Many genes involved in immunity evolve rapidly. It remains unclear, however, to what extent pattern-recognition receptors (PRRs) of the innate immune system in vertebrates are subject to recurrent positive selection imposed by pathogens, as suggested by studies in Drosophila, or whether they are evolutionarily constrained. Here, we show that Toll-like receptor 5 (TLR5), a member of the Toll-like receptor family of innate immunity genes that responds to bacterial flagellin, has undergone a history of adaptive evolution in primates. We have identified specific residues that have changed multiple times, sometimes in parallel in primates, and are thus likely candidates for selection. Most of these changes map to the extracellular leucine-rich repeats involved in pathogen recognition, and some are likely to have an effect on protein function due to the radical nature of the amino acid substitutions that are involved. These findings suggest that vertebrate PRRs might show similar patterns of evolution to Drosophila PRRs, in spite of the acquisition of the more complex and specific vertebrate adaptive immune system. At shorter timescales, however, we found no evidence of adaptive evolution in either humans or chimpanzees. In fact, we found that one mutation that abolishes TLR5 function is present at high frequencies in many human populations. Patterns of variation indicate that this mutation is not young, and its high frequency suggests some functional redundancy for this PRR in humans.

Coccidioidomycosis, a fungal infection endemic to the Southwestern United States, is challenging to diagnose. The coccidioidomycosis enzyme immunoassay (EIA) test is the least expensive and simplest to perform to detect coccidioidomycosis antibodies in the serum. Concerns regarding falsely positive immunoglobulin (Ig) M EIA test results have led to questions about the agreement of commercially available EIA test kits among laboratories. We sought to evaluate the laboratory agreement of the EIA test at three laboratories using both IMMY and Meridian EIA test kits. Sensitivity and specificity of EIA IgM and IgG were calculated as secondary outcomes. The percent agreement of the EIA IgM and IgG test results among all three laboratories was 90% and 89% for IMMY test kits, respectively, and 67% and 80.5% for Meridian test kits, respectively. Agreement between IgM and IgG combined test results was 85.5% and 70.5%, for IMMY and Meridian, respectively. Combined IgM and IgG assays demonstrated a sensitivity of 68% (62.7%-76%) and a specificity of 99.3% (98%-100%) [IMMY] and a sensitivity of 72.4% (57.3%-87.3%) and a specificity of 91.3% (74%-100%) [Meridian]. In summary, results from the IMMY EIA test kit agreed more often across laboratories than Meridian EIA results, especially for the IgM assay. Isolated positive IgM EIA results using the Meridian test kit should be interpreted with caution and consideration of clinical information and test methodology. Further study of the sensitivity and specificity of coccidioidomycosis EIA test kits is warranted.

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