Illumination of parainfluenza virus infection and transmission in living animals reveals a tissue-specific dichotomy.
Illumination of parainfluenza virus infection and transmission in living animals reveals a tissue-specific dichotomy.
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DOI：
10.1371/journal.ppat.1002134
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发表时间：
2011-07
期刊：
影响因子：
6.7
通讯作者：
Russell CJ
中科院分区：
文献类型：
--
作者：
Burke CW;Mason JN;Surman SL;Jones BG;Dalloneau E;Hurwitz JL;Russell CJ
副流感病毒（PIV）是高度传染性的呼吸道副粘病毒，并且是下呼吸道（LRT）疾病的主要原因。由于没有疫苗或抗病毒药物，非药物干预是控制这些病原体的唯一手段。在这里，我们使用生物发光成像可视化小鼠PIV 1（仙台病毒）感染的空间和时间的进展后，活小鼠鼻内接种或接触暴露。产生非减毒的荧光素酶报告病毒（rSeV-luc（M-F*））以允许可视化，所述非减毒的荧光素酶报告病毒表达高水平的荧光素酶，但在体外和体内与野生型仙台病毒表型相似。在直接鼻内接种后，我们意外地观察到上呼吸道（URT）和气管在导致肺部感染或病理很少的条件下支持稳健感染，包括低病毒接种、减毒病毒和对肺部感染具有遗传抗性的小鼠品系。URT和气管对感染的高风险导致100%传播给幼稚接触受体，即使在低剂量（70 PFU）接种遗传抗性BALB/c供体小鼠后。传播的时间与供体动物的URT和气管中高病毒滴度的时间一致，但与供体肺部的感染水平无关。因此，这些数据揭示了与URT感染相关的传播性与肺部感染和免疫反应引起的发病机制之间的脱节。传播后的自然感染在URT和气管中普遍稳健，但在肺中有限，即使在遗传易感的129/SvJ小鼠中也诱导保护性免疫而不减轻体重。总体而言，这些结果揭示了PIV感染在URT和气管与肺之间的二分法，并为研究发病机制、开发活病毒疫苗和测试抗病毒疗法定义了一个新的模型。人副流感病毒（HPIV）是儿科下呼吸道感染住院的主要原因，但尚不清楚为什么原发性感染通常诱导免疫而不引起严重病理。为了研究PIV在活体动物呼吸道内传播的决定因素，我们开发了一种模型，用于感染仙台病毒（HPIV 1的鼠对应物）的活体小鼠的非侵入性成像。该系统使我们能够测量的时间和空间动态的副粘病毒感染后，直接接种或传播的活动物的呼吸道。我们发现，上呼吸道和气管高度容许感染，即使在限制下呼吸道感染和发病的条件下。传播的时间与供体小鼠上呼吸道和气管中的高病毒生长一致，与肺部感染的程度无关。在传播后，感染优先在上呼吸道和气管传播，诱导保护性免疫而不减轻体重。我们的工作揭示了仙台病毒的传播性和致病性之间的脱节，这里开发的实验模型将有助于研究PIV的发病机制。
The parainfluenza viruses (PIVs) are highly contagious respiratory paramyxoviruses and a leading cause of lower respiratory tract (LRT) disease. Since no vaccines or antivirals exist, non-pharmaceutical interventions are the only means of control for these pathogens. Here we used bioluminescence imaging to visualize the spatial and temporal progression of murine PIV1 (Sendai virus) infection in living mice after intranasal inoculation or exposure by contact. A non-attenuated luciferase reporter virus (rSeV-luc(M-F*)) that expressed high levels of luciferase yet was phenotypically similar to wild-type Sendai virus in vitro and in vivo was generated to allow visualization. After direct intranasal inoculation, we unexpectedly observed that the upper respiratory tract (URT) and trachea supported robust infection under conditions that result in little infection or pathology in the lungs including a low inoculum of virus, an attenuated virus, and strains of mice genetically resistant to lung infection. The high permissivity of the URT and trachea to infection resulted in 100% transmission to naïve contact recipients, even after low-dose (70 PFU) inoculation of genetically resistant BALB/c donor mice. The timing of transmission was consistent with the timing of high viral titers in the URT and trachea of donor animals but was independent of the levels of infection in the lungs of donors. The data therefore reveals a disconnect between transmissibility, which is associated with infection in the URT, and pathogenesis, which arises from infection in the lungs and the immune response. Natural infection after transmission was universally robust in the URT and trachea yet limited in the lungs, inducing protective immunity without weight loss even in genetically susceptible 129/SvJ mice. Overall, these results reveal a dichotomy between PIV infection in the URT and trachea versus the lungs and define a new model for studies of pathogenesis, development of live virus vaccines, and testing of antiviral therapies. Human parainfluenza viruses (HPIVs) are a leading cause of pediatric hospitalization for lower respiratory tract infection, yet it is unknown why primary infection typically induces immunity without causing severe pathology. To study the determinants of PIV spread within the respiratory tracts of living animals, we developed a model for non-invasive imaging of living mice infected with Sendai virus, the murine counterpart of HPIV1. This system allowed us to measure the temporal and spatial dynamics of paramyxovirus infection throughout the respiratory tracts of living animals after direct inoculation or transmission. We found that the upper respiratory tract and trachea were highly permissive to infection, even under conditions that limit lower respiratory infection and pathogenesis. The timing of transmission coincided with high virus growth in the upper respiratory tracts and trachea of donor mice independent of the extent of infection in the lungs. After transmission, infection spread preferentially in the upper respiratory tract and trachea, inducing protective immunity without weight loss. Our work reveals a disconnect between Sendai virus transmissibility and pathogenicity, and the experimental model developed here will be instrumental in studying PIV pathogenesis.
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