A major obstacle in infection biology is the limited ability to recapitulate human disease trajectories in traditional cell culture and animal models, which impedes the translation of basic research into clinics. Here, we introduce a three-dimensional (3D) intestinal tissue model to study human enteric infections at a level of detail that is not achieved by conventional two-dimensional monocultures. Our model comprises epithelial and endothelial layers, a primary intestinal collagen scaffold, and immune cells. Upon Salmonella infection, the model mimics human gastroenteritis, in that it restricts the pathogen to the epithelial compartment, an advantage over existing mouse models. Application of dual transcriptome sequencing to the Salmonella-infected model revealed the communication of epithelial, endothelial, monocytic, and natural killer cells among each other and with the pathogen. Our results suggest that Salmonella uses its type III secretion systems to manipulate STAT3-dependent inflammatory responses locally in the epithelium without accompanying alterations in the endothelial compartment. Our approach promises to reveal further human-specific infection strategies employed by Salmonella and other pathogens.IMPORTANCE Infection research routinely employs in vitro cell cultures or in vivo mouse models as surrogates of human hosts. Differences between murine and human immunity and the low level of complexity of traditional cell cultures, however, highlight the demand for alternative models that combine the in vivo-like properties of the human system with straightforward experimental perturbation. Here, we introduce a 3D tissue model comprising multiple cell types of the human intestinal barrier, a primary site of pathogen attack. During infection with the foodborne pathogen Salmonella enterica serovar Typhimurium, our model recapitulates human disease aspects, including pathogen restriction to the epithelial compartment, thereby deviating from the systemic infection in mice. Combination of our model with state-of-the-art genetics revealed Salmonella-mediated local manipulations of human immune responses, likely contributing to the establishment of the pathogen's infection niche. We propose the adoption of similar 3D tissue models to infection biology, to advance our understanding of molecular infection strategies employed by bacterial pathogens in their human host.

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一个先进的人类肠道共培养模型揭示了沙门氏菌感染期间房室化的宿主和病原体策略。

感染生物学的主要障碍是在传统细胞培养和动物模型中概括人类疾病轨迹的能力有限，这阻碍了基础研究向临床的转化。在这里，我们介绍了三维（3D）肠道组织模型，以研究传统肠道二维感染无法达到的细节水平来研究人类肠道感染。我们的模型包括上皮和内皮层，主要的肠胶原支架和免疫细胞。沙门氏菌感染后，该模型模仿人的肠胃炎，因为它将病原体限制在上皮区室，这是现有小鼠模型的优势。在沙门氏菌感染模型中应用双转录组测序揭示了上皮，内皮，单核细胞，和自然杀伤细胞之间以及与病原体之间。我们的结果表明，沙门氏菌利用其III型分泌系统在上皮局部操纵STAT3依赖性炎症反应，而不伴随内皮区室的改变。我们的方法有望揭示沙门氏菌和其他病原体采用的其他人类特异性感染策略。重要感染研究通常采用体外细胞培养或体内小鼠模型作为人类宿主的替代物。鼠和人的免疫力之间的差异以及传统细胞培养物的低复杂性，突显了对替代模型的需求，这些模型将人类系统的体内样特性与简单的实验扰动相结合。这里，我们介绍了一种3D组织模型，该模型包含多种细胞类型的人类肠道屏障（病原体攻击的主要部位）。在食源性病原体肠道沙门氏菌鼠伤寒沙门氏菌感染期间，我们的模型概括了人类疾病的各个方面，包括病原体对上皮区室的限制，从而偏离了小鼠的全身感染。我们的模型与最新遗传学的结合揭示了沙门氏菌介导的人类免疫反应的局部操纵，这可能有助于建立病原体的感染位。我们建议对感染生物学采用类似的3D组织模型，以增进我们对细菌性病原体在其人类宿主中采用的分子感染策略的了解。在食源性病原体肠炎沙门氏菌鼠伤寒沙门氏菌感染期间，我们的模型概述了人类疾病的各个方面，包括病原体对上皮区室的限制，从而偏离了小鼠的全身感染。我们的模型与最新遗传学的结合揭示了沙门氏菌介导的人类免疫反应的局部操纵，这可能有助于建立病原体的感染位。我们建议对感染生物学采用类似的3D组织模型，以增进我们对细菌性病原体在其人类宿主中采用的分子感染策略的了解。在食源性病原体肠道沙门氏菌鼠伤寒沙门氏菌感染期间，我们的模型概括了人类疾病的各个方面，包括病原体对上皮区室的限制，从而偏离了小鼠的全身感染。我们的模型与最新遗传学的结合揭示了沙门氏菌介导的人类免疫反应的局部操纵，这可能有助于建立病原体的感染位。我们建议对感染生物学采用类似的3D组织模型，以增进我们对细菌性病原体在其人类宿主中采用的分子感染策略的了解。从而偏离了小鼠的全身感染。我们的模型与最新遗传学的结合揭示了沙门氏菌介导的人类免疫反应的局部操纵，这可能有助于建立病原体的感染位。我们建议对感染生物学采用类似的3D组织模型，以增进我们对细菌性病原体在其人类宿主中采用的分子感染策略的了解。从而偏离了小鼠的全身感染。我们的模型与最新遗传学的结合揭示了沙门氏菌介导的人类免疫反应的局部操纵，这可能有助于建立病原体的感染位。我们建议对感染生物学采用类似的3D组织模型，以增进我们对细菌性病原体在其人类宿主中采用的分子感染策略的了解。