Lyme Disease IgG N-linked Glycans Contrast the Canonical Inflammatory Signature

Abstract

AbstractLyme disease (LD) infection is caused by Borrelia burgdorferi sensu lato. Due to the limited presence of this pathogen in the bloodstream in humans, diagnosis of LD relies on seroconversion. Immunoglobulins produced in response to infection are differentially glycosylated to promote or inhibit downstream inflammatory responses by the immune system. IgG N-glycan responses to LD have not been characterized. In this study, we analyzed IgG N-glycans from cohorts of healthy controls, acute LD patient serum, and serum collected after acute LD patients completed a 2- to 3-week course of antibiotics and convalesced for 70-90 days. Results indicate that during the acute phase of Bb infection, IgG shifts its glycosylation profile to include structures that are not associated with the classic proinflammatory IgG N-glycan signature. This unexpected result is in direct contrast to what is reported for other inflammatory diseases. Furthermore, IgG N-glycans detected during acute LD infection discriminated between control, acute, and treated cohorts with a sensitivity of 75-100% and specificity of 94.7-100%.Author summaryThe causative agent of Lyme disease (LD), Borrelia burgdorferi sensu lato (Bb), is transmitted from an infected Ixodes tick into the human host dermis during the tick’s blood meal. Currently, LD is the most prevalent vector-borne disease in the US, with an estimated 476,000 annual cases. LD diagnostics rely on patient seroconversion against Bb antigens, and these tests cannot distinguish between an acute patient compared to a patient previously treated for LD. With the goal of identifying novel biomarkers associated specifically with LD infections, we analyzed the glycoprotein Immunoglobulin G (IgG) N-glycan signatures from healthy control, acute LD, and a second time point composed of the same LD patients after antibiotic therapy. We found acute LD IgG N-glycan signatures were significantly different from the canonical pro-inflammatory profile associated with most inflammatory diseases. The dramatic shifts observed in the acute LD time point were further altered at the treated time point. IgG N-glycan signature data was employed to discriminate between acute LD and healthy controls. In addition, IgG N-glycan signatures distinguished patients who completed antibiotic therapy from the acute LD timepoint. Our study will contribute to the accurate and prompt treatment of LD patients and reveals a new research avenue of immune dysregulation associated with LD.Graphical Abstract