Borrelia burgdorferi binds serum amyloid A and modulates subcutaneous adipose tissue immune signaling

Following a tick bite, Borrelia burgdorferi spirochetes replicate in human skin and disseminate through tissues, including subcutaneous adipose tissue. Adipose is a complex organ containing both immune and non-immune cells that play a significant role in the immune response, yet little is known about adipose-specific immune signaling after B. burgdorferi infection. We investigated the landscape of immune signaling within adipose tissue-resident cells during B. burgdorferi infection in human tissue (skin and adipose tissue) ex vivo . Single-cell sequencing pathway analysis revealed upregulation of inflammatory pathways in skin, yet overall downregulation of immune pathways in adipose tissue cells during B. burgdorferi infection. Adipose-resident myeloid cells and adipose stem/progenitor cells (ASPCs) displayed an inflammatory profile characterized by the increased expression of IL-1β, TNF, and NFKB1. CellChat, a cellular communication comparative analysis, showed increased cell-to-cell communication across adipose-resident cell populations. ASPCs demonstrated the strongest outgoing signals, positioning them as key hubs of intercellular communication in adipose tissue. Interestingly, we observed adipose-specific downregulation of serum amyloid A (SAA), an inflammatory serum marker known to have antimicrobial properties and typically elevated in Lyme disease patients during acute infection. Therefore, we further evaluated the interaction between SAA and B. burgdorferi . Here, we show that human recombinant SAA protein directly binds B. burgdorferi spirochetes, reduces spirochete viability in a dose-dependent manner in vitro, and enhances phagocytosis. Taken together, these findings show that adipose tissue is a site of active immune signaling in the setting of infection and identify SAA as a host defense factor against B. burgdorferi .