Dynamics in genome evolution of Vibrio cholerae.

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Contents lists available at ScienceDirect

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Review

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Dynamics in genome evolution of Vibrio cholerae

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Rachana Banerjee a,1, Bhabatosh Das b,1, G. Balakrish Nair b, Surajit Basak c,d,⇑ a

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Department of Bio-Physics, Molecular Biology and Bioinformatics, University of Calcutta, 92, Acharya Prafulla Chandra Road, Kolkata 700009, India Centre for Human Microbial Ecology, Translational Health Science and Technology Institute, 496, Phase III, Udyog Vihar, Gurgaon 122016, Haryana, India c Department of Molecular Biology & Bioinformatics, Tripura University, Suryamaninagar 799 022, Tripura, India d Bioinformatics Centre, Tripura University, Suryamaninagar 799 022, Tripura, India b

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Article history: Received 26 August 2013 Received in revised form 9 January 2014 Accepted 11 January 2014 Available online xxxx

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Keywords: Cholera Vibrio cholerae Pathogen Genome Serogroups Mobile genetic elements

a b s t r a c t Vibrio cholerae, the etiological agent of the acute secretary diarrheal disease cholera, is still a major public health concern in developing countries. In former centuries cholera was a permanent threat even to the highly developed populations of Europe, North America, and the northern part of Asia. Extensive studies on the cholera bug over more than a century have made significant advances in our understanding of the disease and ways of treating patients. V. cholerae has more than 200 serogroups, but only few serogroups have caused disease on a worldwide scale. Until the present, the evolutionary relationship of these pandemic causing serogroups was not clear. In the last decades, we have witnessed a shift involving genetically and phenotypically varied pandemic clones of V. cholerae in Asia and Africa. The exponential knowledge on the genome of several representatives V. cholerae strains has been used to identify and analyze the key determinants for rapid evolution of cholera pathogen. Recent comparative genomic studies have identified the presence of various integrative mobile genetic elements (IMGEs) in V. cholerae genome, which can be used as a marker of differentiation of all seventh pandemic clones with very similar core genome. This review attempts to bring together some of the important researches in recent times that have contributed towards understanding the genetics, epidemiology and evolution of toxigenic V. cholerae strains. Ó 2014 Elsevier B.V. All rights reserved.

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Contents

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1. 2. 3. 4. 5. 6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . History of cholera pandemics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aquatic lifestyle and source of infection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Virulent gene structure in V. cholerae biotypes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ‘Atypical El Tor’: the emerging biotype of cholera pathogen. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Virulence due to V. cholerae. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Serotype switching in V. cholerae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Evolution of genetic characteristics of pandemic V. cholerae strains . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8. Role of lateral gene transfer in the evolution of V. cholerae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.1. Pathogenicity island and virulence factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9. Integrative mobile genetic elements (IMGE): key player for evolution of antibiotic resistance cholera pathogen . . . . . . . . . . . . . . . . . . . . . . . . . 9.1. Integrative mobile genetic elements (IMGE) facilitating antibiotic resistance in pathogenic V. cholerae . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.2. SXT element as the basis of antibiotic resistance of V. cholerae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.3. Superintegrons providing adaptive advantages to V. cholerae genomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Uncited references . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix A. Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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⇑ Corresponding author at: Bioinformatics Centre, Tripura University, Suryamaninagar 799 022, Tripura, India. Tel.: +91 9862924152. 1

E-mail address: [email protected] (S. Basak). Contributed equally.

1567-1348/$ - see front matter Ó 2014 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.meegid.2014.01.006

Please cite this article in press as: Banerjee, R., et al. Dynamics in genome evolution of Vibrio cholerae. Infect. Genet. Evol. (2014), http://dx.doi.org/10.1016/ j.meegid.2014.01.006

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1. Introduction

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Cholera is one of the most potent diarrheal diseases that continue to ravage many developing countries. This is one disease in modern time that is endemic, epidemic and pandemic in nature. Infections due to Vibrio cholerae, the cholera pathogen, have been reported from all over the world, although they are of primary importance in developing countries where endemic cholera remains a serious health threat and are particularly associated with poverty and poor sanitation (Lee, 2001; Basak et al., 2009). Most of the V. cholerae strains are not pathogenic. Indeed, to date only 2 serogroups have been found associated with cholera epidemics and pandemics. Differences in the sugar composition of the heat-stable surface somatic ‘‘O’’ antigen are the basis of the serological classification of V. cholerae (Gardner and Venkatraman, 1935). Currently, more than 200 V. cholerae have been identified, based on the variation of ‘‘O’’ antigen (Shimada et al., 1994; Yamai et al., 1997). All strains of V. cholerae that did not agglutinate with ‘‘O’’ antiserum are referred to as non-O1 V. cholerae. The non-O1 strains are ubiquitous in estuarine environments. They have been isolated from cases of diarrhoea very rarely (20 °C) and salinity are the major determinants of the distribution of V. cholerae strains (Martinelli Filho et al., 2011). With the variations in water temperatures throughout the year in different seasons, the microorganism shows clear seasonality: environmental counts increase during warmer periods and decline during cold weather. This observation might be related to rapid increase in the number of V. cholerae-specific lytic bacteriophages in the local aquatic environment (Nelson et al., 2009, 2008).

