Dysentery in World War 1: Shigella a century on
Authors: David J M Wright, Bohumil S Drasar
Journal: The Lancet (2014)

In 1900, Simon Flexner, while visiting Manila, Philippines, isolated a bacterium from two patients with "red [bloody] diarrhoea" that he thought was the same as Shiga's Shigella dysenteriae. However, in 1902, Martini and Lentz1Martini E Lentz O Ueber die differenzirung der ruhrbacillen mittels der agglutination.Z Hyg Infektions. 1902; 41: 540-558Google Scholar showed that this bacterium was a distinct microbe, Bacterium flexneri, renamed by Ewing2Ewing WH Shigella nomenclature.J Bacteriol. 1949; 57: 633-638PubMed Google Scholar as Shigella flexneri.This organism is likely to have been the most common cause of dysentery in the British Expeditionary Force in France in World War 1. Modern gunnery made it necessary to provide cover for the troops in trenches. Insufficient drainage of the trenches coupled with poor hygiene and no provision for the disposal of excreta meant that soldiers had to survive, often knee deep or worse, in foul water. Diseases such as bacillary dysentery and trench foot were endemic and epidemic in the waterlogged trenches, as discussed by Alison Mather and colleagues in their accompanying Case Report.3Mather AE Baker KS McGregor H et al.Bacillary dysentery from World War 1 and NCTC1, the first bacterial isolate in the National Collection.Lancet. 2014; 384: 1720Summary Full Text Full Text PDF PubMed Scopus (11) Google ScholarGenome sequencing of an early World War 1 isolate of S flexneri, which Kate Baker and colleagues4Baker KS Mather AE McGregor H et al.The extant World War 1 dysentery bacillus NCTC1: a genomic analysis.Lancet. 2014; 38: 1691-1697Summary Full Text Full Text PDF Scopus (24) Google Scholar describe in this issue of The Lancet, gives an in-depth view of the microbe's evolution over the past 100 years. The changes mimic those of the ancestral Escherichia coli as it developed into Shigella, species that are still regarded as a clade of E coli.5Jin Q Yuan Z Xu J et al.Genome sequence of Shigella flexner 2a. Insights into pathogenicity through comparison with genomes of Escherichia coli K12 and 0157.Nucleic Acids Res. 2002; 30: 4432-4441Crossref PubMed Scopus (370) Google Scholar The differences reported between E coli, the descendant enteroinvasive E coli (EIEC), and Shigella are often indistinct (analysis using matrix-assisted laser desorption/ionisation with time-of-flight mass spectrometry is unable to distinguish these microbes)6Deng J Fu L Wang R et al.Comparison of MALDI-TOF MS, gene sequencing and Vitek Z for identification of 73 clinical isolates of enteropathogens.J Thorac Dis. 2014; 6: 53944Google Scholar and they share a common core genome. Molecular-clock calculations suggest that Shigella diverged from several E coli species between 35 000 and 270 000 years ago.7Pupo GM Lan R Reeves PR Multiple independent origins of Shigella clones of Escherichia coli and convergent evolution of many of their characteristics.Proc Natl Acad Sci USA. 2000; 97: 10567-10572Crossref PubMed Scopus (403) Google Scholar Was this a result of early paleolithic man's habits, the way food was prepared or stored, or perhaps diet? Or, if about 35 000 BCE is accepted as the date for S flexneri's appearance, did it occur when man migrated from Africa to Europe? The low infective dose of Shigella might explain how hunter-gatherers could have taken a small amount of contamination with them when moving to new environments.After the evolution of E coli to Shigella, two predominant genetic events were reported. Old characteristics were deleted—as a form of reductive evolution—with the addition of new characteristics that increased pathogenicity, such as the loss of genes relating to motility, the flagellar genes, and the consequent absence of H antigens. Some fermentative catabolic pathways disappeared, accompanied by a loss of lysine decarboxylase, the end-product of which is cadaverine, which impedes intracellular dissemination of Shigella by blocking bacterial escape from phagocytes.8Fernandez IM Silva M Schuch R Cadaverine prevents the escape of Shigella