Pathogenesis and outcome of VA1 astrovirus infection in the human brain are defined by disruption of neural functions and imbalanced host immune responses.

IF 6.7 1区 医学 Q1 Immunology and Microbiology
PLoS Pathogens Pub Date : 2023-08-18 eCollection Date: 2023-08-01 DOI:10.1371/journal.ppat.1011544
Olga A Maximova, Melodie L Weller, Tammy Krogmann, Daniel E Sturdevant, Stacy Ricklefs, Kimmo Virtaneva, Craig Martens, Kurt Wollenberg, Mahnaz Minai, Ian N Moore, Craig S Sauter, Juliet N Barker, W Ian Lipkin, Danielle Seilhean, Avindra Nath, Jeffrey I Cohen
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引用次数: 0

Abstract

Astroviruses (AstVs) can cause of severe infection of the central nervous system (CNS) in immunocompromised individuals. Here, we identified a human AstV of the VA1 genotype, HAstV-NIH, as the cause of fatal encephalitis in an immunocompromised adult. We investigated the cells targeted by AstV, neurophysiological changes, and host responses by analyzing gene expression, protein expression, and cellular morphology in brain tissue from three cases of AstV neurologic disease (AstV-ND). We demonstrate that neurons are the principal cells targeted by AstV in the brain and that the cerebellum and brainstem have the highest burden of infection. Detection of VA1 AstV in interconnected brain structures such as thalamus, deep cerebellar nuclei, Purkinje cells, and pontine nuclei indicates that AstV may spread between connected neurons transsynaptically. We found transcriptional dysregulation of neural functions and disruption of both excitatory and inhibitory synaptic innervation of infected neurons. Importantly, transcriptional dysregulation of neural functions occurred in fatal cases, but not in a patient that survived AstV-ND. We show that the innate, but not adaptive immune response was transcriptionally driving host defense in the brain of immunocompromised patients with AstV-ND. Both transcriptome and molecular pathology studies showed that most of the cellular changes were associated with CNS-intrinsic cells involved in phagocytosis and injury repair (microglia, perivascular/parenchymal border macrophages, and astrocytes), but not CNS-extrinsic cells (T and B cells), suggesting an imbalance of innate and adaptive immune responses to AstV infection in the brain as a result of the underlying immunodeficiencies. These results show that VA1 AstV infection of the brain in immunocompromised humans is associated with imbalanced host defense responses, disruption of neuronal somatodendritic compartments and synapses and increased phagocytic cellular activity. Improved understanding of the response to viral infections of the human CNS may provide clues for how to manipulate these processes to improve outcomes.

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VA1 星状病毒感染人脑的发病机制和结果取决于神经功能的破坏和宿主免疫反应的失衡。
Astroviruses(AstVs)可导致免疫力低下者的中枢神经系统(CNS)受到严重感染。在这里,我们确定了一种 VA1 基因型的人类 AstV--HAstV-NIH--是导致一名免疫力低下的成年人患致命性脑炎的原因。我们通过分析三例 AstV 神经系统疾病(AstV-ND)患者脑组织中的基因表达、蛋白表达和细胞形态,研究了 AstV 的靶细胞、神经生理学变化和宿主反应。我们证明神经元是 AstV 在大脑中的主要靶细胞,小脑和脑干的感染负荷最高。在丘脑、小脑深部核团、浦肯野细胞和桥脑核团等相互连接的大脑结构中检测到 VA1 AstV 表明,AstV 可能通过突触在连接的神经元之间传播。我们发现神经功能的转录失调以及受感染神经元的兴奋性和抑制性突触神经支配的破坏。重要的是,神经功能的转录失调发生在死亡病例中,而在 AstV-ND 存活的患者中却没有发生。我们的研究表明,先天性免疫反应(而非适应性免疫反应)转录驱动了免疫功能低下的 AstV-ND 患者大脑中的宿主防御功能。转录组和分子病理学研究表明,大多数细胞变化与参与吞噬和损伤修复的中枢神经系统内细胞(小胶质细胞、血管周围/实质边缘巨噬细胞和星形胶质细胞)有关,而与中枢神经系统外细胞(T 细胞和 B 细胞)无关,这表明由于潜在的免疫缺陷,大脑中先天性免疫反应和适应性免疫反应对 AstV 感染的反应失衡。这些结果表明,免疫功能低下的人类脑部感染 VA1 AstV 与宿主防御反应失衡、神经元体突区和突触破坏以及吞噬细胞活性增加有关。提高对人类中枢神经系统病毒感染反应的认识可能会为如何操纵这些过程以改善结果提供线索。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
PLoS Pathogens
PLoS Pathogens 生物-病毒学
CiteScore
11.40
自引率
3.00%
发文量
598
审稿时长
2 months
期刊介绍: Bacteria, fungi, parasites, prions and viruses cause a plethora of diseases that have important medical, agricultural, and economic consequences. Moreover, the study of microbes continues to provide novel insights into such fundamental processes as the molecular basis of cellular and organismal function.
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