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4. Virulent gene structure in V. cholerae biotypes

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Pathogenic strains harbour cholera toxin prophage (CTXU) that carries the genes encoding the cholera toxin (CT). Cholera toxin is

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Fig. 3. Structure of CTX-phi, RS1 and RS2 elements in different varieties of Vibrio cholerae O1 serotypes. Different varieties of rstR gene i.e., rstRclassical and rstREl Tor has been colored differently. Similarly, Different varieties of ctxB gene i.e., ctxBclassical and ctxBEl Tor has been colored differently.

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the key virulence factor directly responsible for the major clinical symptoms of the disease (Kaper et al., 1995). CT binds to a specific receptor (GM1) on host enterocytes and is internalized, leading to elevated intracellular cAMP levels and resulting in a major loss of water and electrolytes in profuse secretory diarrhoea (Broeck et al., 2007). Hence, the ability to produce CT is essential for the outbreak of the diseases. The genome sequence analysis of a clinical V. cholerae VC35 strain from an outbreak case in Malaysia indicates multiple genes involved in host adaptation (Osama et al., 2012). CTXU carried by toxigenic V. cholerae strains consists of two functionally distinct gene clusters, namely, the core and the RS2 region (Fig. 3) (Waldor and Mekalanos, 1996a). While the core region encodes the phage morphogenesis proteins and cholera toxin, the functions needed for the phage replication and regulation of phage gene expression are present in the RS2 region. The genomic arrangement of the core region includes the ctxAB genes, encoding CT, together with five other genes encoding Psh, Core-encoded pilin (Cep), pIIICTX, Accessory cholera enterotoxin (Ace) and Zonula occludens (Zot), which are required for phage morphogenesis. The RS2 region encodes proteins with roles in the replication (RstA), integration (RstB) and regulation (RstR) of CTXU gene expression on the V. cholerae chromosome (Waldor et al., 1997). In toxigenic V. cholerae El Tor strains, a satellite phage known as RS1 is invariably present adjacent to CTXU (Fig. 3). RS1 is similar to RS2, except that it contains an additional gene, rstC, which encodes an antirepressor protein. This protein promotes the transcription of CTXU genes that are required to generate infectious particles (Waldor et al., 1997). Free replicative CTXU is highly unstable and detrimental to cholera pathogen. Two host encoded tyrosine recombinases, XerC and XerD, mediate the integration of CTX/ in specific chromosomal attachment sites (dif) of V. cholerae (Huber and Waldor, 2002; Das et al., 2010). Although, the integration of CTX/ is irreversible, it could produce large number of virion by using its rolling circle

replication machinery (Val et al. 2005; Das et al. 2010). Replication of prophage is only detectable when it present in tandem or flunked by RS1 in the chromosome. Several other filamentous Vibriophages participate in the continuous evolution of V. cholerae also present in the same CTX attachment sites and seem to use same recombination machinery for chromosomal integration (Das et al., 2011a, 2011b, 2013).

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5. ‘Atypical El Tor’: the emerging biotype of cholera pathogen

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There are many V. cholerae O1 strains exist that cannot be classified into any of the two biotypes, Classical and El Tor. These unusual V. cholerae O1 strains are termed as ‘atypical El Tor’ which appear to have a mix of both classical and El Tor traits. Naturally occurring atypical El Tor variants were first observed by Nair and colleagues (Nair et al., 2002) among hospital strains of V. cholerae O1 isolated between 1991 and 1994 in Matlab, Bangladesh. These strains were designated as Matlab (MT) variants. Ribotyping (Nair et al., 2002) and PCR-based identification of the El Tor-specific gene clusters VSP-I, VSP-II and RTX (Safa et al., 2006) suggested that the MT variants originated from the El Tor biotype. However, pulsedfield gel electrophoresis analysis showed patterns that were a mixture of those from classical and El Tor biotypes (Safa et al., 2005). Further studies showed that many of the MT variants harboured ctxB allele, which are characteristic of CTXUCla (Nair et al., 2002; Safa et al., 2006). Mozambique, a cholera-endemic country in East Africa, reported a large and extended cholera outbreak in 2004. The involved V. cholerae strains displayed phenotypic characteristics of the El Tor biotype. The Mozambique variants contained, in the small chromosome, two tandem copies of the prophage whose sequence was almost identical to that of the typical CTXUCla (Faruque et al., 2007; Das et al., 2007). Notably, this was the first report of atypical El Tor strains harbouring CTXUCla in Africa. El

