Infection of the human lymphoid organ on-a-chip with Borrelia burgdorferi reveals novel mechanisms of immunosuppression and autoimmunity in Lyme disease

Abstract In mice and one human case study, Borrelia burgdorferi (Bb), the causative agent of Lyme disease (LD), disrupts germinal center architecture and function. Bb proteins also mimic self-antigens. Thus, the antibody response may be of poor quality and target self antigens. To understand this pathology and its relevance to human infection-induced autoimmune diseases, we infected human lymphoid organ chips (Goyal et al., Adv Sci., 2022) created from healthy volunteers with Bb. We discovered unexpected and severe suppression of the adaptive immune system by Bb. T cell and B cell activation were absent in all of the donors (n>10) activated by Bb. Further, T cell proliferation was suppressed by Bb. Yet, some donors displayed hypergammaglobulinemia (hyperIg), seen in many antibody-mediated autoimmune diseases. We collected the exosomes secreted from the lymphoid organ chips and performed mass spectrometry to identify proteins associated with Bb infection and hyperIg. A heat-killed, fixed suspension of Staph. aureus Cowan I (SAC), commonly used to benchmark patient immune responses, was used as a control. We identified complement and coagulation factors, chaperone proteins, and immunological synapse proteins as key players in discriminating between successful activation, immunosuppression, and hyperIg (Bb). Our studies establish an innovative way to study human infectious diseases and their role in autoimmunity and reveal novel therapeutic targets to treat post-treatment Lyme disease.