Cholera: Insights into pathogen resistance and autoimmune disease from a Bangladeshi population

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Cholera is an ancient disease that continues to impact much of the world’s population. Vibrio cholerae, the bacterium responsible for cholera, infects humans through contaminated food or drinking water. Once consumed, the bacteria passes through the stomach to the small intestine, where it must then get through the protective mucosal lining to attach itself to the walls of the small intestine. Cholera is a deadly disease — when left untreated, mortality can be as high as 50%¹.

In Bangladesh, more than half of the country’s adult population exhibits evidence of a previous cholera infection², indicating that some people are able to survive this infection, perhaps because they are resistant to it. To better understand the genetic basis of resistance to this often-fatal disease, researchers examined the genomes of individuals from the Ganges River Delta, the “historic geographic epicenter of cholera”³. They identified strong signals of positive selection in genes responsible for innate immunity, including the NF-kB signaling pathway. These genes get activated by cholera, and result in an immune response that protects the lining of the gut from infection⁴. The signals of positive selection indicate that certain variants of these genes may confer cholera resistance to natives of the Ganges River Delta.

More broadly, this work sheds light on why the Vibrio cholerae bacterium responsible for cholera is more likely to flourish in the small intestines of some individuals but not others. The pathways under selection in this population are also relevant for understanding many common autoimmune diseases, such as inflammatory bowel disease (IBD) and ulcerative colitis (UC), which also involve the functioning of the immune system in the digestive tract, but in these cases, result in an overreaction. The study is a great illustration of the power of population genetics methods like selection scans to complement classical genotype-phenotype studies.

1. Sack, D. A. (2004). Sack RB, Nair GB, and Siddique AK. Cholera. Lancet, 363, 223–233.
2. Glass, R. I., Svennerholm, A. M., Khan, M. R., Huda, S., Imdadul Huq, M., & Holmgren, J. (1985). Seroepidemiological studies of EI Tor cholera in Bangladesh: association of serum antibody levels with protection. Journal of infectious diseases, 151(2), 236–242.
3. Karlsson, E. K., Harris, J. B., Tabrizi, S., Rahman, A., Shlyakhter, I., Patterson, N., … & Sheikh, A. (2013). Natural selection in a bangladeshi population from the cholera-endemic ganges river delta. Science translational medicine, 5(192), 192ra86–192ra86.
4. Smith, P. D., Smythies, L. E., Shen, R., Greenwell-Wild, T., Gliozzi, M., & Wahl, S. M. (2011). Intestinal macrophages and response to microbial encroachment. Mucosal immunology, 4(1), 31.