Department of Immunology and Microbial Disease, Albany Medical College, Albany, NY 12208.
Center for Functional Genomics, University at Albany-State University of New York, Rensselaer, NY 12144.
Proc Natl Acad Sci U S A. 2022 Jan 11;119(2). doi: 10.1073/pnas.2110166119.
Hemachromatosis (iron-overload) increases host susceptibility to siderophilic bacterial infections that cause serious complications, but the underlying mechanisms remain elusive. The present study demonstrates that oral infection with hyperyersiniabactin (Ybt) producing Δ mutant (termed Δ) results in severe systemic infection and acute mortality to hemochromatotic mice due to rapid disruption of the intestinal barrier. Transcriptome analysis of Δ-infected intestine revealed up-regulation in cytokine-cytokine receptor interactions, the complement and coagulation cascade, the NF-κB signaling pathway, and chemokine signaling pathways, and down-regulation in cell-adhesion molecules and Toll-like receptor signaling pathways. Further studies indicate that dysregulated interleukin (IL)-1β signaling triggered in hemachromatotic mice infected with Δ damages the intestinal barrier by activation of myosin light-chain kinases (MLCK) and excessive neutrophilia. Inhibiting MLCK activity or depleting neutrophil infiltration reduces barrier disruption, largely ameliorates immunopathology, and substantially rescues hemochromatotic mice from lethal Δ infection. Moreover, early intervention of IL-1β overproduction can completely rescue hemochromatotic mice from the lethal infection.
血色病（铁过载）增加了宿主对嗜铁细菌感染的易感性，从而导致严重的并发症，但潜在的机制仍不清楚。本研究表明，通过口服感染产生hyperyersiniabactin (Ybt)的Δ突变体（称为Δ），会导致血色病小鼠发生严重的全身感染和急性死亡，这是由于肠道屏障的迅速破坏。对Δ感染肠道的转录组分析显示，细胞因子-细胞因子受体相互作用、补体和凝血级联、NF-κB 信号通路和趋化因子信号通路上调，而细胞黏附分子和 Toll 样受体信号通路下调。进一步的研究表明，在感染Δ的血色病小鼠中失调的白细胞介素（IL）-1β信号通过肌球蛋白轻链激酶（MLCK）的激活和过度嗜中性粒细胞引发肠道屏障损伤。抑制 MLCK 活性或耗尽嗜中性粒细胞浸润可减少屏障破坏，在很大程度上改善免疫病理学，并从致命的Δ感染中挽救血色病小鼠。此外，早期干预 IL-1β的过度产生可以完全挽救血色病小鼠免受致命的感染。
