Background Chronic norovirus infection (CNI) causes significant morbidity in immunocompromised patients. No effective prevention or treatment currently exists. Methods Two patients with inborn errors of immunity, X-linked severe combined immunodeficiency (X-SCID) and DOCK8 deficiency, were followed longitudinally for clinical course, immune reconstitution, norovirus-specific T-cell (NST) response, B-cell reconstitution, and norovirus-specific antibody production. Samples were obtained in the peri-hematopoietic stem cell transplant (HSCT) setting before and after CNI clearance. The norovirus strain causing CNI was followed longitudinally for norovirus stool viral loads and sequencing. Results The noroviruses were identified as GII.4 Sydney[P4 New Orleans] in 1 patient and GII.17[P17] in the other. An exacerbation of diarrhea post-HSCT in the patient with X-SCID was consistent with norovirus infection but not with graft-versus-host disease on pathologic samples. Both patients recovered polyfunctional NSTs in the CD4 and CD8 T-cell compartments that recognized multiple norovirus structural and nonstructural viral antigens. T-cell responses were minimal during active CNI but detectable after resolution. Mapping of NST responses between the patient with DOCK8 deficiency and his matched sibling donor were nearly identical. B-cell reconstitution or new endogenous antibody production for immunoglobulin A or immunoglobulin G was not observed. Conclusions This report is the first to demonstrate reconstitution of NST immunity after HSCT closely temporally aligned with clearance of CNI, suggesting that cellular immunity is sufficient for norovirus clearance.

中文翻译：

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先天性免疫缺陷和慢性诺如病毒感染患者造血干细胞移植后诺如病毒特异性 T 细胞反应的重建


背景 慢性诺如病毒感染 （CNI） 导致免疫功能低下患者的显着发病率。目前尚无有效的预防或治疗方法。方法 对 2 例先天性免疫缺陷 X 连锁重症联合免疫缺陷病 （X-SCID） 和 DOCK8 缺陷患者进行纵向随访，了解临床病程、免疫重建、诺如病毒特异性 T 细胞 （NST） 反应、B 细胞重建和诺如病毒特异性抗体产生。在 CNI 清除前后，在造血周围干细胞移植 （HSCT） 环境中获得样本。纵向跟踪引起 CNI 的诺如病毒株粪便病毒载量和测序。结果 1 例患者诺如病毒检测为 GII.4 Sydney[P4 New Orleans]，1 例患者检测为 GII.17[P17]。X-SCID 患者 HSCT 后腹泻加重与诺如病毒感染一致，但与病理样本上的移植物抗宿主病不一致。两名患者在 CD4 和 CD8 T 细胞区室中回收了识别多种诺如病毒结构性和非结构性病毒抗原的多功能 NST。在活动性 CNI 期间 T 细胞反应最小，但在消退后可检测到。DOCK8 缺陷患者与其匹配的兄弟姐妹供体之间的 NST 反应映射几乎相同。未观察到免疫球蛋白 A 或免疫球蛋白 G 的 B 细胞重建或新的内源性抗体产生。结论 本报告首次证明 HSCT 后 NST 免疫的重建与 CNI 的清除在时间上密切相关，表明细胞免疫足以清除诺如病毒。