flexneri from the phagolysosome: a connection between bacterial dissemination and neutrophil epithelial signalling.J Infect Dis. 2001; 184: 743-753Crossref PubMed Scopus (44) Google Scholar Changes in the bacterial cell envelope resulting in no K (capsular) antigens have also been reported. However, many more insertion sequences, including those related to genomic pathogenicity islands, appeared. Insertion sequences constitute 7% of the Shigella genome, compared with 1·5% of E coli K12.9Wei J Goldberg MB Burland V et al.Complete genome sequence and comparative genomics of Shigella flexneri 2a strain 2457T.Infect Immun. 2003; 71: 2775-2786Crossref PubMed Scopus (330) Google Scholar Specific virulence factors, such as adhesins and EIEC toxin, which damage intestinal mucosal epithelium and precipitate bleeding,10Bando SY Moreno AC Albuquerque JA Amhaz JM Moreira-Filho CA Martinez MB Expression of bacterial virulence factor and cytokines during in vitro macrophage infection by Escherichia coli and Shigella flexneri: a comparative study.Mem Inst Oswaldo Cruz. 2010; 105: 786-791Crossref PubMed Scopus (15) Google Scholar were also acquired. Antigenic variation of the O antigen helps the bacterium to avoid the immune response, and genetic changes in the large virulent plasmid (which is responsible for different pathogenic determinants such as the T3 secretory system) tend to parallel those found in the bacterial chromosome.Baker and colleagues4Baker KS Mather AE McGregor H et al.The extant World War 1 dysentery bacillus NCTC1: a genomic analysis.Lancet. 2014; 38: 1691-1697Summary Full Text Full Text PDF Scopus (24) Google Scholar show the same trend occurring over the past 100 years in the S flexneri isolate from World War 1, with insertion sequences facilitating the gain of some antimicrobial resistance elements and the discovery of unique pseudogenes. New virulence factors also appeared, such as shigella enterotoxin 1,11Noriega FR Ming Liao L Fornal SB Fasano A Levine MM Prevalence of Shigella enterotoxins among Shigella isolates of diverse origins.J Infect Dis. 1995; 172: 1408-1410Crossref PubMed Scopus (70) Google Scholar and the number of pathogenicity islands increased. The occurrence of a new serotype Xv from China, replacing the more common Asian serotype of S flexneri type 2a but remaining in the same serotype cluster, renders any immunity obtained from the old 2a serotype irrelevant.12Qui S Wang Z Chen C et al.Emergence of a novel Shigella serotype 4s strain which evolved from a serotype X variant in China.J Clin Microbiol. 2011; 49: 1148-1150Crossref PubMed Scopus (24) Google Scholar The large plasmid was lost in the World War 1 isolate, presumably because of serial passage. Since this plasmid carries many virulence genes, such as those promoting type 3 secretion system effectors and SK2, which assists intercellular and intracellular spread of Shigella,13Bernadini ML Meunier J d'Hautville H Coquis-Rendon M Sansonetti J Identification of icsA, a plasmid locus of Shigella flexneri that governs bacterial intra-inter cellular spread through interaction with F-actin.Proc Natl Acad Sci USA. 1989; 86: 3867-3871Crossref PubMed Scopus (535) Google Scholar only chromosomal changes could be investigated. The mutation of the variant (v) portion in the (S flexneri 2a) Xv Chinese serotype, unlike all the other genes for serotypes, is a plasmid mutation.14Knirel YA Lan R Senchenkova SN et al.O-antigen structure of Shigella flexneri serotype Vv and the effect of the last lpt gene variation on phosphoethanolamine modification of S. flexneri O-antigens.Glycobiology. 