Single-cell analyses of secondary syphilis in skin reveals implications for immune evasion and transmission

Summary: Abstract Body: Syphilis is a complex infection where symptomatic stages alternate with phases of latency and, hence, an interesting disease model to study immune evasion. We used single-cell and bulk RNA sequencing along with IHC and assessed immune responses in both blood and keratinocytes to live Treponema pallidum (T. pallidum). For single-cell sequencing, skin biopsies were collected from five subjects with secondary syphilis and four healthy controls. Single-cell data from secondary syphilis skin lesions demonstrated a polymorphous immune infiltrate, which was validated by IHC and demonstrated prominent B cell/plasma cell infiltration with colocalization of T cells, B cells and antigen-presenting cells. Prominent immune-stromal crosstalk was observed, with concomitant pro-inflammatory and regulatory responses, and was accompanied by altered keratinocyte differentiation and decrease in intraepidermal communication, which may provide a niche in the epidermis where T. pallidum can be present. While PBMC immune responses were blunted by T. pallidum, keratinocytes responded with upregulation of type-I interferon responses, that were abolished in MYD88-deficient, but not STING-deficient keratinocytes, suggesting engagement of TLR sensing in skin as a driver of immune responses in syphilitic skin lesions. These data shed light on the mechanisms by which T. pallidum evades immune responses and promotes transmission through the skin. Joseph Kirma⁷, Irène G. Sérézal^{1, 7}, Mrinal K. Sarkar⁷, Christopher Cole⁷, Xianying Xing⁷, Rachael Bogle⁷, Jennifer Fox⁷, Anthony M. Coon⁷, Craig Dobry⁷, Michelle Kahlenberg^{2, 7}, Paul Harms^{3, 7}, Allison C. Billi⁷, Alex Tsoi^{7, 4, 5}, Lorenzo Giacani⁶, Johann E. Gudjonsson^{7, 2} 1. Dept of Dermatology, INSERM 1098/Franche Comté University, Besançon University Hospital, Besançon, France. 2. Division of Rheumatology, Dept of Internal Medicine, University of Michigan, Ann Arbor, MI, United States. 3. Dept of Pathology, University of Michigan, Ann Arbor, MI, United States. 4. Dept of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI, United States. 5. Dept of Biostatistics, University of Michigan, Ann Arbor, MI, United States. 6. Dept of Medicine, University of Washington, Seattle, WA, United States. 7. Dept of Dermatology, University of Michigan, Ann Arbor, MI, United States. Innate Immunity, Microbiology, and Microbiome