Non-tuberculous Mycobacteria as triggers of Systemic Lupus Erythematosus - Summary Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by inflammatory flares and progressive organ damage. Current treatments, including glucocorticoids (GCs), can lead to increased susceptibility to infections, particularly non-tuberculous mycobacteria (NTMs). This proposal aims to investigate the interactions between NTM infections, specifically Mycobacterium abscessus (Mab), and lupus onset/flares, while considering the impact of GC treatment. Using a preclinical mouse model, we demonstrated that inhalation of crystalline silica accelerates lupus onset and progression through alveolar macrophage (AM)- initiated inflammation. To further explore pulmonary inflammation's role in lupus, we employed a novel ex vivo model using fetal liver-derived alveolar-like macrophages (FLAMs) from lupus-resistant (C57BL/6J) and lupus- susceptible (B6.SLE1,2,3) mice. Our preliminary results revealed distinct transcriptional and inflammatory responses between B6.SLE and B6 FLAMs when exposed to various pathogen-associated molecular patterns. Notably, infection with a specific Mab clinical isolate (Mab41) induced a robust type I interferon response in B6.SLE FLAMs but not in B6 FLAMs, suggesting that certain bacterial-host genotype combinations may trigger unique inflammatory responses. We propose that Mab infections are an underappreciated trigger for lupus onset and flares which is further complicated by GC treatment. To test this prediction directly we will explore mechanistic interactions between distinct Mab clinical isolates (CIs), lupus progression, and GC therapy. In Aim1 we will examine the pathogenesis and inflammatory differences of distinct Mab CIs in both B6 and B6.SLE FLAMs. We will then test how distinct ex vivo outcomes correlate with the loss of immune tolerance and lupus progression during in vivo infection. In Aim 2 we will determine how GC treatment alters interactions between Mab CIs, inflammation, and lupus onset. This exploratory proposal will be the first to examine connections between NTM infection, lupus progression and GC treatment. Our innovative ex vivo and in vivo models, including a novel oral prednisone diet model, have the potential to fundamentally change our understanding of how respiratory bacterial infections contribute to autoimmune disease progression. By exploring these novel connections, we will enhance our understanding of lupus pathogenesis and identify new avenues for prevention and treatment.
