Research Article: The Rising Dominance of Shigella sonnei: An Intercontinental Shift in the Etiology of Bacillary Dysentery

Date Published: June 11, 2015

Publisher: Public Library of Science

Author(s): Corinne N. Thompson, Pham Thanh Duy, Stephen Baker, Archie C. A. Clements.

Abstract: Shigellosis is the major global cause of dysentery. Shigella sonnei, which has historically been more commonly isolated in developed countries, is undergoing an unprecedented expansion across industrializing regions in Asia, Latin America, and the Middle East. The precise reasons underpinning the epidemiological distribution of the various Shigella species and this global surge in S. sonnei are unclear but may be due to three major environmental pressures. First, natural passive immunization with the bacterium Plesiomonas shigelloides is hypothesized to protect populations with poor water supplies against S. sonnei. Improving the quality of drinking water supplies would, therefore, result in a reduction in P. shigelloides exposure and a subsequent reduction in environmental immunization against S. sonnei. Secondly, the ubiquitous amoeba species Acanthamoeba castellanii has been shown to phagocytize S. sonnei efficiently and symbiotically, thus allowing the bacteria access to a protected niche in which to withstand chlorination and other harsh environmental conditions in temperate countries. Finally, S. sonnei has emerged from Europe and begun to spread globally only relatively recently. A strong selective pressure from localized antimicrobial use additionally appears to have had a dramatic impact on the evolution of the S. sonnei population. We hypothesize that S. sonnei, which exhibits an exceptional ability to acquire antimicrobial resistance genes from commensal and pathogenic bacteria, has a competitive advantage over S. flexneri, particularly in areas with poorly regulated antimicrobial use. Continuing improvement in the quality of global drinking water supplies alongside the rapid development of antimicrobial resistance predicts the burden and international distribution of S. sonnei will only continue to grow. An effective vaccine against S. sonnei is overdue and may become one of our only weapons against this increasingly dominant and problematic gastrointestinal pathogen.

Partial Text: Shigellosis, caused by members of the bacterial genus Shigella, is a severe and occasionally life-threatening diarrheal infection. Worldwide, Shigella spp. are the most common cause of acute, bloody diarrhea (dysentery) and are responsible for a significant proportion of the burden of morbidity and mortality associated with diarrheal disease [1,2]. In Asia alone, it is estimated that there are 125 million infections and 14,000 deaths due to shigellosis annually [3]. As a result of the considerable global burden, low infectious dose [4], clinical severity, and frequent reports of emerging antimicrobial resistance against first- and, more recently, second-line therapies [5,6], a vaccine against Shigella infections is a growing necessity. Yet, more than a century after the discovery of the agent of bacillary dysentery, there is still neither a licensed vaccine nor agreement on the precise mechanisms that induce Shigella immunity [7]. Vaccine development is further complicated by the probable need for a multivalent combination of O polysaccharide antigens to protect against a variety of heterogeneously distributed serotypes [8].

Reasons behind the conventional dominance of S. sonnei in industrialized countries remain unclear [13]. However, an increasing proportion of shigellosis due to S. sonnei generally correlates with improving economic prosperity [12], which in the context of many rapidly developing countries, has led to a proportional decrease in S. flexneri and the simultaneous emergence of S. sonnei [14]. This shift toward S. sonnei has been documented in many regions in Asia, Latin America, and the Middle East (Fig 1) [15–20], with proven explanations behind such an epidemiological phenomenon lacking. This review aims to summarize the existing evidence as to why S. sonnei may predominate in high-income countries and why it is now emerging in regions traditionally dominated by S. flexneri and explores the implications of the growing threat of this increasingly antimicrobial-resistant pathogen for public health globally.

One of the principal theories regarding the lack of S. sonnei in industrializing areas focuses on the Gram-negative bacteria P. shigelloides, which like Shigella falls within the large eubacterial family of the Enterobacteriaece. P. shigelloides and S. sonnei share an identical lipopolysaccharide (LPS) O-side chain (confirmed by nuclear magnetic resonance [NMR] and mass spectrometry) that is thought to be the major surface antigen targeted by the adaptive immune system during Shigella infection [21,22]. These surface antigens are cross-reactive, and vaccines prepared from O-antigen derived from P. shigelloides have been shown to be reasonably effective in preventing infection with S. sonnei in humans [23,24]. The O-antigen gene cluster is located on the S. sonnei invasion plasmid and is essential for penetration of host epithelial cells [25]. Evidence suggests not only that S. sonnei acquired the O-antigen gene cluster from P. shigelloides but also that this acquisition was the defining event in the emergence of S. sonnei [26].