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Tor strains isolated before 2001 in Bangladesh carried the ctxB allele, producing CT of the typical El Tor biotype. However, all El Tor strains isolated after that date in this country harbour ctxB, producing CT of the classical biotype (Nair et al., 2006). These atypical El Tor strains have been designated ‘altered El Tor’ contains both ctxB and rstREl (Nguyen et al., 2009). V. Cholerae strains isolated from Kolkata, India just before first O139 outbreaks displayed genetic traits similar to atypical O1 El Tor Traits isolated from Africa (Das et al. 2007). Das et al. (2007) reported that in atypical O1 El Tor strains of Indian origin carry tandem copies of Ctx-Prophages in small chromosome only. Nevertheless, the Ctx-Prophage present in the small chromosome encodes classical type ctxB (Das et al., 2007). Several El Tor strains isolated between 1991 and 2004 from Asian and African countries other than India, Bangladesh and Mozambique also harbour the classical CT allele ctxB; these variants were designated as ‘hybrid El Tor’ (Safa et al., 2008). Continued investigation has revealed that several of these strains carry both rstRCla and rstREl, indicating the presence of two different copies of CTXU, either as a tandem array or located on different chromosomes (Nguyen et al., 2009).

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6. Virulence due to V. cholerae

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Although V. cholerae as a species is ubiquitous in the environment, strains responsible for the disease cholera are restricted to a fairly tight subset of strains. The main gene clusters responsible for the appearance of cholera are associated with production of cholera toxin (Waldor and Mekalanos, 1996a) and the vibrio pathogenicity island, which includes the TCP (toxin-coregulated pilus) gene, essential for binding of the microorganism to the intestinal mucosa (Chun et al., 2009; Faruque et al., 2004). Even though

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virtually all strains that cause cholera produce cholera toxin and have the vibrio pathogenicity island (Supplementary Table 1), not all V. cholerae that carry one or both of these gene complexes cause cholera; several studies have noted the isolation of one or both from environmental strains that appear to lack other components of the genetic background essential for virulence in humans (Faruque et al., 2004; Li et al., 2002). Initially, a V. cholerae O1 serogroup strain first acquired the pathogenic island VPI-1, which encodes TCP, an essential colonization factor and the receptor for CTXU. This proposition is supported by the near sequence identity between classical and El Tor biotype strains across most of the VPI-1 region (Karaolis et al., 2001). A second pathogenic island, VPI-2, which encodes genes involved in restriction modification and N-acetyl neuraminic acid utilization, is found predominantly among O1 and O139 epidemic V. cholerae isolates (Jermyn and Boyd, 2002) and was most likely present in an O1 serogroup strain that gave rise to classical and El Tor biotype strains. Following the acquisition of VPI-1 and VPI-2 by an O1 serogroup progenitor strain, classical and El Tor biotype isolates emerged and diverged from one another through the acquisition of VSP-I, VSP-II, and RS1U (Fig. 4). Studies based on comparative nucleotide sequence analysis of CTXU genes indicate that this region was acquired independently in classical and El Tor biotype isolates (Boyd et al., 2000). The V. cholerae classical biotype was responsible for the sixth cholera pandemic, which began in 1899, and presumably previous cholera pandemics. V. cholerae El Tor biotype isolates, which are responsible for the ongoing seventh cholera pandemic, which began in 1961, acquired at least three regions in addition to CTXU: RS1U, which facilitates CTXU production, and VSP-I and VSP-II, whose roles in V. cholerae virulence are unknown (Dziejman et al., 2002).

Fig. 4. Comparative-genomics-based model for the evolution of pathogenic V. cholerae strains. It also depicts the acquisition of mobile DNA elements in the V. cholerae chromosomes.


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6.1. Serotype switching in V. cholerae

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The V. cholerae O139 strains that emerged in 1992 were derived from an El Tor progenitor by O-antigen switching likely facilitated by bacteriophages as well as the acquisition of a novel CTXU and SXT constin (Bik et al., 1996; Davis and Waldor, 2000; Waldor et al., 1997) (Fig. 4). The O139 Bengal strain is similar to the O1 classical and El Tot strains, producing major V. cholerae virulence factors such as cholera toxin and the toxin coregulated pilus (TCP) (Mooi and Bik, 1997). However, there are important differences between the O139 and O1 strains (Stroeher, 1995). The major differences between the two serogroups are that O139 Bengal contains a distinct O antigen and produces a polysaccharide capsule (Comstock et al., 1996). Bik et al. (1995) suggested that O139 arose from a strain closely related to the V. cholerae O1 El Tor by acquisition of novel DNA which was inserted into, and replaced part of, the O antigen gene cluster of the recipient strain. Their results suggest that the otnAB (otnA and otnB) DNA determines the distinct antigenic properties of the O139 cell surface. The otnAB DNA was not detected in O1 strains, but was present in two non-Ol V. cholerae strains with serotypes O69 and O141.

