Cystic fibrosis (CF) is a severe genetic condition caused by mutations in the gene responsible for the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein. This disorder primarily affects the lungs and digestive system, resulting from the inheritance of two mutated gene copies, one from each parent. The high frequency of the CF allele in certain populations, particularly those of European descent, has long puzzled researchers. This prevalence has led to the proposal that carrying a single copy of the CF allele, known as the heterozygous state, may confer a protective advantage against historical infectious diseases, specifically Tuberculosis (TB). This hypothesis suggests that the partially altered cellular environment in a carrier is less hospitable to the bacterium that causes TB.
The CFTR Protein and Cystic Fibrosis
The CFTR protein functions as an ion channel embedded in the membranes of cells lining the lungs, pancreas, and other organs. Its primary role is to regulate the flow of chloride and bicarbonate ions across the cell surface. This ion movement controls the movement of water, which keeps mucus and other secretions thin and flowing freely. When both copies of the CFTR gene are mutated, the resulting protein is either non-functional or entirely absent. This failure in ion transport leads to a reduction of water on the cell surface, causing the mucus layer to become abnormally thick and sticky. This viscous mucus obstructs ducts and airways, leading to chronic lung infections and progressive organ damage characteristic of cystic fibrosis.
The Evolutionary Hypothesis
The high frequency of the CF allele in Caucasian populations, where approximately one in 25 individuals is a carrier, suggests a long-standing evolutionary pressure. This phenomenon is known as heterozygote advantage, where carrying one copy of a potentially harmful recessive allele provides a survival benefit. For example, the sickle cell trait protects carriers from severe malaria. Similarly, scientists propose that a historical infectious agent, such as Mycobacterium tuberculosis (Mtb) or Salmonella typhi, created a selective advantage for CF carriers. The high mortality rates associated with diseases like the widespread TB pandemic in Europe could have favored individuals with the single CF mutation, allowing the allele to persist in the population over time.
Proposed Biological Mechanism of Protection
The hypothesized protection against Mtb in CF carriers centers on the interaction between the bacterium and the host’s immune cells. Tuberculosis begins when Mtb is engulfed by alveolar macrophages in the lungs, cells designed to destroy invading microbes. However, Mtb is a highly successful pathogen because it has evolved a mechanism to arrest the normal maturation of the phagosome, the internal compartment containing the bacterium. This arrest prevents the phagosome from fusing with the highly acidic, microbicidal lysosome, allowing Mtb to survive and replicate in a mildly acidic environment.
CFTR and Phagosome Environment
The CFTR protein, even when partially functional in a carrier, influences the internal environment of the macrophage. In normal cells, CFTR transports chloride ions into the phagosome, which is necessary for the compartment to become fully acidic. The slightly impaired CFTR function in a heterozygous carrier may subtly alter the ion balance or pH of the macrophage’s compartments. This partial dysfunction is theorized to interfere with Mtb’s mechanism for arresting phagosome maturation, inadvertently forcing the Mtb-containing phagosome to follow a more destructive path.
Interference with Bacterial Metabolism
An additional mechanism involves the bacterium’s cell wall synthesis. The Mtb bacterium requires sulfate, which it accesses using the enzyme arylsulfatase B. Studies suggest that CF carriers have a reduced activity of this enzyme. This reduction in host cell enzyme activity may limit Mtb’s ability to incorporate sulfate into its cell walls, thereby reducing its virulence and growth rate. This dual effect—disruption of the phagosome and interference with bacterial metabolism—could grant carriers a selective edge against the infection.
Current Scientific Evidence and Status
The idea that the CF allele protects against TB remains a compelling but scientifically contested hypothesis. Epidemiological studies have provided mixed results, though some research suggests a correlation between high CF carrier rates and historically high TB mortality. For instance, spatial studies have shown an inverse correlation between the rate of CF carriers and TB incidence in certain regions, lending exploratory support to reduced susceptibility.
Despite this, proof from direct cellular or clinical studies has been elusive, and some research indicates that CF carriers might be at a higher risk for other types of respiratory infections. The strongest evidence for heterozygote advantage relates to protection against Typhoid fever, where the loss of CFTR function prevents Salmonella typhi from entering intestinal cells. However, the mechanism for TB is more complex and involves the immune system’s internal cell machinery. While the evolutionary argument is robust, the current scientific consensus is that the protective effect of the CF allele against Mycobacterium tuberculosis is limited or inconclusive.