Abstract
Lyme carditis is an extracutaneous manifestation of Lyme disease characterized by episodes of atrioventricular block of varying degrees and additional, less reported cardiomyopathies. The molecular changes associated with the response to Borrelia burgdorferi over the course of infection are poorly understood. Here, we identify broad transcriptomic and proteomic changes in the heart during infection that reveal a profound down-regulation of mitochondrial components. We also describe the long-term functional modulation of macrophages exposed to live bacteria, characterized by an augmented glycolytic output, increased spirochetal binding and internalization, and reduced inflammatory responses. In vitro, glycolysis inhibition reduces the production of tumor necrosis factor (TNF) by memory macrophages, whereas in vivo, it produces the reversion of the memory phenotype, the recovery of tissue mitochondrial components, and decreased inflammation and spirochetal burdens. These results show that B. burgdorferi induces long-term, memory-like responses in macrophages with tissue-wide consequences that are amenable to be manipulated in vivo.
Highlights
Lyme borreliosis, caused by the infection with the spirochete, Borrelia burgdorferi, is the most common arthropod-borne infection in the Northern Hemisphere with around 300,000 cases every year in the United States [1,2] and approximately 250,000 new cases yearly in Europe [3]
We have recently identified transcriptional traits and signaling pathways associated with the short-time stimulation of monocytes/macrophages from both human and murine origin with B. burgdorferi, such as peroxisome proliferator-activated receptor (PPAR) and the Tolllike receptor (TLR) family member, CD180 [33]
We first analyzed by tissue MALDI Imaging (MALDI-IMS) global proteomic changes in the hearts of 3-week-infected mice with B. burgdorferi compared to uninfected controls
Summary
Lyme borreliosis, caused by the infection with the spirochete, Borrelia burgdorferi, is the most common arthropod-borne infection in the Northern Hemisphere with around 300,000 cases every year in the United States [1,2] and approximately 250,000 new cases yearly in Europe [3]. Symptoms associated with infection may be debilitating and long-lasting despite appropriate antibiotic treatment. B. burgdorferi shows a marked tropism for cardiac tissue [4] where it can persist for months to years even after antibiotic treatment [5,6,7] and in spite of the development of strong immune responses. Apparent in a small percentage of Lyme borreliosis cases, 11 fatalities associated with Lyme carditis have been reported since 1985 (https://www.cdc.gov/lyme/signs_symptoms/lymecarditis.html) [4]
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