Andersen Nanna-Sophie B, Larsen Simon M, Nissen Sara K, Jørgensen Sofie E, Mardahl Maibritt, Christiansen Mette, Kay Lise, Mogensen Trine H
Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
Front Microbiol. 2019 Jul 9;10:1495. doi: 10.3389/fmicb.2019.01495. eCollection 2019.
Poliovirus (PV) is one of the most studied viruses. Despite efforts to understand PV infection within the host, fundamental questions remain unanswered. These include the mechanisms determining the progression to viremia, the pathogenesis of neuronal infection and paralysis in only a minority of patients. Because of the rare disease phenotype of paralytic poliomyelitis (PPM), we hypothesize that a genetic etiology may contribute to the disease course and outcome.
We used whole-exome sequencing (WES) to investigate the genetic profile of 18 patients with PPM. Functional analyses were performed on peripheral blood mononuclear cells (PBMCs) and monocyte-derived macrophages (MdMs).
We identified rare variants in host genes involved in interferon signaling, viral replication, apoptosis, and autophagy. Upon PV infection of MdMs, we observed a tendency toward increased viral burden in patients compared to controls, suggesting reduced control of PV infection. In MdMs from patients, the IFNβ response correlated with the viral burden.
We suggest that genetic variants in innate immune defenses and cell death pathways contribute to the clinical presentation of PV infection. Importantly, this study is the first to uncover the genetic profile in patients with PPM combined with investigations of immune responses and viral burden in primary cells.
脊髓灰质炎病毒（PV）是研究最为深入的病毒之一。尽管人们努力了解PV在宿主体内的感染情况，但一些基本问题仍未得到解答。这些问题包括决定病毒血症进展的机制、仅少数患者发生神经元感染和麻痹的发病机制。由于麻痹性脊髓灰质炎（PPM）疾病表型罕见，我们推测遗传病因可能影响疾病进程和结局。
我们使用全外显子组测序（WES）来研究18例PPM患者的基因谱。对外周血单核细胞（PBMC）和单核细胞衍生巨噬细胞（MdM）进行功能分析。
我们在参与干扰素信号传导、病毒复制、凋亡和自噬的宿主基因中鉴定出罕见变异。在MdM感染PV后，我们观察到与对照组相比，患者的病毒载量有增加趋势，提示对PV感染的控制减弱。在患者的MdM中，IFNβ反应与病毒载量相关。
我们认为先天免疫防御和细胞死亡途径中的基因变异导致了PV感染的临床表现。重要的是，本研究首次揭示了PPM患者的基因谱，并结合了对原代细胞免疫反应和病毒载量的研究。