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7. Evolution of genetic characteristics of pandemic V. cholerae strains

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The present cholera outbreak in different parts of the world have been commenced by the rapid evolution of multiple descendants of a V. cholerae O1 El Tor ancestor mainly due to lateral gene transfer events via transduction, conjugation, and transformation. Chun and his co-workers (Chun et al., 2009) have compared 23 V. cholerae genomes through genome-based phylogeny and revealed that all the seven pandemic strains share nearly identical gene content. The phylogenetic analysis of pathogenic V. cholerae strains showed that all V. cholerae serogroup O1 strains from sixth and seventh pandemic constructed a tight a monophyletic clade, which also supported the evolution of sixth and seventh pandemic isolates from a common ancestor. V. cholerae O1 El Tor and O139 strains isolated from the Indian subcontinent and Africa epidemics during 1975–2004 were also found to be present in this seventh pandemic clade. A hypothetical evolutionary pathway proposed for V. cholerae by (Chun et al., 2009) concludes that the ancestor for the seventh pandemic strains was a V. cholerae O1 El Tor strain containing several GIs like VPI-1, VPI-2 and GI-1 to GI-10. This hypothetical ancestral strain received VSP-1, VSP-2 and GI-11 by lateral gene transfer, and gave rise to the V. cholerae O1 El Tor and O139 strains. This hypothetical ancestral strain shows quite higher similarity to V. cholerae O1 El Tor BX330286, isolated from a water sample collected in Australia in 1986. For example, the present cholera pandemic is recognized as a change among different seventh pandemic strains, like the emergence of V. cholerae O139, V. cholerae O1 El Tor hybrid, and V. cholerae O1 El Tor with altered cholera toxin subunit B, which represents transitions due to the presence of few different GIs, among genetically nearly identical strains. In addition, V. cholerae O139 differs from other seventh pandemic strains in having an O139 antigen specific genomic island (Waldor and Mekalanos, 1994).

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8. Role of lateral gene transfer in the evolution of V. cholerae

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Due to its extreme genome plasticity V. cholerae continually presents newly emerging pathogenic clones carrying different combinations of phenotypic and genotypic features and thereby significantly affecting public health efforts to control disease. Genes identified in O-antigen biosynthetic (wbf) regions for V. cholerae serogroups O5, O8, and O108 showed greater

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similarities to polysaccharide biosynthesis genes from species other than V. cholerae demonstrating the plasticity of O-antigen genes in V. cholerae (Aydanian et al., 2011). In a recent study, the genome sequences of 23 V. cholerae strains isolated from a variety of sources over the past 98 years were compared in order to reveal evolutionary mechanisms with particular regard to its pandemic clones (Chun et al., 2009). The main conclusion suggests that V. cholerae undergoes extensive genetic recombination via lateral gene transfer. Specifically, transition between clones in the current seventh pandemic is characterized by different assortments of laterally transferred genomic islands, resulting in emergence of new pathogenic clones, exemplified by V. cholerae O139 and V. cholerae O1 El Tor hybrid clones. This suggests that genome assets are more informative in defining the different pandemic strains than serogroup classification (Chun et al., 2009). Furthermore, in addition to the known genomic islands, this study revealed the presence of new regions in the genome of V. cholerae considered genomic islands that have likely been acquired by LGT. The role of LGT in the evolution of the V. cholerae genome has remained the focus of research, but it is well known that major virulence genes and several important adaptative functions are clustered in regions of the chromosome that have been acquired by lateral transfer from other conspecific or distantly related organisms. This extreme genome plasticity has generated a significant heterogeneous group of strains capable of inhabiting different environments such as the water and marine environment worldwide and the human host (Colwell, 1996; Faruque et al., 1998; Chun et al., 2009). Lateral gene transfer has been proposed to be common between Vibrio mimicus and V. cholerae, especially for virulence-related genes (Haley et al., 2010; Wang et al., 2011). It has been suggested that genes in the O1 biogenesis region are closely related even in distinct genetic lineages, indicative of LGT (González-Fraga et al., 2008). The serogroups-based classification system subdivides the species on the basis of more than 200 subsets, of which only two are associated with major epidemic potential, namely V. cholerae O1 and O139 (Kaper et al., 1995). It is now widely accepted that the O139 serogroup originated by the replacement of the O1 antigen synthesis genes by those encoding the O139, acquired via lateral gene transfer. The LGT event caused a substitution of the gene clusters responsible for LPS synthesis of a V. cholerae O1 El Tor (Waldor and Mekalanos, 1994). The evolution of a new serogroup capable of causing epidemic cholera provides a fascinating example of how V. cholerae can improve its fitness by acquisition of new genes (Fig. 4). Changes observed in V. cholerae O139 likely reflect a selective advantage by evading the evolving immunity of an endemic infected population (Faruque and Mekalanos, 2003a).

