Background: The airway epithelium represents a critical component of the human lung that helps orchestrate defenses against respiratory tract viral infections, which are responsible for more than 2.5 million deaths/year globally. Innate immune activities of the airway epithelium rely on Toll-like receptors (TLRs), nucleotide binding and leucine-rich-repeat pyrin domain containing (NLRP) receptors, and cytosolic nucleic acid sensors. ATP Binding Cassette (ABC) transporters are ubiquitous across all three domains of life—Archaea, Bacteria, and Eukarya—and expressed in the human airway epithelium. ABCF1, a unique ABC family member that lacks a transmembrane domain, has been defined as a cytosolic nucleic acid sensor that regulates CXCL10, interferon-β expression, and downstream type I interferon responses. We tested the hypothesis that ABCF1 functions as a dsDNA nucleic acid sensor in human airway epithelial cells important in regulating antiviral responses.

Methods: Expression and localization experiments were performed using in situ hybridization and immunohistochemistry in human lung tissue, while confirmatory transcript and protein expression was performed in human airway epithelial cells. Functional experiments were performed with siRNA methods in a human airway epithelial cell line. Complementary transcriptomic analyses were performed to explore the contributions of ABCF1 to gene expression patterns.

Results: Using archived human lung and human airway epithelial cells, we confirm expression of ABCF1 gene and protein expression in these tissue samples, with a role for mediating CXCL10 production in response to dsDNA viral mimic challenge. Although, ABCF1 knockdown was associated with an attenuation of select genes involved in the antiviral responses, Gene Ontology analyses revealed a greater interaction of ABCF1 with TLR signaling suggesting a multifactorial role for ABCF1 in innate immunity in human airway epithelial cells.

Conclusion: ABCF1 is a candidate cytosolic nucleic acid sensor and modulator of TLR signaling that is expressed at gene and protein levels in human airway epithelial cells. The precise level where ABCF1 protein functions to modulate immune responses to pathogens remains to be determined but is anticipated to involve IRF-3 and CXCL10 production.

背景：气道上皮细胞是人类肺部的一个关键组成部分，有助于协调防御呼吸道病毒感染，全球每年有超过 250 万人死于呼吸道病毒感染。气道上皮的先天免疫活性依赖于 Toll 样受体 (TLR)、核苷酸结合和富含亮氨酸的重复吡啶结构域 (NLRP) 受体和胞质核酸传感器。ATP 结合盒 (ABC) 转运蛋白在生命的所有三个领域——古细菌、细菌和真核生物——中无处不在，并在人类气道上皮细胞中表达。ABCF1 是一种独特的 ABC 家族成员，缺乏跨膜结构域，已被定义为调节 CXCL10、干扰素-β 表达和下游 I 型干扰素反应的胞质核酸传感器。

方法：使用进行表达和定位实验原位在人肺组织中进行杂交和免疫组织化学，而在人气道上皮细胞中进行确认性转录物和蛋白质表达。使用 siRNA 方法在人气道上皮细胞系中进行功能实验。进行互补转录组分析以探索 ABCF1 对基因表达模式的贡献。

结果：使用存档的人肺和人气道上皮细胞，我们确认了这些组织样本中 ABCF1 基因和蛋白质表达的表达，其作用是介导 CXCL10 产生以响应 dsDNA 病毒模拟攻击。虽然，ABCF1 敲低与参与抗病毒反应的选定基因的减弱有关，但基因本体论分析揭示了 ABCF1 与 TLR 信号传导的更大相互作用，表明 ABCF1 在人类气道上皮细胞的先天免疫中具有多因素作用。

结论：ABCF1 是一种候选胞质核酸传感器和 TLR 信号调节剂，在人气道上皮细胞的基因和蛋白质水平上表达。ABCF1 蛋白发挥调节对病原体免疫反应的作用的精确水平仍有待确定，但预计将涉及 IRF-3 和 CXCL10 的产生。