The Goldilocks Conundrum: The protective and adverse roles of immunoregulation by NOD-like receptors (NLRs) during brucellosis

Abstract

Abstract Brucellosis (Brucella spp.) is a bacterial zoonotic disease characterized by immune evasion. By hiding inside of macrophage vacuoles, Brucella often persist in hosts and instigate lifelong chronic inflammatory conditions. Despite mechanisms to combat host immune defense, NOD-like (NLR) pattern recognition receptors play an important role in immunoregulation during brucellosis. We have previously demonstrated that formation of pro-inflammatory NLRs into the multi-protein complex termed the inflammasome plays a protective role against brucellosis, resulting from the initiation of inflammatory cell death following recognition of Brucella genomic (g)DNA. Despite this investigation, the role of anti-inflammatory NLRs such as NLRX1 during brucellosis has not been determined. Here, we infected wildtype (WT) and Nlrx1−/− mice with Brucella abortus to evaluate the effect of an anti-inflammatory NLR during brucellosis. We found that WT mice displayed a stronger phenotypic presentation of infection, exhibiting increased splenomegaly, as well as elevated bacterial load and WBC infiltration in the liver when compared with knockout mice. This indicates that NLRX1 may exacerbate brucellosis presentation in vivo. Through further in vitro studies infecting murine WT and Nlrx1−/− macrophages, we found that NLRX1 attenuated inflammation, particularly in response to Brucella gDNA, and led to increased bacterial load in WT macrophages. Ultimately, these results indicate that NLRX1 may play an adverse role during brucellosis through reducing inflammation. This study further emphasizes the multifaceted role of NLRs during brucellosis and “Goldilocks Conundrum” in establishing immune system homeostasis in NLR-mediated diseases. Supported by the Virginia-Maryland College of Veterinary Medicine (VT/UMD Joint Seed Grant; DVM/PhD Student Support) and the NIH/NIAID (R03AI151494) Supported by the Virginia-Maryland College of Veterinary Medicine (VT/UMD Joint Seed Grant; DVM/PhD Student Support) and the NIH/NIAID (R03AI151494)