Second-Pandemic Strain of<i>Vibrio cholerae</i>from the Philadelphia Cholera Outbreak of 1849

Summ a r yIn the 19th century, there were several major cholera pandemics in the Indian subcontinent, Europe, and North America.The causes of these outbreaks and the genomic strain identities remain a mystery.We used targeted high-throughput sequencing to reconstruct the Vibrio cholerae genome from the preserved intestine of a victim of the 1849 cholera outbreak in Philadelphia, part of the second cholera pandemic.This O1 biotype strain has 95 to 97% similarity with the classical O395 genome, differing by 203 single-nucleotide polymorphisms (SNPs), lacking three genomic islands, and probably having one or more tandem cholera toxin prophage (CTX) arrays, which potentially affected its virulence.This result highlights archived medical remains as a potential resource for investigations into the genomic origins of past pandemics.C holera is a diarrheal disease caused by colonization of the intestines by cholera toxin-expressing strains of the waterborne enteric bacterium V. cholerae.An outbreak can arise suddenly, especially in vulnerable populations with compromised sanitation infrastructure, as in the devastating 2010 outbreak in Haiti. 1 In 2012 alone, V. cholerae infected 3 million to 4 million people, killing nearly 100,000. 2 Although all pathogenic V. cholerae strains possess a similar genomic backbone that may have facilitated adaptation to human intestinal mucosa, 3,4 the predominant pathogenic strain, serogroup O1, harbors two genetically distinct biotypes: classical and El Tor (for descriptions of these and other terms, see the Glossary).In the 20th century, for unknown reasons, El Tor replaced classical as the dominant bio type.There have been seven documented pandemics since 1817, 5 but the causal V. cholerae strains have been genetically characterized only for the two most recent outbreaks.Therefore, although most assume that the classical biotype was responsible for the earlier pandemics, 6 the identities of the strains that caused them remain unknown.Diverse tissue specimens archived by medical practitioners at the time of an outbreak represent an essentially untapped genetic museum for pathogen research.One extraordinary collection includes a preserved intestine from a patient who died from cholera in the 1849 Philadelphia outbreak (Fig. 1), collected by Dr. John Neill.By coupling targeted enrichment with high-throughput sequencing, 7 we used trace degraded DNA from this specimen to reconstruct a mid-19th century V. cholerae genome and to test the hypothesis that the O1 classical biotype was responsible for the second cholera pandemic.

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