Cystic Fibrosis Gene Mutations Offer Resistance to Cholera

Cystic fibrosis is a disease identified by the thick and sticky mucus a person creates. They have a difficult time clearing this mucus from their lungs, so multiple medications and physical modalities are used to treat it. Cystic fibrosis gene carriers could be protected against cholera which could be one explanation for how the gene has lasted throughout history.

Key Takeaways

• Cystic fibrosis (CF) causes thick mucus buildup in lungs and other organs, but CF carriers were found to resist cholera.

• Having reduced functional CFTR offers strong protection against cholera’s severe secretory diarrhea effects.

• This heterozygote advantage likely gave CF carriers better survival and reproduction during cholera outbreaks.

In those of European descent, cystic fibrosis is the most frequent, severe, recessive disorder. If two parents are carriers of the cystic fibrosis gene, their child has a 25% chance of having cystic fibrosis and a 50% chance of being a carrier of the gene. The current life expectancy for someone with cystic fibrosis is 50 years old, a massive improvement beyond infancy just a handful of decades ago. It is believed 1 in 35 Americans are carriers of the gene.

How Cholera Causes Severe Diarrhea

Cholera is an acute intestinal infection acquired by ingesting food or water contaminated with the Vibrio cholerae bacterium. After reaching the small intestines, V. cholerae releases an enterotoxin which activates adenylate cyclase enzyme activity in intestinal epithelial cells. This leads to increased chloride and fluid secretion into the intestinal lumen, causing the profuse watery diarrhea characteristic of cholera.

The extreme dehydration, electrolyte imbalance, and fluid loss caused by the diarrhea can lead to vascular collapse, shock, kidney failure, and death if not treated urgently through fluid and electrolyte replacement. Thus, the cholera toxin-stimulated secretory diarrhea is responsible for cholera’s ability to kill infected patients.

CFTR Defects Impair Cholera Toxin Response

The CFTR protein transports chloride and bicarbonate ions across epithelial cell membranes in the lungs, pancreas, and other organs. Normally, cholera toxin activates CFTR channel opening, allowing positively charged sodium ions to follow the chloride efflux from cells. This osmotically draws water into the intestinal lumen, flushing fluids and electrolytes into stools.

However, those with cystic fibrosis have CFTR mutations which disrupt this ion and fluid transport. CF epithelial cells fail to secrete chloride and water in response to adenylate cyclase activation. Researchers confirmed that cholera toxin exposure induced little to no fluid secretion in intestinal tissue from CF knockout mice completely lacking CFTR expression compared to normal mice.

CF Carriers Have Reduced Cholera Diarrhea

Carriers of CF mutations possess one normal and one mutated CFTR gene copy. This CF heterozygous genotype leads to around half the normal quantity of functional CFTR proteins being produced.

When CF heterozygote mice with roughly 50% CFTR expression were exposed to cholera toxin, their intestinal fluid secretion was intermediate between CF homozygotes and wildtype mice but still substantially lower than normal.

This demonstrates CF carrier status confers strong protection against cholera toxin-induced diarrhea. By limiting life-threatening fluid and electrolyte losses, CF carriers likely possessed better survival and reproduction during cholera outbreaks. This heterozygote advantage provides evolutionary selection pressure to maintain CF mutations at high frequencies.

Cholera Risk Greatly Reduced Globally

The high global mortality rate from cholera during the late 19th century has now plunged through sanitation infrastructure separating sewage from drinking water alongside prompt fluid replacement therapy. With supportive medical care, cholera is no longer the selective force it once was. Still, the discovered CF link shows how genetic conditions can emerge from protective effects against infectious diseases like cholera.

Routine carrier screening allows couples to assess CF risks before starting a family. See your doctor to discuss diagnostic testing options.

Away Clinic also provides helpful guidance for questions about cystic fibrosis and referrals for genetic testing. For travel vaccines like cholera and typhoid, feel free to make an appointment online at any of our locations.