Acinetobacter baumannii lipooligosaccharide core region promotes CD14-dependent TLR4 endocytosis and enhances pathogenicity through interferon-β production

Bacterial strains harboring lipooligosaccharides (LOS) with a core region are more pathogenic than those without it; however, the underlying mechanism remains to be fully elucidated. Lipid A has been believed to be the primary moiety of LOS that regulates Toll-like receptor 4 (TLR4) signaling, with the core region having minimal impact. In this study, we aimed to elucidate the influence of the LOS core region of Acinetobacter baumannii on immune response and pathogenesis. We conducted a series of step-by-step experiments and deciphered the association between the core region of the LOS and the immune response. The influence of this core region on the mechanism of TLR4 signaling pathways and further pathogenesis has also been deciphered. One A. baumannii wild strain with an intact LOS core region, its LOS core region gene ( lpsB )-deficient strain, and the lpsB gene-complemented strain were used in this study. Membrane vesicles released from the strains were collected, quantified, normalized to the particle number, and used in subsequent experiments. Cytokine and chemokine gene expression, protein production, and RNA sequencing analyses were measured. A step-by-step approach was used to explore the underlying mechanism. The effect of the LOS core region on pathogenesis was determined using mouse experiments. Specifically, the LOS core promotes CD14-associated TLR4 endocytosis and boosting the expression of TRIF-associated genes, including Infb1 . This enhancement in interferon-β production correlates with increased pathogenicity in an animal model. These findings highlight the significance of the LOS core region in modulating immune responses through TRIF signaling, challenging previous assumptions regarding the role of this core region in LOS-mediated pathogenesis.