Borrelia burgdorferi initiates early transcriptional re-programming in macrophages that supports long-term suppression of inflammation.

Borrelia burgdorferi (Bb), the causative agent of Lyme disease, establishes a long-term infection and leads to disease manifestations that are the result of host immune responses to the pathogen. Inflammatory manifestations resolve spontaneously despite continued bacterial presence, suggesting inflammatory cells become less responsive over time. This is mimicked by in vitro repeated stimulations, resulting in tolerance, a phenotypic subset of innate immune memory. We performed comparative transcriptional analysis of macrophages in acute and memory states and identified sets of Tolerized, Hyper-Induced, Secondary-Induced and Hyper-Suppressed genes resulting from memory induction, revealing previously unexplored networks of genes affected by cellular re-programming. Tolerized gene families included inflammatory mediators and interferon related genes as would be predicted by the attenuation of inflammation over time. To better understand how cells mediate inflammatory hypo-responsiveness, we focused on genes that could mediate maintenance of suppression, such as Hyper-Induced genes which are up-regulated in memory states. These genes were notably enriched in stress pathways regulated by anti-inflammatory modulators. We examined one of the most highly expressed negative regulators of immune pathways during primary stimulation, Aconitate decarboxylase 1 (Acod1), and tested its effects during in vivo infection with Bb. As predicted by our in vitro model, we show its inflammation-suppressive downstream effects are sustained during in vivo long-term infection with Bb, with a specific role in Lyme carditis. Author summary: Lyme disease, caused by the spirochete Borrelia burgdorferi (Bb), is a long-term infection whose inflammatory manifestations are primarily due to an exuberant immune response to the pathogen. Although Bb can persist in its hosts for prolonged periods, most patients will resolve their symptoms even without antibiotic treatment. This suggests that the host has evolved methods of dampening the inflammatory response. Tolerance is a phenotypic subset of innate immune memory, a response resulting from epigenetic changes induced by a primary stimulus or during an acute infection. This transcriptional memory can be retained, affecting how a person responds during long-term infection or to subsequent infections. To better understand the gene expression changes between acute and memory states, we used an in vitro model of repeated stimulations and performed RNA sequencing. We identified a complex transcriptional profile network involved in the suppression of inflammatory responses and revealed novel gene expression subsets and pathways that may be important in maintenance of memory as well as gene sets responsible in the induction of memory during primary stimulation. We focused on one such gene, Acod1, a negative regulator of inflammation, and show that its anti-inflammatory effects are maintained in an animal model of Bb infection. [ABSTRACT FROM AUTHOR]