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8.1. Pathogenicity island and virulence factors

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Major virulence factors in V. cholerae are contained within regions of the genome of foreign origin (Davis and Waldor, 2000). Virulent strains carry the genome of a temperate prophage, CTXU, that encompasses the genes ctxAB, encoding the cholera toxin CT, as well as accessory toxins ace and zot (Waldor and Mekalanos, 1996a). The CTXU is associated with another genetic element, RS1 (Fig. 3), which is involved in the replication and site specific integration of the phage (Davis and Waldor, 2000). The receptor for the CTX phage is a type IV pilus, the toxin coregulated pilus TCP, which is the bacterial appendix involved in the colonization of the intestine of the human host. Interestingly, Vibrio Pathogenicity island VPI-I carries genes encoding the synthesis of the pilus. Furthermore, the two elements are linked in a complex pathway that controls expression of the toxin under the regulative action of the ToxR transcriptional activator (Karaolis et al., 2001). It has been suggested that the VPI-I island represents the genome of a

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prophage integrated into the V. cholerae chromosome, but repeated attempts to induce and isolate the phage have failed to validate the hypothesis (Faruque et al., 2003b). The close linkage of CTXU and VPI-I provides a fascinating example of co-evolution involving different genetic entities and their relationship with the host genome. A second pathogenicity island, Vibrio Pathogenicity island 2 (VPI-2), present in the genome of V. cholerae (Jermyn and Boyd, 2002; Murphy and Boyd, 2008) is a 57.3 kb Pathogenicity island encoding 52 ORFs and includes several gene clusters, such as a type 1 restriction modification (RM) system (hsdR and hsdM), a sialic acid metabolism gene cluster, genes required for utilization of aminosugars, including the nanH neuramidase, a gene cluster that shows homology to Mu phage. The neuramidase protein is involved in V. cholerae pathogenicity in two ways. On one hand, it generates the GM1 ganglioside receptor for cholera toxin from higher order sialogangliosides, with release of sialic acid (an amino sugar present in all mucous membranes). On the other hand, it appears to be part of the mucinase complex that is responsible for digestion of the intestinal mucus, enhancing V. cholerae colonization of the gut (Murphy and Boyd, 2008). VPI-2 exhibits all of the characteristics of a horizontally transferred element. The genomic island encodes for a phage-like integrase, which was found to be responsible for insertion/excision of the island to and from the host genome (Murphy and Boyd, 2008). It has been shown that VPI-2 forms a circular intermediate (CI) upon excision, which likely represents the mobile form of this genetic element. Mobilization of VPI-2 has not yet been demonstrated. The absence of a gene cluster encoding a conjugative apparatus (tra gene operon), or type IV secretion system, suggests that the island is mobilized by other genetic elements or that it is an ancient mobile element which has lost part of its genetic structure. To date, all toxigenic V. cholerae O1 serogroup isolates contained VPI-2, whereas non-toxigenic isolates lack the island (Murphy and Boyd, 2008). Two other gene clusters associated with the seventh pandemic strains were identified by comparative genomics, using microarray analysis, and named Vibrio Seventh Pandemic (VSP) I and II (Dziejman et al., 2002). These clusters were absent in classical and prepandemic V. cholerae El Tor strains and showed an unusual G + C content (40%), compared with the entire V. cholerae genome (47%) (Dziejman et al., 2002). VSP-I is a 16-kb region inserted in chromosome I between ORFs VC0174 to VC0186 and comprising 11 genes, VC0175–0185. Recently, VSP-I has been reported in V. Q4 cholerae non-O1/non-O139 (O‘‘ Shea et al., 2004). VSP-II was originally identified as a 7.5-kb island, spanning genes VC0490 to VC0497 in V. cholerae O1 El Tor N16961 (Dziejman et al., 2002) and, subsequently, found to include a larger 26.9-kb region, spanning from VC0490 to VC0516 (O‘‘ Shea et al., 2004). Its site of integration is a tRNA-methionine locus, VC0516.1. As described in V. cholerae O1 El Tor N16961, VSP-II encodes type IV pilin, two methyl-accepting chemotaxis proteins, an AraC-like transcriptional regulator, a DNA repair protein, and a P4-like integrase (VC0516) at the 30 end of the island. Murphy and Boyd (2008) found that both VSP-I and VSP-II are able to excise from the chromosome, forming an extra-chromosomal circular intermediate through site-specific recombination mediated by the integrase encoded in the island (Murphy and Boyd, 2008).

