Evolution of Pandemic Cholera at its Global Source

The seventh pandemic of cholera, caused by the 7 ^th Pandemic El Tor Lineage (7PET) Vibrio cholerae , was previously shown to have emanated in three global waves from the Bay of Bengal, bordering Bangladesh and India. However, the respective roles of the Ganges delta and basin regions in seeding these global pandemic waves were not known. We find that while there are transmission events between Bangladesh and India, V. cholerae within the two countries has largely evolved separately over the past 20 years, contained by national borders rather than following hydrological features such as the Ganges delta and basin. Evolution within Bangladesh was distinct from that seen in India, involving rapid gain and loss of genes and mobile genetic elements, particularly those involved in phage defence. The loss/gain of these anti-phage elements mirrored loss/gain of anti-defence systems in lytic phage ICP1. Importantly, the loss of these systems was associated with increased risk of severe disease and transmission outside of Bangladesh. Here we show that the Ganges basin, falling across Bangladesh and Northern India, rather than the Ganges delta, acts as a global launch pad for pandemic disease. This completely shifts our understanding of Bangladesh as the purported global source of cholera, and the role of phage in controlling spread of lineages within the current seventh pandemic.