Acanthamoeba is the most common amoeba found globally, with a wide distribution in both aquatic and nonaquatic environments [35]. Amoeba such as Acanthamoeba are known to act as environmental hosts for a variety of intracellular pathogens including Helicobacter pylori, Vibrio cholerae, and also various Shigella spp. [36–38]. The uptake of bacteria into amoebic cysts allows the bacteria to persist in adverse environmental conditions, including desiccation, starvation, and a variety of chemical and physical agents [39]. Acanthamoeba cysts, which form when triggered by nutritional or osmotic stress, are particularly resistant to chlorine treatment [40]. Found commonly through environmental sampling [41], Acanthamoeba has been identified in public water supplies in developed countries with appropriate chlorination levels [42] and in hospital water supplies [43] and can also be isolated from drinking water supplies in industrializing regions [44].

Phylogeographical analyses of a large number of S. sonnei isolates spanning several continents and several decades in a publication by Holt et al. demonstrated that all contemporary S. sonnei infections are due to a small number of clones that dispersed globally from Europe within the last 500 years [34]. Four distinct lineages of S. sonnei were identified, with lineage III the most prevalent globally, becoming dominant in Asia, Africa, and South America [34]. S. sonnei belonging to lineage III are characterized by the presence of distinct class II integron (In2), which confers resistance to trimethoprim, streptothricin, and streptomycin [55]. Many lineage III isolates were also found to harbor a genetic locus on a small plasmid conferring resistance to a variety of additional antimicrobials including tetracycline and sulphonamides. Holt and colleagues indicated that In2 was likely acquired during the mid-20th century, after which the clone spread internationally, undergoing contemporary global dispersal and localized clonal expansions [34].

Taken together, evidence suggests that the global burden of S. sonnei may be growing compared to that of S. flexneri. This phenomenon may not only be due to the global improvements in water quality and an ability of S. sonnei to grow successfully within Acanthamoeba but may also be due to a potential, but as yet unproven, ability to acquire and/or maintain a wider array of antimicrobial resistance genes. Indeed, it has been speculated that the plasmid composition and resistance profiles may differ between the Shigella species isolated from contemporaneous patient populations in the same locations (Fig 2) [15,66–71]. Although S. sonnei can acquire extended-spectrum beta-lactamase (ESBL)-mediated resistance from other Enterobacteriaceae, particularly E. coli and Klebsiella spp. [72], it is not currently known whether S. flexneri and S. sonnei acquire resistance genes from each other. Toro et al. suggested that there is a greater restriction barrier for conjugal plasmids between S. sonnei and S. flexneri than between other Gram-negative donors and recipients [67]. A differential ability to acquire and/or maintain plasmids between S. flexneri and S. sonnei from other bacterial donors may also explain discrepant resistance profiles between contemporaneous species, although such a phenomenon has yet to be explicitly investigated.

We predict that the combination of improving water supplies and rapid acquisition and maintenance of mobile elements conferring advantageous resistance genes is accelerating a Shigella species shift toward S. sonnei dominance, which traditionally has been shown to occur over a period of decades in individual countries (Table 1, S1 Table) [78,79]. To counter this rapid species replacement, many questions regarding the epidemiology of S. sonnei and, crucially, vaccine development need to be addressed. Identifying prominent transmission routes of S. sonnei and S. flexneri in resource-poor countries should remain a primary goal. Indeed, experiments to determine the relative fitness of each species in varying environmental conditions and investigating antimicrobial fitness [80] would provide information on potential niche preferences and add insight into which accessory gene pools each species samples from. Finally, longitudinal monitoring of water supplies for the presence of both P. shigelloides and A. castellanii would help to verify the hypotheses presented in this review in regard to both a reduction of population immunity against the S. sonnei O-antigen as well as an environmental amoeba niche for these bacteria.



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