9. Integrative mobile genetic elements (IMGE): key player for evolution of antibiotic resistance cholera pathogen IMGEs are segments of DNA that encode or exploit host proteins that mediate the intra- and inter-chromosomal movement of DNA. The several IMGEs found in V. cholerae genome directly contribute to the evolutionary fitness of the pathogen because they carry

7

antibiotic resistance, xenobiotic degradation and/or virulence factors. Several integrative mobile genetic elements (IMGEs) like phages, plasmids, integrative conjugative elements (ICEs), transposons, integron are transferred to the V. cholerae either from closely or distantly related organisms by conjugation, transformation or transduction and integrated in either or both chromosomes by homologous or site-specific recombination (Das et al., 2013).

527

9.1. Integrative mobile genetic elements (IMGE) facilitating antibiotic resistance in pathogenic V. cholerae

534

The most striking example of real-time evolution that has been observed in bacteria over the past six decades is the emergence of antibiotic resistance bacterial pathogens. Three classes of antibiotic-resistance bacterial pathogens (Methicillin resistant Staphylococcus aureous, multidrug-resistant and pandrug-resistant Gram-negative bacteria, and multidrug and extensively resistant Mycobacterium tuberculosis) are emerging as major threats to public health. Regardless of the pathogens classes, all antibiotic resistance traits are encoded by the segment of mobile DNA elements. An antibiotic resistance V. cholerae isolates emerged in late 1970s. Clinical V. cholerae isolates resistance against commonly used antibiotics like Ampicillin (Ap), Kanamycin (Kn), Sterptomycin (Sm), Spectinomycin (Sp), and Tetracyclin (TC) were reported during 1977 and 1980 in Tanzania and Bangladesh, respectively (Table 1). Resistance was attributed due to target modifications or acquisition of resistance gene cassettes from mobile genetic elements (Threlfall et al. 1980). Among various IMGEs, integrative conjugative elements and superintegron are the major source of antibiotic resistance in cholera pathogens (Waldor et al., 1998; Mazel, 2006).

536

9.2. SXT element as the basis of antibiotic resistance of V. cholerae

555

The evolution of antibiotic resistance is a very multifaceted method in case of bacteria. For example, some bacteria show intrinsic resistance for few antibiotics, while the others attain resistance for them either by some mutations in their own genome or by acquiring some antibiotic resistance genes. Horizontal gene transfer causes much larger changes in bacterial genomes so that it can carry out more new functions to get adapted in different environments (Lawrence, 1999). Mobile integrons like SXT are crucial for the gain of new genetic information and genomic recombination. They play significant role in bacterial antibiotic-resistance through acquisition, rearrangement and expression of antibioticresistant genes contained in gene cassettes (Mutreja et al., 2011). V. cholerae strains are the most striking example from this perspective, where such cassette arrays are widespread and can range from 30 kb to 150 kb. Integrative and conjugative elements (ICE) from SXT family are linear DNA sequences that are able to integrate themselves into the bacterial genomes and get transferred by conjugation. SXT is a 99.5 kb ICE which was discovered in the chromosome of V. cholerae O139 MO10 from India and provided such a name for its role in sulfamethoxazole and trimethoprim resistances (Waldor et al., 1996b). Genes resistant to the antibiotics like chloramphenicol (floR), streptomycin (strA and strB), sulfamethoxazole (sul2), trimethoprim (dfrA18 or dfrA1) and tetracycline (tetA and tetR) differentiates between SXTs by showing different arrangements. The antibiotic resistant gene cluster from SXTMO10 found in V. cholerae O139, that interrupts the rumAB operon, were found to be present in a transposon like element, whereas SXTET or ICEVchInd1 isolated in clinical V. cholerae O1 (Hochhut et al., 2001), shows a shorter resistance cluster in rumAB operon, by possessing the gene dfrA1 and lacking the gene dfrA18 gene (Hochhut et al., 2001). In addition, SXTLAOS or ICEVchLao1 isolated from Laos can be characterized by tetA resistance gene and by the absence of trimethoprim resistance genes (Iwanaga et al., 2004).

556


528 529 530 531 532 533

535

537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554

557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588

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Table 1 List of mobile DNA elements encoded antibiotic resistance gene cassettes reported in clinical V. cholerae.

