MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK.
Translational Gastroenterology Unit, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK.
Nat Commun. 2018 Nov 19;9(1):4883. doi: 10.1038/s41467-018-07329-0.
Non-typhoidal Salmonella (NTS) are highly prevalent food-borne pathogens. Recently, a highly invasive, multi-drug resistant S. Typhimurium, ST313, emerged as a major cause of bacteraemia in children and immunosuppressed adults, however the pathogenic mechanisms remain unclear. Here, we utilize invasive and non-invasive Salmonella strains combined with single-cell RNA-sequencing to study the transcriptome of individual infected and bystander monocyte-derived dendritic cells (MoDCs) implicated in disseminating invasive ST313. Compared with non-invasive Salmonella, ST313 directs a highly heterogeneous innate immune response. Bystander MoDCs exhibit a hyper-activated profile potentially diverting adaptive immunity away from infected cells. MoDCs harbouring invasive Salmonella display higher expression of IL10 and MARCH1 concomitant with lower expression of CD83 to evade adaptive immune detection. Finally, we demonstrate how these mechanisms conjointly restrain MoDC-mediated activation of Salmonella-specific CD4 T cell clones. Here, we show how invasive ST313 exploits discrete evasion strategies within infected and bystander MoDCs to mediate its dissemination in vivo.
非伤寒沙门氏菌（NTS）是高度流行的食源性病原体。最近，一种高度侵袭性、多药耐药的 S. Typhimurium，ST313，成为儿童和免疫抑制成年人菌血症的主要原因，但其发病机制尚不清楚。在这里，我们利用侵袭性和非侵袭性沙门氏菌菌株结合单细胞 RNA 测序来研究参与传播侵袭性 ST313 的感染和旁观者单核细胞衍生树突状细胞（MoDC）的转录组。与非侵袭性沙门氏菌相比，ST313 指导高度异质的先天免疫反应。旁观者 MoDC 表现出高度激活的表型，可能使适应性免疫偏离受感染的细胞。携带侵袭性沙门氏菌的 MoDC 显示出更高水平的 IL10 和 MARCH1 的表达，同时降低 CD83 的表达，以逃避适应性免疫检测。最后，我们证明了这些机制如何共同抑制 MoDC 介导的沙门氏菌特异性 CD4 T 细胞克隆的激活。在这里，我们展示了侵袭性 ST313 如何在感染和旁观者 MoDC 内利用离散的逃避策略来介导其在体内的传播。
