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

ABSTRACT 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 . IMPORTANCE Borrelia burgdorferi is the bacterium that is transmitted by ticks and causes Lyme disease. These bacteria replicate in the skin to cause the localized skin rash erythema migrans, then disseminate to cause symptoms in other organs, including the joints and heart. Adipose tissue, or fat, is adjacent to skin, joints, and heart—all target organs of infection. In this study, we set out to understand how adipose tissue/fat plays a role in Lyme disease. We discovered that B. burgdorferi infection leads to an immune response in adipose tissue cells with specific downregulation of a gene called serum amyloid A (SAA). Our work shows that B. burgdorferi bacteria bind serum amyloid A (SAA), leading to decreased viability in vitro and enhanced uptake of B. burgdorferi by white blood cells. These findings highlight the dynamic role our fat can play during B. burgdorferi infection and can lead to the identification of new treatments for Lyme disease.