An ancient haplotype containing antimicrobial peptide gene variants is associated with severe fungal skin disease in Persian cats

Dermatophytosis, also known as ringworm, is a contagious fungal skin disease affecting humans and animals worldwide. Persian cats exhibit severe forms of the disease more commonly than other breeds of cat, including other long-haired breeds. Certain types of severe dermatophytosis in humans are reportedly caused by monogenic inborn errors of immunity. The goal of this study was to identify genetic variants in Persian cats contributing to the phenotype of severe dermatophytosis. Whole-genome sequencing of case and control Persian cats followed by a genome-wide association study identified a highly divergent, disease-associated haplotype on chromosome F1 containing the S100 family of genes. S100 calcium binding protein A9 (S100A9), which encodes a subunit of the antimicrobial heterodimer known as calprotectin, contained 13 nonsynonymous variants between cases and controls. Evolutionary analysis of S100A9 haplotypes comparing cases, controls, and wild felids suggested the divergent disease-associated haplotype was likely introgressed into the domestic cat lineage and maintained via balancing selection. We demonstrated marked upregulation of calprotectin expression in the feline epidermis during dermatophytosis, suggesting involvement in disease pathogenesis. Given this divergent allele has been maintained in domestic cat and wildcat populations, this haplotype may have beneficial effects against other pathogens. The pathogen specificity of this altered protein should be investigated before attempting to reduce the allele frequency in the Persian cat breed. Further work is needed to clarify if severe Persian dermatophytosis is a monogenic disease or if hidden disease-susceptibility loci remain to be discovered. Consideration should be given to engineering antimicrobial peptides such as calprotectin for topical treatment of dermatophytosis in humans and animals. Author summary Fungal skin infections known as ringworm or dermatophytosis affect billions of humans and animals worldwide. Normally the disease is self-limiting in affected individuals. The Persian cat breed is a popular breed known for its long hair coat and short nose as well as its propensity to develop severe, chronic dermatophytosis. By examining the genomes of Persian cats, we discovered that a specific region of DNA is highly altered between cats with and without severe dermatophytosis. The DNA sequence in this region is particularly divergent within a cluster of genes involved in immune defense against pathogens. Notably, alterations to the DNA sequence cause several changes in the antimicrobial protein known as calprotectin, which defends against pathogens in the skin of cats. Persian cats with severe dermatophytosis have a version of calprotectin similar to a version maintained by certain desert-dwelling wild felids such as sand cats and Asiatic wildcats. Therefore, we think this version of the protein is beneficial in some environments or against certain pathogens but not against the fungus that causes ringworm in cats. Our findings suggest changes to calprotectin may affect pathogen specificity and engineered calprotectin could be considered as a novel therapy for dermatophytosis in humans and animals.