2013; 23: 475-485Crossref PubMed Scopus (21) Google ScholarGood hygiene, especially when preparing food, and reliable sanitation are the best prevention against bacillary dysentery. There are no significant non-human hosts, which makes vaccination an ideal solution for elimination of the disease. However, although many studies are in progress,15Octavia S Lan R Shigella and Shigellosis: genetics, epidemiology and pathogenesis.in: Tan Y-W Sussman M Liu D Poxton I Schwartzman J Molecular medical microbiology. vol 2. Academic Press, London, UK2015: 1181Google Scholar vaccines are not yet available. Multiple antibiotic resistance of Shigella means treatment is not straightforward, even though some regional variation in resistance exists.The focus on the treatment of soldiers has more recently been extended to civilian populations of war zones. Admirable in itself, this approach also reduces the sources of infection to which soldiers are exposed, underlining the role of the military in humanitarian work. Nowadays epidemics of bacillary dysentery in the armed services are not often reported; rather, they tend to occur in refugee camps and in impoverished urban slums.We declare no competing interests. In 1900, Simon Flexner, while visiting Manila, Philippines, isolated a bacterium from two patients with "red [bloody] diarrhoea" that he thought was the same as Shiga's Shigella dysenteriae. However, in 1902, Martini and Lentz1Martini E Lentz O Ueber die differenzirung der ruhrbacillen mittels der agglutination.Z Hyg Infektions. 1902; 41: 540-558Google Scholar showed that this bacterium was a distinct microbe, Bacterium flexneri, renamed by Ewing2Ewing WH Shigella nomenclature.J Bacteriol. 1949; 57: 633-638PubMed Google Scholar as Shigella flexneri. This organism is likely to have been the most common cause of dysentery in the British Expeditionary Force in France in World War 1. Modern gunnery made it necessary to provide cover for the troops in trenches. Insufficient drainage of the trenches coupled with poor hygiene and no provision for the disposal of excreta meant that soldiers had to survive, often knee deep or worse, in foul water. Diseases such as bacillary dysentery and trench foot were endemic and epidemic in the waterlogged trenches, as discussed by Alison Mather and colleagues in their accompanying Case Report.3Mather AE Baker KS McGregor H et al.Bacillary dysentery from World War 1 and NCTC1, the first bacterial isolate in the National Collection.Lancet. 2014; 384: 1720Summary Full Text Full Text PDF PubMed Scopus (11) Google Scholar Genome sequencing of an early World War 1 isolate of S flexneri, which Kate Baker and colleagues4Baker KS Mather AE McGregor H et al.The extant World War 1 dysentery bacillus NCTC1: a genomic analysis.Lancet. 2014; 38: 1691-1697Summary Full Text Full Text PDF Scopus (24) Google Scholar describe in this issue of The Lancet, gives an in-depth view of the microbe's evolution over the past 100 years. The changes mimic those of the ancestral Escherichia coli as it developed into Shigella, species that are still regarded as a clade of E coli.5Jin Q Yuan Z Xu J et al.Genome sequence of Shigella flexner 2a. Insights into pathogenicity through comparison with genomes of Escherichia coli K12 and 0157.Nucleic Acids Res. 2002; 30: 4432-4441Crossref PubMed Scopus (370) Google Scholar The differences reported between E coli, the descendant enteroinvasive E coli (EIEC), and Shigella are often indistinct (analysis using matrix-assisted laser desorption/ionisation with time-of-flight mass spectrometry is unable to distinguish these microbes)6Deng J Fu L Wang R et al.Comparison of MALDI-TOF MS, gene sequencing and Vitek Z for identification of 73 clinical isolates of enteropathogens.J Thorac Dis. 2014; 6: 53944Google Scholar and they share a common core genome. Molecular-clock calculations suggest that Shigella diverged from several E coli species between 35 000 and 270 000 years ago.7Pupo GM Lan R Reeves PR Multiple independent origins of Shigella clones of Escherichia coli and convergent evolution of many of their characteristics.Proc Natl Acad Sci USA. 2000; 97: 10567-10572Crossref PubMed Scopus (403) Google Scholar Was this a result of early paleolithic man's habits, the way food was prepared or stored, or perhaps diet? Or, if about 35 000 BCE is accepted as the date for S flexneri's appearance, did it occur when man migrated from Africa to Europe? The low infective dose of Shigella might explain how hunter-gatherers could have taken a small amount of contamination with them when moving to new environments. After the evolution of E coli to Shigella, two predominant genetic events were reported. Old