SCGB1D2 is a Sex-Specific Mucosal Defense that impacts Lyme Disease Susceptibility 2251807

Abstract Introduction Lyme disease is a tick-borne disease caused by bacteria of the genus Borrelia. The host factors that modulate susceptibility for Lyme disease have remained mostly unknown. Infection-Associated Chronic Illness (IACI) post-exposure to Borrelia burgdorferi (B. burgdorferi) skews female and Lyme disease increases risk for multiple gynecological conditions. The mechanisms of which are not well defined. We identify Secretoglobin family 1D member 2 (SCGB1D2), a small secreted protein, as a sex-biased host mucosal defense factor for Lyme disease. Methods We used genetic and epidemiological data from FinnGen and the Estonian Biobank to identify variants associated with Lyme disease risk. Protein expression data from Human Protein Atlas were assessed. Functional studies tested recombinant SCGB1D2 reference and missense (P53L) proteins for their ability to inhibit Bb growth in vitro. In vivo effects were validated using a murine infection model. Results A common SCGB1D2 variant is linked to higher Lyme disease susceptibility. The recombinant reference protein markedly inhibited Bb growth, while the P53L variant showed reduced efficacy. In mice, recombinant SCGB1D2 injected with the bacteria lowered total bacterial burden longitudinally. Expression analyses confirmed SCGB1D2 is expressed in the cervix and sweat gland cells. Importantly, there are sex-differences in sweat patterns. SCGB1D2 expression is progesterone receptor—dependent and has been implicated in reproductive conditions such as endometriosis. Conclusion SCGB1D2 is a sex-dependent host defense factor that restricts B. burgdorferi growth and influences Lyme disease susceptibility. These data suggest broader implications in sex differences and mucosal defense to B. burgdorferi. SCGB1D2’s localization to skin and secretory tissues, hormonal immune modulation, and B. burgdorferi antimicrobial properties reveal not only a larger understanding of Lyme disease sex differences in mucosal defense but also a novel therapeutic potential for Lyme disease. Funding Source Emily and Malcolm Fairbairn, Instrumentarium Science Foundation and Academy of Finland, Finnish Medical Foundation, Younger Family, and Bay Area Lyme Foundation Topic Categories Mucosal and Regional Immunology (MUC)