Latin America has experienced two of the largest cholera epidemics in modern history; one in 1991 and the other in 2010. However, confusion still surrounds the relationships between globally circulating pandemic Vibrio cholerae clones and local bacterial populations. We used whole-genome sequencing to characterize cholera across the Americas over a 40-year time span. We found that both epidemics were the result of intercontinental introductions of seventh pandemic El Tor V. cholerae and that at least seven lineages local to the Americas are associated with disease that differs epidemiologically from epidemic cholera. Our results consolidate historical accounts of pandemic cholera with data to show the importance of local lineages, presenting an integrated view of cholera that is important to the design of future disease control strategies.
Capsule production is essential for K. pneumoniae to cause infections, but its regulation and mechanism of synthesis are not fully understood in this organism. We have developed and applied a new method for genome-wide identification of capsule regulators. Using this method, many genes that positively or negatively affect capsule production in K. pneumoniae were identified, and we use these data to propose an integrated model for capsule regulation in this species. Several of the genes and biological processes identified have not previously been linked to capsule synthesis. We also show that the methods presented here can be applied to other species of capsulated bacteria, providing the opportunity to explore and compare capsule regulatory networks in other bacterial strains and species.
importance word count: 239/120 17 Two-part abstract 18Abstract: Klebsiella pneumoniae infections affect infants and the immunocompromised, and 19 the recent emergence of hypervirulent and multi-drug resistant K. pneumoniae lineages is a 20 critical healthcare concern. Hypervirulence in K. pneumoniae is mediated by several factors, 21including the overproduction of extracellular capsule. However, the full details of how K. 22 pneumoniae capsule biosynthesis is achieved or regulated are not known. We have developed 23 a robust and sensitive procedure to identify genes influencing capsule production, density-24 TraDISort, which combines density gradient centrifugation with transposon-insertion 25 sequencing. We have used this method to explore capsule regulation in two clinically-26 relevant Klebsiella strains; K. pneumoniae NTUH-K2044 (capsule type K1), and K. 27 pneumoniae ATCC43816 (capsule type K2). We identified multiple genes required for full 28 capsule production in K. pneumoniae, as well as putative suppressors of capsule in NTUH-29 K2044, and have validated the results of our screen with targeted knockout mutants. Further 30 investigation of several of the K. pneumoniae capsule regulators identified -ArgR, 31MprA/KvgB, SlyA/KvgA and the Sap ABC transporterrevealed effects on capsule amount 32 and architecture, serum resistance and virulence. We show that capsule production in K. 33 pneumoniae is at the centre of a complex regulatory network involving multiple global 34 regulators and environmental cues, and that the majority of capsule regulatory genes are 35 located in the core genome. Overall our findings expand our understanding of how capsule is 36 regulated in this medically-important pathogen, and provide a technology that can be easily 37 implemented to study capsule regulation in other bacterial species. 38 39 Importance: Capsule production is essential for K. pneumoniae to cause infections, but its 40 regulation and mechanism of synthesis are not fully understood in this organism. We have 41 developed and applied a new method for genome-wide identification of capsule regulators. 42 Using this method, many genes that positively or negatively affect capsule production in K. 43 pneumoniae were identified, and we use these data to propose an integrated model for 44 capsule regulation in this species. Several of the genes and biological processes identified 45 have not previously been linked to capsule synthesis. We also show that the methods 46 presented here can be applied to other species of capsulated bacteria, providing the 47 opportunity to explore and compare capsule regulatory networks in other bacterial strains and 48 species. 49 51Klebsiella pneumoniae is an ubiquitous Gram-negative bacterium, found both in the 52 environment and as an asymptomatic coloniser of the mucosal surfaces of mammals (1). K. 53pneumoniae is also an opportunistic pathogen, and can express a multitude of virulence 54 factors which enable it to cause infections in humans (1-4). Historically associated with 55 infections...
In order to control and eradicate epidemic cholera, we need to understand how epidemics begin, how they spread, and how they decline and eventually end. This requires extensive sampling of epidemic disease over time, alongside the background of endemic disease that may exist concurrently with the epidemic. The unique circumstances surrounding the Argentinian cholera epidemic of 1992–1998 presented an opportunity to do this. Here, we use 490 Argentinian V. cholerae genome sequences to characterise the variation within, and between, epidemic and endemic V. cholerae. We show that, during the 1992–1998 cholera epidemic, the invariant epidemic clone co-existed alongside highly diverse members of the Vibrio cholerae species in Argentina, and we contrast the clonality of epidemic V. cholerae with the background diversity of local endemic bacteria. Our findings refine and add nuance to our genomic definitions of epidemic and endemic cholera, and are of direct relevance to controlling current and future cholera epidemics.
The sixth global cholera pandemic lasted from 1899 to 1923. However, despite widespread fear of the disease and of its negative effects on troop morale, very few soldiers in the British Expeditionary Forces contracted cholera between 1914 and 1918. Here, we have revived and sequenced the genome of NCTC 30, a 102-year-old Vibrio cholerae isolate, which we believe is the oldest publicly available live V. cholerae strain in existence. NCTC 30 was isolated in 1916 from a British soldier convalescent in Egypt. We found that this strain does not encode cholera toxin, thought to be necessary to cause cholera, and is not part of V. cholerae lineages responsible for the pandemic disease. We also show that NCTC 30, which predates the introduction of penicillin-based antibiotics, harbours a functional β-lactamase antibiotic resistance gene. Our data corroborate and provide molecular explanations for previous phenotypic studies of NCTC 30 and provide a new high-quality genome sequence for historical, non-pandemic V. cholerae .
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