Klimaj Stefan D, LaPointe Autumn, Martinez Kimberly, Acosta Eduardo Hernandez, Kell Alison M
Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, New Mexico, United States of America.
PLoS Pathog. 2024 Nov 25;20(11):e1012728. doi: 10.1371/journal.ppat.1012728. eCollection 2024 Nov.
Pathogenic hantaviruses are maintained world-wide within wild, asymptomatic rodent reservoir hosts, with increasingly frequent human spillover infections resulting in severe hemorrhagic fever or cardio-pulmonary disease. With no approved therapeutics or vaccines, research has, until recently, focused on understanding the drivers of immune-mediated pathogenesis. An emerging body of work is now investigating the mechanisms that allow for asymptomatic, persistent infections of mammalian reservoir hosts with highly pathogenic RNA viruses. Despite limited experimental data, several hypotheses have arisen to explain limited or absent disease pathology in reservoir hosts. In this study, we directly tested two leading hypotheses: 1) that reservoir host cells induce a generally muted response to viral insults, and 2) that these viruses employ host-specific mechanisms of innate antiviral antagonism to limit immune activation in reservoir cells. We demonstrate that, in contrast to human endothelial cells which mount a robust antiviral and inflammatory response to pathogenic hantaviruses, primary Norway rat endothelial cells do not induce antiviral gene expression in response to infection with their endemic hantavirus, Seoul orthohantavirus (SEOV). Reservoir rat cells do, however, induce strong innate immune responses to exogenous stimulatory RNAs, type I interferon, and infection with Hantaan virus, a closely related hantavirus for which the rat is not a natural reservoir. We also find that SEOV-infected rat endothelial cells remain competent for immune activation induced by exogenous stimuli or subsequent viral infection. Importantly, these findings support an alternative model for asymptomatic persistence within hantavirus reservoir hosts: that efficient viral replication within reservoir host cells may prevent the exposure of critical motifs for cellular antiviral recognition and thus limits immune activation that would otherwise result in viral clearance and/or immune-mediated disease. Defining the mechanisms that allow for infection tolerance and persistence within reservoir hosts will reveal novel strategies for viral countermeasures against these highly pathogenic zoonotic threats.
致病性汉坦病毒在全球范围内的野生无症状啮齿类动物宿主中持续存在，人类溢出感染日益频繁，导致严重的出血热或心肺疾病。由于没有获批的治疗方法或疫苗，直到最近，研究一直集中在了解免疫介导发病机制的驱动因素上。现在，越来越多的研究工作正在探究哺乳动物宿主细胞能够无症状持续感染高致病性RNA病毒的机制。尽管实验数据有限，但已经出现了几种假说来解释宿主中疾病病理有限或不存在的原因。在本研究中，我们直接测试了两个主要假说：1）宿主细胞对病毒攻击通常产生微弱反应；2）这些病毒利用宿主特异性的先天抗病毒拮抗机制来限制宿主细胞中的免疫激活。我们证明，与对致病性汉坦病毒产生强烈抗病毒和炎症反应的人类内皮细胞不同，原代挪威大鼠内皮细胞在感染其地方性汉坦病毒——汉城正汉坦病毒（SEOV）时，不会诱导抗病毒基因表达。然而，宿主大鼠细胞对外源刺激性RNA、I型干扰素以及感染大鼠并非天然宿主的密切相关汉坦病毒——汉滩病毒会产生强烈的先天免疫反应。我们还发现，感染SEOV的大鼠内皮细胞对外源刺激或随后的病毒感染诱导的免疫激活仍有反应。重要的是，这些发现支持了汉坦病毒宿主中无症状持续感染的另一种模型：宿主细胞内高效的病毒复制可能会阻止细胞抗病毒识别关键基序的暴露，从而限制免疫激活，否则这种免疫激活会导致病毒清除和/或免疫介导的疾病。确定宿主中允许感染耐受和持续存在的机制将揭示针对这些高致病性人畜共患病威胁的病毒对策新策略。
