School of Pharmacy, University College London, London, United Kingdom.
Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden.
Infect Immun. 2019 Apr 23;87(5). doi: 10.1128/IAI.00878-18. Print 2019 Mar.
Gastrointestinal (GI) colonization of 2-day-old (P2) rat pups with K1 results in translocation of the colonizing bacteria across the small intestine, bacteremia, and invasion of the meninges, with animals frequently succumbing to lethal infection. Infection, but not colonization, is strongly age dependent; pups become progressively less susceptible to infection over the P2-to-P9 period. Colonization leads to strong downregulation of the gene encoding trefoil factor 2 (Tff2), preventing maturation of the protective mucus barrier in the small intestine. Trefoil factors promote mucosal homeostasis. We investigated the contribution of Tff2 to protection of the neonatal rat from K1 bacteremia and tissue invasion. Deletion of , using clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9, sensitized P9 pups to K1 bacteremia. There were no differences between homozygotes and the wild type with regard to the dynamics of GI colonization. Loss of the capacity to elaborate Tff2 did not impact GI tract integrity or the thickness of the small-intestinal mucus layer but, in contrast to P9 wild-type pups, enabled K1 bacteria to gain access to epithelial surfaces in the distal region of the small intestine and exploit an intracellular route across the epithelial monolayer to enter the blood circulation via the mesenteric lymphatic system. Although primarily associated with the mammalian gastric mucosa, we conclude that loss of Tff2 in the developing neonatal small intestine enables the opportunistic neonatal pathogen K1 to enter the compromised mucus layer in the distal small intestine prior to systemic invasion and infection.
新生 2 日龄（P2）大鼠肠道定植 K1 会导致定植菌穿过小肠发生易位、菌血症和脑膜侵袭，动物常因感染而死亡。感染而非定植强烈依赖于年龄；在 P2 至 P9 期间，幼鼠对感染的易感性逐渐降低。定植导致编码三叶因子 2（Tff2）的基因强烈下调，阻止了小肠保护性粘液屏障的成熟。三叶因子促进粘膜稳态。我们研究了 Tff2 对保护新生大鼠免受 K1 菌血症和组织侵袭的作用。利用成簇规律间隔短回文重复（CRISPR）-Cas9 缺失 ，使 P9 幼鼠对 K1 菌血症敏感。 homozygotes 与野生型在 GI 定植的动力学方面没有差异。缺乏产生 Tff2 的能力并不影响肠道完整性或小肠粘液层的厚度，但与 P9 野生型幼鼠不同的是，它使 K1 细菌能够进入小肠远端的上皮表面，并通过上皮单层利用细胞内途径通过肠系膜淋巴系统进入血液循环。尽管 Tff2 主要与哺乳动物胃粘膜相关，但我们的结论是，在发育中的新生小肠中丧失 Tff2 可使机会性病原体 K1 在全身侵袭和感染之前进入受损的远端小肠粘液层。
