysaccharide. This structure is on the very outer surface of the bacterial cell and is therefore a target for recognition by the host immune system.

Conjugation

The transfer of genetic material between bacterial cells through cell-to-cell contact or by a bridge-like connection between two cells.

Transduction

A mode of horizontal gene transfer whereby genetic material is transferred from one bacterium to another by a virus.

Flagellum

A multiprotein thread-like structure protruding from prokaryotic or eukaryotic cells that is used for motility and for the sensory perception of extracellular chemicals and temperature.

Fimbriae

Appendages composed of the protein curlin and found on many Gram-negative and some Gram-positive bacteria. Fimbriae are used mainly for adherence to bacterial cells, host cells and abiotic surfaces.

Pathogen-associated molecular pattern

(PAMP). A set of specific molecules that are present on groups of pathogens and are recognized by the innate immune system. These conserved molecular motifs in bacteria, such as lipopolysaccharide and flagellin, are usually recognized by Toll-like receptors and other pattern-recognition receptors.

Cadaverine

A diamine with a putrid odour. It is the product of lysine decarboxylation.

Quinolinate

A dicarboxylic acid generated as the downstream product of tryptophan catabolism. It acts as a substrate for the biosynthesis of nicotinic acid mononucleotide and, ultimately, the formation of the coenzyme NAD.

Class II integrons

Mobile genetic elements that are capable of carrying genes, including antimicrobial-resistance genes, and integrating into bacterial chromosomes by site-specific recombination. An integron contains at least an integrase, an attachment site and a promoter. Classification is based on the type of integrase.

Pulsed-field gel electrophoresis

(PFGE). A molecular typing technique based on the migration pattern of DNA fragments of variable lengths, generated by restriction enzyme treatment, in an electrical field.

Multilocus sequence typing

(MLST). A DNA sequence-based molecular typing scheme in which each isolate is distinguished by a combination of unique alleles of housekeeping genes (by comparing their genetic variations).

Homoplasies

Phenotypic or genotypic characteristics that are shared by a set of organisms but not inherited from a common ancestor.

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DOI

https://doi.org/10.1038/nrmicro.2016.10

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