Cystic fibrosis (CF) and tuberculosis (TB) are distinct diseases that have significantly impacted human health. CF is a genetic disorder, while TB is a bacterial infection. An intriguing question is whether the allele responsible for cystic fibrosis, when present in a single copy, could offer a degree of protection against tuberculosis.
Understanding Cystic Fibrosis and Tuberculosis
Cystic fibrosis is an inherited condition primarily affecting the lungs and digestive system. It results from mutations in the gene that produces the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which regulates the flow of salt and water across cell membranes. This malfunction leads to the production of thick, sticky mucus, particularly in the lungs, making individuals susceptible to chronic infections and progressive lung damage.
Tuberculosis is an infectious disease caused by the bacterium Mycobacterium tuberculosis. This bacterium typically attacks the lungs, but it can also affect other parts of the body. Historically, TB has been a leading cause of death worldwide.
The Protective Hypothesis
The hypothesis suggests that individuals carrying one copy of the mutated CFTR allele (heterozygotes) might possess an advantage against tuberculosis. This concept is known as heterozygote advantage, where having a single copy of a gene mutation confers a beneficial trait, even if two copies lead to a severe disease. The persistent high frequency of the CF allele in certain populations, particularly those of European descent, has led researchers to investigate potential selective pressures that could maintain such a seemingly detrimental gene. It is proposed that the partial alteration of CFTR function in carriers might create an environment less hospitable for Mycobacterium tuberculosis.
Investigating the Mechanisms
Several mechanisms have been proposed to explain how the CF allele might offer protection against tuberculosis. One theory suggests that a reduced number of functional CFTR channels in carrier cells could limit the ways Mycobacterium tuberculosis can enter these cells, thereby decreasing the likelihood of infection.
Another proposed mechanism involves the altered activity of an enzyme called arylsulfatase B in CF carriers. Mycobacterium tuberculosis incorporates sulfate into its cell walls, a process that relies on this enzyme. A reduced activity of arylsulfatase B in CF carriers could impair the bacterium’s ability to synthesize its cell walls effectively, potentially reducing its virulence and providing a protective effect.
Evidence and Research Findings
Evidence supporting the protective hypothesis comes from various research types. Epidemiological studies have investigated the correlation between CF carrier rates and TB incidence in populations. For instance, a study in Brazil found a significant negative correlation between the rate of CF carriership and the incidence of tuberculosis, suggesting lower susceptibility to TB infection among carriers. This finding remained consistent even after accounting for several environmental and immunological factors.
Modeling studies have also contributed to this understanding, indicating that historical tuberculosis pandemics, particularly in Europe, could have exerted sufficient selective pressure to explain the current high prevalence of the CF allele. However, carrying the CF allele does not provide complete immunity, as individuals with cystic fibrosis can still contract tuberculosis, although it is considered an infrequent finding. Furthermore, some research suggests that CFTR heterozygotes might actually be at a higher risk for certain other respiratory infections, indicating a complex interplay of genetic factors and disease susceptibility.
Evolutionary Significance
The potential protection against tuberculosis offered by the heterozygous CFTR allele holds significant evolutionary implications. The persistence of an allele that causes a severe, often fatal, genetic disease when homozygous can be explained by a selective advantage in the heterozygous state. This phenomenon, known as balancing selection, allows the allele to remain prevalent in a population despite its detrimental effects in two copies.
In regions historically burdened by diseases like tuberculosis, individuals carrying one copy of the CFTR mutation may have had a survival or reproductive advantage, allowing them to pass on the allele to future generations. This provided a strong selective pressure, contributing to the current distribution and frequency of the CF allele in human populations.