589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635

Gene

Target antibiotic

Host

References

blaNDM-1 strAB sul2 dfrA18 floR aacA-aphD tetG aphA1 aadA1 arr2 blaP1 cat1 qnrVC3 aac-Ib ereA2

Ampicillin Streptomycin Sulphonamide Trimithoprim Florfenicol Gentamycin Tetracyclin Kanamycine Spectinomycin Rifampicin Ampicillin Chloramphinicol Ciprofloxacin Amikacin Erythromycin

Plasmid PlasmidICE ICE ICE ICE Plasmid Plasmid Plasmid Transposon Integron Plasmid Plasmid Integron Integron Integron

Mandal et al. (2012) Pan et al. (2008); Hochhut et al. (2001) Waldor et al., (1996b) Waldor et al., (1996b) Waldor et al., (1996b) Pan et al. (2008) Ceccarelli et al. (2006) Ceccarelli et al. (2006) Goldstein et al. (1986) Fluit and Schmitz. (2004) Ceccarelli et al. (2006) Ceccarelli et al. (2006) Thungapathra et al. (2002) Thungapathra et al. (2002) Thungapathra et al. (2002)

Another SXT element isolated from Vietnam i.e., ICEVchVie1 was found to be very much closer to ICEVchLao1, but containing the tetR gene in addition (Ehara et al., 2004). More recent variants of SXT have been obtained from the clinical isolates of Vibrio fluvialis (ICEVflInd1), V. cholerae environmental isolates from Mexico (ICEVchMex1) (Ahmed et al., 2005; Burrus et al., 2006). In numerous African cholera epidemics these mobile genetic elements have been found to play crucial roles offering multiple drug resistance in several V. cholerae strains. Characterization of class 1 integrons in clinical and environmental V. cholerae strains isolated from the Brazilian Amazon revealed that aadA2 and aadA7 gene cassettes were found in class 1 integrons present in environmental V. cholerae non-O1/non-O139. These class 1 integron containing strains were found to persist in environment for a long time, which proves the role of class 1 integrons in increasing fitness for their environment. Class 1 integrons conferring resistance to the antibiotics amikacin/tobramycin, b-lactams, erythromycin, gentamicin, kanamycin, aminoglycosides and trimethoprim to V. cholerae by means of their gene-cassettes content, has been found to prevail in South-Africa, which is correlated with SXTMO10. On the other hand, typical class 2 integrons in V. cholerae were found in V. cholerae non-O1/ non-O139 isolates from India and from Bangladesh and V. cholerae isolates from Ghana (Ahmed et al., 2006; Opintan et al., 2008), containing the gene cassette array, dfrA1/sat1/ aadA1, that confer resistance to trimethoprim, streptothricin and streptomycin/spectinomycin, respectively. The presence of a rare class 2 integron in only one strain of the V. cholerae O1 Amazonia lineage, harbouring sat1 and aadA1 genes, acts as a proof for integron mobilization and gene cassette loss and acquisition (Canto et al., 2010). V. cholerae O1 Amazonia belongs to a distinct profile compared to strains from El Tor and classical biotypes (Thompson et al., 2011). All these above findings suggest that environmental Vibrio species act as gene-cassette reservoirs that promote the emergence of antibiotic resistant in pathogenic Vibrio species. Till date, from South Africa (Mozambique) three different ICEs belonging to the SXT/R391 family has been identified. They are (i) ICEVchMoz7 containing floR and dfrA1 resistance genes and an inserted region in Hotspot 1 belonging to R391, (ii) ICEVchMoz8 containing dfrA1 only, and a specific molecular rearrangement, and (iii) ICEVchMoz9, containing floR, strA, strB, sul2 and dfrA1 resistance genes and an inserted region in Hotspot 1 belonging to R391. Besides SXT related ICEs has been also found to circulate in Zimbabwe, Somalia and Rwanda. V. cholerae strain N16961, causing seventh pandemic and Latin American epidemic strains have been found to lack SXT and therefore remain vulnerable to antibiotics. But the V. cholerae strains causing the most recent pandemic in Haiti has been found to contain SXT region, which has been proved

to be transferred from the V. cholerae strain MJ1236. Though, these Haitian varieties have been found to be close relatives of the strain N16961.