characteristics were deleted—as a form of reductive evolution—with the addition of new characteristics that increased pathogenicity, such as the loss of genes relating to motility, the flagellar genes, and the consequent absence of H antigens. Some fermentative catabolic pathways disappeared, accompanied by a loss of lysine decarboxylase, the end-product of which is cadaverine, which impedes intracellular dissemination of Shigella by blocking bacterial escape from phagocytes.8Fernandez IM Silva M Schuch R Cadaverine prevents the escape of Shigella flexneri from the phagolysosome: a connection between bacterial dissemination and neutrophil epithelial signalling.J Infect Dis. 2001; 184: 743-753Crossref PubMed Scopus (44) Google Scholar Changes in the bacterial cell envelope resulting in no K (capsular) antigens have also been reported. However, many more insertion sequences, including those related to genomic pathogenicity islands, appeared. Insertion sequences constitute 7% of the Shigella genome, compared with 1·5% of E coli K12.9Wei J Goldberg MB Burland V et al.Complete genome sequence and comparative genomics of Shigella flexneri 2a strain 2457T.Infect Immun. 2003; 71: 2775-2786Crossref PubMed Scopus (330) Google Scholar Specific virulence factors, such as adhesins and EIEC toxin, which damage intestinal mucosal epithelium and precipitate bleeding,10Bando SY Moreno AC Albuquerque JA Amhaz JM Moreira-Filho CA Martinez MB Expression of bacterial virulence factor and cytokines during in vitro macrophage infection by Escherichia coli and Shigella flexneri: a comparative study.Mem Inst Oswaldo Cruz. 2010; 105: 786-791Crossref PubMed Scopus (15) Google Scholar were also acquired. Antigenic variation of the O antigen helps the bacterium to avoid the immune response, and genetic changes in the large virulent plasmid (which is responsible for different pathogenic determinants such as the T3 secretory system) tend to parallel those found in the bacterial chromosome. Baker and colleagues4Baker KS Mather AE McGregor H et al.The extant World War 1 dysentery bacillus NCTC1: a genomic analysis.Lancet. 2014; 38: 1691-1697Summary Full Text Full Text PDF Scopus (24) Google Scholar show the same trend occurring over the past 100 years in the S flexneri isolate from World War 1, with insertion sequences facilitating the gain of some antimicrobial resistance elements and the discovery of unique pseudogenes. New virulence factors also appeared, such as shigella enterotoxin 1,11Noriega FR Ming Liao L Fornal SB Fasano A Levine MM Prevalence of Shigella enterotoxins among Shigella isolates of diverse origins.J Infect Dis. 1995; 172: 1408-1410Crossref PubMed Scopus (70) Google Scholar and the number of pathogenicity islands increased. The occurrence of a new serotype Xv from China, replacing the more common Asian serotype of S flexneri type 2a but remaining in the same serotype cluster, renders any immunity obtained from the old 2a serotype irrelevant.12Qui S Wang Z Chen C et al.Emergence of a novel Shigella serotype 4s strain which evolved from a serotype X variant in China.J Clin Microbiol. 2011; 49: 1148-1150Crossref PubMed Scopus (24) Google Scholar The large plasmid was lost in the World War 1 isolate, presumably because of serial passage. Since this plasmid carries many virulence genes, such as those promoting type 3 secretion system effectors and SK2, which assists intercellular and intracellular spread of Shigella,13Bernadini ML Meunier J d'Hautville H Coquis-Rendon M Sansonetti J Identification of icsA, a plasmid locus of Shigella flexneri that governs bacterial intra-inter cellular spread through interaction with F-actin.Proc Natl Acad Sci USA. 1989; 86: 3867-3871Crossref PubMed Scopus (535) Google Scholar only chromosomal changes could be investigated. The mutation of the variant (v) portion in the (S flexneri 2a) Xv Chinese serotype, unlike all the other genes for serotypes, is a plasmid mutation.14Knirel YA Lan R Senchenkova SN et al.O-antigen structure of Shigella flexneri serotype Vv and the effect of the last lpt gene variation on phosphoethanolamine modification of S. flexneri O-antigens.Glycobiology. 