■疱疹病毒,包括玫瑰病毒,与自身免疫性疾病有关.这些感染的普遍存在和慢性性质使得很难在急性感染和随后的自身免疫发展之间建立因果关系。我们已经证明了鼠玫瑰病毒(MRV),与人类玫瑰病毒高度相关,新生儿感染后可诱发胸腺萎缩和中枢耐受破坏。此外,新生儿MRV感染导致成年小鼠自身免疫的发展,在急性感染消退后很久。这表明MRV诱导持久的免疫失调。
■在当前的研究中,我们利用单细胞RNA测序(scRNAseq)研究了MRV在胸腺中的嗜性,并确定了被新生儿MRV感染破坏的胸腺中的细胞过程.然后,我们利用向性数据建立了细胞培养系统。
■这里,我们描述了MRV在急性新生儿感染期间如何改变胸腺转录组.我们发现MRV感染导致炎症发生重大变化,感染胸腺的分化和细胞周期途径。我们还观察到特定细胞群体的相对数量的变化。此外,利用晚期病毒转录本的表达作为病毒复制的代理,我们确定了胸腺中MRV的细胞嗜性。这种方法表明,双重否定,双正,和CD4单阳性胸腺细胞,以及髓样胸腺上皮细胞在体内被MRV感染。最后,通过将伪时间分析应用于病毒转录本,我们称之为“伪动力学”,“我们确定了与特定细胞类型和感染状态相关的病毒基因转录模式。我们利用这些信息建立了第一个体外易感MRV感染的细胞培养系统。
■我们的研究提供了新生儿感染后胸腺中玫瑰病毒嗜性的第一个完整图景。此外,我们确定了急性新生儿MRV感染期间胸腺细胞群的主要转录组改变.这些研究提供了对新生儿MRV感染后发生的早期事件的重要见解,这些事件破坏了中枢耐受性并促进了自身免疫性疾病。
UNASSIGNED: Herpesviruses, including the roseoloviruses, have been linked to autoimmune disease. The ubiquitous and chronic nature of these infections have made it difficult to establish a causal relationship between acute infection and subsequent development of autoimmunity. We have shown that murine roseolovirus (MRV), which is highly related to human roseoloviruses, induces thymic atrophy and disruption of central tolerance after neonatal infection. Moreover, neonatal MRV infection results in development of autoimmunity in adult mice, long after resolution of acute infection. This suggests that MRV induces durable immune dysregulation.
UNASSIGNED: In the current studies, we utilized single-cell RNA sequencing (scRNAseq) to study the
tropism of MRV in the thymus and determine cellular processes in the thymus that were disrupted by neonatal MRV infection. We then utilized
tropism data to establish a cell culture system.
UNASSIGNED: Herein, we describe how MRV alters the thymic transcriptome during acute neonatal infection. We found that MRV infection resulted in major shifts in inflammatory, differentiation and cell cycle pathways in the infected thymus. We also observed shifts in the relative number of specific cell populations. Moreover, utilizing expression of late viral transcripts as a proxy of viral replication, we identified the cellular
tropism of MRV in the thymus. This approach demonstrated that double negative, double positive, and CD4 single positive thymocytes, as well as medullary thymic epithelial cells were infected by MRV in vivo. Finally, by applying pseudotime analysis to viral transcripts, which we refer to as \"pseudokinetics,\" we identified viral gene transcription patterns associated with specific cell types and infection status. We utilized this information to establish the first cell culture systems susceptible to MRV infection in vitro.
UNASSIGNED: Our research provides the first complete picture of roseolovirus
tropism in the thymus after neonatal infection. Additionally, we identified major transcriptomic alterations in cell populations in the thymus during acute neonatal MRV infection. These studies offer important insight into the early events that occur after neonatal MRV infection that disrupt central tolerance and promote autoimmune disease.