AUTHOR=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. 

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

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1549206

DOI=10.3389/fimmu.2025.1549206

ISSN=1664-3224

ABSTRACT=IntroductionSyphilis 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.MethodsImmunohistochemistry (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 MyD88 knock-out keratinocytes were exposed to live Treponema pallidum cells to define initial skin responses to the bacteria.ResultsImmunohistochemistry 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 T. pallidum inhibited immune responses, while exposure to sonicated cells triggered CXCL1 and CXCL3 upregulation. Keratinocytes responded to both intact and sonicated T. pallidum with upregulation of type-I interferon responses that, however, were abolished in MYD88–deficient but not in STING–deficient keratinocytes.DiscussionOur data provide novel insights into the contribution of epidermal TLR sensing through MYD88 to the host response to syphilis infection, highlighting mechanisms by which T. pallidum evades immune responses in skin that may facilitate transmission of this pathogen through the skin.