2013; 23: 475-485Crossref PubMed Scopus (21) Google Scholar Good hygiene, especially when preparing food, and reliable sanitation are the best prevention against bacillary dysentery. There are no significant non-human hosts, which makes vaccination an ideal solution for elimination of the disease. However, although many studies are in progress,15Octavia S Lan R Shigella and Shigellosis: genetics, epidemiology and pathogenesis.in: Tan Y-W Sussman M Liu D Poxton I Schwartzman J Molecular medical microbiology. vol 2. Academic Press, London, UK2015: 1181Google Scholar vaccines are not yet available. Multiple antibiotic resistance of Shigella means treatment is not straightforward, even though some regional variation in resistance exists. The focus on the treatment of soldiers has more recently been extended to civilian populations of war zones. Admirable in itself, this approach also reduces the sources of infection to which soldiers are exposed, underlining the role of the military in humanitarian work. Nowadays epidemics of bacillary dysentery in the armed services are not often reported; rather, they tend to occur in refugee camps and in impoverished urban slums. We declare no competing interests. The changing role of the British state and its citizensA J P Taylor, the British historian, noted that before World War 1, "a sensible, law-abiding Englishman could pass through life and hardly notice the existence of the state, beyond the post office and the policeman".1 After the war, the life of a British citizen would be shaped by the state and its institutions in ways that could never previously have been imagined. Full-Text PDF Refugees and health: lessons from World War 1The vast territory and huge number of civilians affected by World War 1 caused an unprecedented displacement and forced migration of people in Europe and beyond.1 There is little consensus on the actual number displaced, but more than 9 million were internally displaced persons and more than 3 million were refugees.1–3 Although not comparable to the conflict in World War 1, today there are more than 51 million people worldwide who have been forcibly displaced; these include internally displaced persons, refugees, and asylum seekers, the largest number since World War 2. Full-Text PDF Disability and socioeconomic inclusion after World War 1Much has been written about the health legacies of World War 1: from early research on the psychological consequences of trauma to advances in prosthetics and plastic surgery, improvements in field medicine and nursing, and the eventual discovery of antibiotics.1–3 World War 1 also left a legacy of disability, with millions of men left permanently impaired. But, as historian Deborah Cohen4 has written, the responses of the German and British Governments to these millions of war disabled were strikingly different and, it might be argued, have left another equally enduring legacy. Full-Text PDF The extant World War 1 dysentery bacillus NCTC1: a genomic analysisThis S flexneri 2a lineage is a well adapted pathogen that has continued to respond to selective pressures. We have created a valuable historical benchmark for shigellae in the form of a high-quality reference sequence for a publicly available isolate. Full-Text PDF Open AccessBacillary dysentery from World War 1 and NCTC1, the first bacterial isolate in the National CollectionIn early 1915, a 28-year-old man arrived at No 14 Stationary Hospital in Wimereux, France. Although no clinical records remain, we believe he would have presented with bloody diarrhoea and severe abdominal cramping, and he was diagnosed with dysentery. On March 13, 1915, the patient, who we believe was Private Ernest Cable of the 2nd Battalion of the East Surrey Regiment (appendix), died. Lieutenant William Broughton-Alcock, whose military records1 identify him as a bacteriologist for No 14 Stationary Hospital, collected this isolate—later identified as a Shigella flexneri serotype 2a bacterium—which was the first bacterial isolate deposited in the UK National Collection of Type Cultures (NCTC)2 using the original isolate name Cable. Full-Text PDF