Legionnaire Disease, Susceptibility To

A number sign (#) is used with this entry because susceptibility to Legionnaire disease is associated with polymorphisms in the gene encoding Toll-like receptor-5 (TLR5; 603031).

Description

Legionnaire disease (LD) is a type of pneumonia caused by Legionella pneumophila, a flagellated gram-negative bacterium found primarily in warm water environments. The disease and the bacterium were discovered following an outbreak traced to a 1976 American Legion convention in Philadelphia. A number of risk factors for acquiring LD have been identified, including age, smoking, chronic lung disease, cancer, and immunosuppression (summary by Hawn et al., 2003).

Molecular Genetics

Hawn et al. (2003) identified 4 SNPs in the TLR5 coding region in 40 healthy individuals. One of the SNPs, a C-to-T transition at nucleotide 1174, changed arg392 to a stop codon (603031.0001), truncating the extracellular domain and eliminating the transmembrane domain and cytoplasmic tail. Cells expressing the stop codon variant, but not the other 3 variants, were unable to respond to flagellin or to the flagellated bacterium Legionella pneumophila. Hawn et al. (2003) examined genotypes in a case-control cohort from the 1999 Bovenkarspel, Netherlands, flower show LD epidemic and found that 2 of the variants, the stop codon variant and an A-to-G transition at nucleotide 1775 that changed asn592 to ser (603031.0002), were associated with susceptibility to LD independent of smoking, a known risk factor for LD. All cases with the stop codon variant were heterozygotes. No DNA from the 18 fatal cases was available for analysis. Stimulation of a lung cell line with flagellin, but not with the TLR4 (603030) ligand lipopolysaccharide, potently induced dose-dependent production of IL8 (146930) and IL6 (147620). Individuals heterozygous for the stop codon variant produced significantly less IL6 compared with individuals with wildtype TLR5, suggesting a dominant effect of the variant in association with impaired proinflammatory cytokine production. Hawn et al. (2003) noted that the genotype frequency of 1174TC and 1174TT is approximately 10%.