Severe Dermatophytosis in Persian Cats: A Multi-omics Approach to Unraveling Pathogenesis

In recent years, a surge in cases of chronic and treatment resistant dermatophytosis (ringworm) in humans has brought renewed interest in studying this disease. Persian cats are prone to developing a severe form of dermatophytosis characterized by extensive and chronic infections not seen in other cat breeds. Identifying a cause for severe disease in Persian cats may inform our understanding of pathogenesis in both animals and humans. We took a two-part, next-generation-sequencing (NGS)-based approach to identify a cause for severe dermatophytosis in Persian cats. First, we examined the Persian cat microbiota using 16S and ITS amplicon sequencing and analysis. We found that cutaneous bacterial and fungal populations were not overtly different between case and control cats with the exception of the presence of the dermatophyte Microsporum canis. The microbiota diversity and composition did not appear to contribute significantly to defense against dermatophytes, although more work may be needed to confirm this finding. Second, we sought to identify genetic variation associated with severe dermatophytosis using whole genome sequencing (WGS), genome-wide association study (GWAS), tests of natural selection, and functional assays. WGS and GWAS revealed a highly divergent, disease-associated haplotype on chromosome F1 containing the S100 family of genes. In particular, S100A9 contained thirteen nonsynonymous variants between cases and controls. Comparison of the divergent Persian cat S100A9 haplotypes with those of wild felids indicated that the disease-associated haplotype may have been introgressed into the ancestor of the sand cat and domestic cat from a wild felid ancestor. The haplotype then appears to have been maintained under balancing selection. We demonstrated that S100A8/S100A9 (an antimicrobial peptide known as calprotectin) expression is upregulated in the feline epidermis during dermatophytosis, confirming a role of S100A9 in the immune response to dermatophytes. Studies show that amino acid substitutions in antimicrobial peptides (AMPs) can alter pathogen specificity. Given that this divergent haplotype has been maintained in domestic cats, it may have beneficial effects against other feline pathogens. Calprotectin proteins represent a promising therapy for dermatophytosis in humans and animals, especially if particular amino acid substitutions can be shown to heighten antimicrobial activity against these ubiquitous fungal pathogens