Persistent Peptidoglycan from Borrelia burgdorferi as a Hidden Driver of Post-Infectious Inflammation

Despite widespread awareness of Lyme disease as a tick-borne illness caused by Borrelia burgdorferi, the long-term complications that linger in a significant subset of patients continue to challenge both the scientific community and medical practitioners. Most patients recover fully after antibiotic therapy, yet up to 15% report enduring symptoms such as profound fatigue, joint pain, and cognitive dysfunction that can persist for months or even years. These manifestations, uncoupled from any detectable live bacteria, blur the line between infection and inflammation, and raise a pressing question: what biological remnants, if any, might be responsible for sustaining this chronic state?

The root of the problem lies in the fundamental disconnect between clinical observation and molecular understanding. Traditional diagnostics and treatment protocols are predicated on the assumption that bacterial clearance equates to cure. However, the persistence of symptoms in some individuals long after the infection has ostensibly resolved suggests that this view may be overly simplistic. In the absence of viable pathogens, attention has increasingly turned to the possibility that non-living bacterial components may continue to stimulate the immune system in maladaptive ways. Still, pinpointing the precise agents responsible has proven remarkably difficult, in part due to the stealthy nature of B. burgdorferi and its ability to evade conventional immunological detection.

new research paper published in Science Translational Medicine and conducted by Dr. Mecaila McClune, Dr. Osamudiamen Ebohon, Dr. Jules Dressler, Dr. Marisela Davis,Dr. Juselyn Tupik, Dr. Robert  Lochhead, Professor Carmen Booth, Professor  Allen Steere  and led by Professor Brandon Jutras from the Northwestern University and Massachusetts General Hospital and Harvard Medical School, investigated the peptidoglycan (PG) of B. burgdorferi—a rigid, mesh-like structure essential for bacterial integrity, but one with unique chemical properties that distinguish it from that of other pathogens. Prior findings had hinted at the presence of PG remnants in the synovial fluid of Lyme arthritis patients even after antibiotic therapy, raising the tantalizing prospect that this material could be a culprit in chronic inflammation. Yet the fate of this PG—how it behaves in the body, where it travels, and whether it triggers systemic effects—remained largely unexplored.

To uncover how Borrelia burgdorferi peptidoglycan (PGBb) behaves inside a living host, the researchers first devised a real-time tracking system by tagging purified PGBb with fluorescent dyes. They injected these labeled polymers into live mice and observed their distribution using advanced imaging techniques. What stood out immediately was that, unlike peptidoglycan from more commonly studied bacteria such as E. coli or S. aureus, the PGBb was not rapidly cleared. Instead, it accumulated persistently in the liver, where it remained for weeks—something no other bacterial PG tested had shown. The team was struck by this resilience, particularly because the liver is not typically a known reservoir for this pathogen, and they saw in the fluorescence an unsettling suggestion: that inert bacterial material could linger long after the organism itself was gone.

Digging deeper, they wanted to understand whether this persistence was rooted in the unusual chemistry of the B. burgdorferi PG. So they engineered a comparison study using PGs from several bacteria with well-characterized differences in their chemical makeup. Surprisingly, the unique glycan terminus of PGBb—GlcNAc-GlcNAc-1,6-anhydroMurNAc—seemed to partially drive its persistence. Even when other bacterial PGs were matched for concentration and fluorescence intensity, none remained in tissue as long. A mutant strain of B. burgdorferi that lacked this specific sugar modification showed diminished retention, hinting at a role for the rare glycan in tissue sequestration. The team next explored the cells responsible for capturing and retaining the PG. Through meticulous cell culture studies, they found that both Kupffer cells and hepatocytes—major players in liver filtration—readily engulfed PGBb. Notably, hepatocytes exhibited an unexpected preference for internalizing PGBb over other PG types. This wasn’t random; it was confirmed by phagocytosis inhibitors, which diminished uptake, underscoring that the process was active, not passive. Yet even after internalization, the PGBb wasn’t quickly broken down. It lingered inside cells far longer than its bacterial counterparts. Importantly, this wasn’t a silent presence. Mice with persistent PGBb in their livers exhibited elevated liver enzymes and changes in protein expression tied to immune activation and even metabolic dysregulation. Human immune cells exposed to the same material in vitro echoed this disturbance, particularly in pathways linked to fatigue and inflammation. Piece by piece, the experiments built a story of quiet molecular sabotage—a bacterial relic capable of outlasting its maker and subtly reshaping host biology.

The significance of this study lies in its ability to bridge a long-standing gap between unresolved patient symptoms and the absence of detectable infection. For years, individuals suffering from post-treatment Lyme disease syndrome (PTLDS) have lived in a clinical gray zone—dismissed by some as psychosomatic, yet unmistakably affected. What this research offers is not just validation, but a plausible, biologically grounded explanation: that Borrelia burgdorferi’s uniquely structured peptidoglycan can persist in host tissues and act as a long-lived inflammatory trigger, even when the bacteria themselves are no longer present. This reframes our understanding of chronic symptoms—not as a failure to clear infection, but as an immune system reacting to persistent, non-viable microbial debris. One of the most powerful implications is that PGBb behaves unlike peptidoglycans from other bacteria. Its chemical distinctiveness—particularly the rare G-G-anhM glycan terminus—seems to make it invisible to the usual clearance mechanisms, allowing it to lodge in the liver and synovial tissues for extended periods. This isn’t just a biochemical curiosity—it’s a clinical pivot point. It suggests that residual bacterial structures, not just active infection or autoimmunity, could be driving prolonged inflammation and metabolic imbalance in a subset of patients. The discovery that hepatocytes, not just immune cells, can phagocytose and retain this material opens up new dimensions in understanding organ-specific persistence. Moreover, the transcriptomic and proteomic disturbances observed—especially in energy metabolism and immune signaling—mirror patient-reported symptoms like fatigue and cognitive dysfunction. These molecular echoes of disease provide a foundation for the development of biomarkers that could eventually guide diagnosis or therapy. Perhaps most importantly, this work may alter treatment strategies. If persistent peptidoglycan is partly responsible for lingering illness, therapies designed to neutralize or accelerate its clearance could reduce the need for extended antibiotic use or reliance on immunosuppressants.