Vascular leak ensues a vigorous proinflammatory cytokine response to Tacaribe arenavirus infection in AG129 mice.
Vascular leak ensues a vigorous proinflammatory cytokine response to Tacaribe arenavirus infection in AG129 mice.
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DOI：
10.1186/1743-422x-10-221
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发表时间：
2013-07-02
期刊：
影响因子：
4.8
通讯作者：
Gowen BB
中科院分区：
文献类型：
--
作者：
Sefing EJ;Wong MH;Larson DP;Hurst BL;Van Wettere AJ;Schneller SW;Gowen BB
塔卡里贝病毒（TCRV）是一种生物危害性较低的相对高致病性分支B新世界沙粒病毒，导致病毒性出血热综合征，并需要在最大限度的遏制设施不容易获得大多数研究人员。AG 129 I型和II型干扰素受体敲除小鼠已被证明对TCRV感染易感，但导致致死性疾病的致病机制尚不清楚。为了深入了解AG 129小鼠TCRV感染的发病机制，我们评估了感染过程中的血液学和细胞因子反应，以及血管内皮通透性的变化。我们还用MY-24治疗了TCRV攻击的小鼠，MY-24是一种在急性感染期间防止死亡而不影响病毒载量的化合物，并测量了感染后40天的血清和组织病毒滴度，以确定病毒是否最终在恢复的小鼠中被清除。我们发现，病毒血症和脾肿大的发展先于白色血细胞的升高和已知破坏内皮屏障的高水平促炎介质的检测，这可能有助于增加血管通透性和体重减轻，这在小鼠通常死于TCRV攻击前几天观察到。在用MY-24治疗的存活小鼠中，病毒血症和肝病毒滴度直到感染后2-3周才被清除，之后小鼠开始恢复减轻的体重。值得注意的是，在研究结束时，肺、脾、脑和肾组织中仍存在大量病毒载量。我们的研究结果表明，血管渗漏可能是TCRV感染小鼠死亡的一个促成因素，因为组织病理学结果通常是轻度至中度的，并且如MY-24治疗所证明的，动物可以在面对高病毒载量的情况下存活。
Tacaribe virus (TCRV) is a less biohazardous relative of the highly pathogenic clade B New World arenaviruses that cause viral hemorrhagic fever syndromes and require handling in maximum containment facilities not readily available to most researchers. AG129 type I and II interferon receptor knockout mice have been shown to be susceptible to TCRV infection, but the pathogenic mechanisms contributing to the lethal disease are unclear. To gain insights into the pathogenesis of TCRV infection in AG129 mice, we assessed hematologic and cytokine responses during the course of infection, as well as changes in the permeability of the vascular endothelium. We also treated TCRV-challenged mice with MY-24, a compound that prevents mortality without affecting viral loads during the acute infection, and measured serum and tissue viral titers out to 40 days post-infection to determine whether the virus is ultimately cleared in recovering mice. We found that the development of viremia and splenomegaly precedes an elevation in white blood cells and the detection of high levels of proinflammatory mediators known to destabilize the endothelial barrier, which likely contributes to the increased vascular permeability and weight loss that was observed several days prior to when the mice generally succumb to TCRV challenge. In surviving mice treated with MY-24, viremia and liver virus titers were not cleared until 2–3 weeks post-infection, after which the mice began to recover lost weight. Remarkably, substantial viral loads were still present in the lung, spleen, brain and kidney tissues at the conclusion of the study. Our findings suggest that vascular leak may be a contributing factor in the demise of TCRV-infected mice, as histopathologic findings are generally mild to moderate in nature, and as evidenced with MY-24 treatment, animals can survive in the face of high viral loads.