636

9.3. Superintegrons providing adaptive advantages to V. cholerae genomes

639

Inspite of having similar structural organization like mobile integrons, the observations regarding superintegrons suggests that they are ancestral to mobile integrons. It has been assumed that they have been evolved through the entrapment of intI genes and attI sites by transposons (Mazel, 2006). Distinct copy-number variations affecting the super-integron region have been observed in case of Haitian V. cholerae isolates (Chin et al., 2011). The struc- Q5 ture of super-integron region of the Haitian V. cholerae isolates have been found to have close similarity with the strain MDC126 and CIRS101 causing outbreak in Bangladesh, lacking a segment with 41 open reading frames. Most interestingly, the Haitian strains have been found to contain a unique single open reading frame, which differentiates their super-integron region from all the previous V. cholerae strains (Dasgupta et al., 2012). The clinical isolates from the 1991 outbreak in Peru i.e., strain C6706 and the strain N16961 has been found to contain superintegrons having similar structural features. But the strain causing 2008 outbreak in Bangladesh i.e., strain MDC126 has distinct structure of superintegrons than the strain C6706 and strain N16961 (Chin et al., 2011). The V. cholerae strain causing outbreak in Haiti has similar structural features like MDC126. Both of them lack a segment that contains 41 open reading frames. In addition, strain MDC126 contains a single open reading frame less than Haitian strains. The superintegrons regions present in Haitian strains have been found to contain more close similarly with that of the strain CIRS101 (Chin et al., 2011).

641

10. Conclusion

667

As cholera persists and evolves over time, we should be prepared to keep improving our genomic knowledge of V. cholerae. Whole-genome sequencing can be used to track genomic evolution and functional variation in real time, to identify patterns of disease spread within a region, and to identify the source of an epidemic by tracing relationships to other strains around the world. Wholegenome sequencing is a powerful epidemiological tool whose applications towards understanding infectious disease are only beginning to be explored (Sealfon et al., 2012). Even though V. cholerae is one of the bacterial species with the most representative

668


637 638

640

642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666

669 670 671 672 673 674 675 676 677

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genome sequences in the public domain, more work is needed to reveal the fine details of the evolutionary mechanism behind the emergence of the various pandemic clones. Due to the invention of next generation sequencing technology, large-scale comparative genomics has become feasible for important bacterial human pathogens, such as Salmonella typhi, Bacillus anthracis and Escherichia coli/Shigella. Unlike these species, V. cholerae is a true inhabitant of the environment, a nonclonal species, and is the cause of pandemics and thereby offers a prime example and framework to explain the general mechanism of the short-term and long-term evolution of bacterial species. Therefore, future challenge for researcher investigating the evolution of toxigenic V. cholerae strains should be aimed at explaining more about the emergence of pathogenic strains and factors involved in the natural selection of the species.

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(Mandal et al. (2006) and Stroeher et al. (1995)).

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Acknowledgement

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BD and GBN acknowledge Department of Biotechnology, Govt. of India (Grant No. BT/MB/THSTI/HMC-SFC/2011) and Department of Science & Technology, Govt. of India (Grant No. SB/FT/LS-309/ 2012) for financial support for the preparation of review. SB acknowledges the Bioinformatics facility at the Bioinformatics Centre, Tripura University.

702

Appendix A. Supplementary data

703 705

Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.meegid.2014. 01.006.

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Intestinal Colonization Dynamics of Vibrio cholerae.

Whole-genome sequence comparisons reveal the evolution of Vibrio cholerae O1.

Chromosome segregation in Vibrio cholerae.

Letter: Isolation of Vibrio cholerae.

Genome dynamics during experimental evolution.

Acquisition and evolution of SXT-R391 integrative conjugative elements in the seventh-pandemic Vibrio cholerae lineage.

Genomic science in understanding cholera outbreaks and evolution of Vibrio cholerae as a human pathogen.

Induction of melanin biosynthesis in Vibrio cholerae.

Molecular Characterization of Vibrio cholerae O1 Reveals Continuous Evolution of Its New Variants in India.

The Dynamics of Genetic Interactions between Vibrio metoecus and Vibrio cholerae, Two Close Relatives Co-Occurring in the Environment.

Dynamics of Vibrio cholerae abundance in Austrian saline lakes, assessed with quantitative solid-phase cytometry.

Siderophore production by Vibrio cholerae.

Regulatory cascade controls virulence in Vibrio cholerae.

Genome Sequences of Clinical Vibrio cholerae Isolates from an Oyster-Borne Cholera Outbreak in Florida.

Draft Genome Sequence of Environmental Vibrio cholerae 2012EL-1759 with Similarities to the V. cholerae O1 Classical Biotype.

Genome Sequence of Vibrio cholerae Strain O1 Ogawa El Tor, Isolated in Mexico, 2013.

Transposon-facilitated recombination in Vibrio cholerae.

Vibrio cholerae serogroup O1 in northeast Thailand.

Membrane-bound enterotoxin of Vibrio cholerae.

Pili of Vibrio cholerae non-O1.

Penicillin binding proteins of Vibrio cholerae.

Transformation of Vibrio cholerae by plasmid DNA.

New attenuated derivatives of Vibrio cholerae.

Immunological properties of Vibrio cholerae lipopolysaccharides.