Characterizing the immune infiltrate in secondary syphilis: implications for transmission and pathology

• Published in: Frontiers in immunology Vol. 16; p. 1549206
• Main Authors: Gallais Sérézal, Irène, Kirma, Joseph, Sarkar, Mrinal K., Cole, Christopher, Xing, Xianying, Bogle, Rachael, Fox, Jennifer, Coon, Anthony, vanStraalen, Kelsey R., Dobry, Craig, Xu, Linda H., Kahlenberg, J. Michelle, Harms, Paul W., Billi, Allison C., Tsoi, Lam C., Giacani, Lorenzo, Gudjonsson, Johann E.
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 25.03.2025
• Subjects: Adult; Female; host-pathogen adaptation; Humans; immune evasion; Immunology; keratinocytes; Keratinocytes - immunology; Keratinocytes - metabolism; Keratinocytes - microbiology; Male; Myeloid Differentiation Factor 88 - genetics; Single-Cell Analysis; Skin - immunology; Skin - microbiology; Skin - pathology; syphilis; Syphilis - immunology; Syphilis - microbiology; Syphilis - pathology; Syphilis - transmission; transcriptome (RNA-seq); Treponema pallidum - immunology; syphilis; host-pathogen adaptation; keratinocytes; immune evasion; transcriptome (RNA-seq)
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2025.1549206

Syphilis is a complex disease with variable clinical presentation where symptomatic and potentially infectious stages alternate with periods of latency, representing a fascinating model to study immune evasion and host immune responses. Immunohistochemistry (IHC), bulk, and single-cell RNA sequencing were performed on formalin-fixed paraffin-embedded skin biopsies collected from subjects with secondary syphilis. Additionally, PBMCs from healthy individuals and either primary or knock-out keratinocytes were exposed to live cells to define initial skin responses to the bacteria. Immunohistochemistry of secondary syphilis skin lesions showed a polymorphous immune infiltrate with colocalization of T cells, B cells and antigen-presenting cells. Single-cell analysis revealed distinct cellular contributions to the immune response, with prominent immune-stromal crosstalk accompanied by altered keratinocyte differentiation and decreased intraepidermal communication. Notably, prominent inflammatory signals were countered by concomitant regulatory responses, particularly in infiltrating myeloid cells. Exposure of PBMCs to live inhibited immune responses, while exposure to sonicated cells triggered and upregulation. Keratinocytes responded to both intact and sonicated with upregulation of type-I interferon responses that, however, were abolished in MYD88-deficient but not in STING-deficient keratinocytes. Our data provide novel insights into the contribution of epidermal TLR sensing through MYD88 to the host response to syphilis infection, highlighting mechanisms by which evades immune responses in skin that may facilitate transmission of this pathogen through the skin.