Clinical features in Indian children differed from those reported in most studies that involved an African population. Multiple organ dysfunctions emerged as an important presenting feature and a new predictor of death in childhood malaria.

The Vibrio cholerae biotype “El Tor” is responsible for all of the current epidemic and endemic cholera outbreaks worldwide. These outbreaks are clonal, and it is hypothesized that they originate from the coastal areas near the Bay of Bengal, where the lytic bacteriophage ICP1 (International Centre for Diarrhoeal Disease Research, Bangladesh cholera phage 1) specifically preys upon these pathogenic outbreak strains. ICP1 has also been the dominant bacteriophage found in cholera patient stools since 2001. However, little is known about the genomic differences between the ICP1 strains that have been collected over time. Here, we elucidate the pan-genome and the phylogeny of the ICP1 strains by aligning, annotating, and analyzing the genomes of 19 distinct isolates that were collected between 2001 and 2012. Our results reveal that the ICP1 isolates are highly conserved and possess a large core-genome as well as a smaller, somewhat flexible accessory-genome. Despite its overall conservation, ICP1 strains have managed to acquire a number of unknown genes, as well as a CRISPR-Cas system which is known to be critical for its ongoing struggle for co-evolutionary dominance over its host. This study describes a foundation on which to construct future molecular and bioinformatic studies of these V. cholerae-associated bacteriophages.

The Vibrio cholerae biotype 'El Tor' is responsible for all current epidemic and endemic 12 cholera outbreaks worldwide. These outbreaks are clonal and are hypothesized to originate from 13 the coastal areas near the Bay of Bengal where the lytic bacteriophage ICP1 specifically preys upon 14 these pathogenic outbreak strains. ICP1 has also been the dominant bacteriophage found in 15 cholera patient stool since 2001. However, little is known about its genomic differences between 16 ICP1 strains collected over time. Here we elucidate the pan-genome and phylogeny of ICP1 strains 17 by aligning, annotating and analyzing the genomes of 19 distinct isolates collected between 2001 18 and 2012. Our results reveal that ICP1 isolates are highly conserved and possess a large 19 core-genome as well as a smaller, somewhat flexible accessory-genome. Despite its overall 20 conservation, ICP1 strains have managed to acquire a number of unknown genes as well as a 21 CRISPR-Cas system, which is known to be critical for its ongoing struggle for co-evolutionary 22 dominance over its host. This study describes a foundation on which to construct future molecular 23 and bioinformatic studies of this V. cholerae-associated bacteriophages. 24 25 phage 26 27 42 environment where they can outnumber their prokaryotic hosts by several orders of magnitude [8]. 43As such, bacteriophage play a key role in the evolution of their hosts through both selection and 44 phage-mediated lateral gene transfer [9]. These processes are likely to be very important to V. 45 cholerae strain evolution in the Bay of Bengal as well. Previous work has identified a V. cholerae 46 2 of 11 O1-specific [10] lytic myoviridae bacteriophage (ICP1) to be of particular interest in this system [11]. 47In Bangladesh, ICP1 has been found in water samples [12,13] and it has been identified as the 48 dominant phage in cholera patient stool samples since 2001 [11]. The persistence of this phage over 49 time indicates that V. cholerae has strategies to limit ICP1 predation, and that ICP1 can evolve to 50 overcome such defenses. Indeed, from this natural genetic laboratory, several complex and 51 surprising adaptations/acquisitions have occurred in the race for survival between V. cholerae and 52 ICP1. These include self-mobilizing chromosomal islands that can provide a rapid and efficient 53 response to ICP1 infection [14] and the first known example of a bacteriophage-encoded 54 CRISPR-Cas system [15]. Initial characterization of eight ICP1 isolates collected between 2001-2011 55 noted the relative low level of diversity and lack of major genomic rearrangements, deletions or 56 insertions [11] (with the exception of its remarkable CRISPR-Cas acquisition [15]). Here we build 57 upon the initial characterization of ICP1 to perform a comparative genomic analysis on 19 58 individual ICP1 isolates to reconstruct their phylogenetic relationships over time, identify the core 59 and accessory genomes, and infer possible gene function where possible. 60V. cholerae is an organism that a...

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