TY - JOUR T1 - Group B streptococcal membrane vesicles induce proinflammatory cytokine production and are sensed in an NLRP3 inflammasome-dependent mechanism in human macrophages JF - bioRxiv DO - 10.1101/2022.08.10.503555 SP - 2022.08.10.503555 AU - Cole R. McCutcheon AU - Jennifer A. Gaddy AU - David M. Aronoff AU - Shannon D. Manning AU - Margaret G. Petroff Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/08/12/2022.08.10.503555.abstract N2 - Group B Streptococcus (GBS) is a major cause of fetal and neonatal mortality worldwide. Many of the adverse effects associated with invasive GBS are associated with inflammation that leads to chorioamnionitis, preterm birth, sepsis, and meningitis; therefore, understanding bacterial factors that promote inflammation is of critical importance. Membrane vesicles (MVs), which are produced by many pathogenic and non-pathogenic bacteria, may modulate host inflammatory responses. In mice, GBS MVs injected intra-amniotically can induce preterm birth and fetal death. Although it is known that GBS MVs induce large-scale leukocyte recruitment into infected tissues, the immune effectors driving these responses are unclear. Here, we hypothesized that macrophages respond to GBS-derived MVs by producing proinflammatory cytokines and are recognized through one or more pattern recognition receptors. We show that THP-1 macrophage-like cells produce high levels of neutrophil- and monocyte-specific chemokines in response to MVs derived from different clinical isolates of GBS. Interleukin (IL)-1β was significantly upregulated in response to MVs, which was independent of NF-kB signaling but dependent on both caspase-1 and NLRP3. These data indicate that MVs contain one or more pathogen-associated molecular patterns that can be sensed by the immune system. Furthermore, this study identifies the NLRP3 inflammasome as a novel sensor of GBS MVs. Our data additionally indicate that MVs may serve as immune effectors that can be targeted for immunotherapeutics, particularly given that similar responses were observed across this subset of GBS isolates. ER -