Depletion of Alveolar Macrophages Does Not Prevent Hantavirus Disease Pathogenesis in Golden Syrian Hamsters.
Depletion of Alveolar Macrophages Does Not Prevent Hantavirus Disease Pathogenesis in Golden Syrian Hamsters.
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DOI：
10.1128/jvi.00304-16
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发表时间：
2016-07-15
影响因子：
5.4
通讯作者：
Hooper JW
中科院分区：
文献类型：
--
作者：
Hammerbeck CD;Brocato RL;Bell TM;Schellhase CW;Mraz SR;Queen LA;Hooper JW
安第斯病毒(ANDV)与人类一种致命的血管渗漏综合征有关，称为汉坦病毒肺综合征(HPS)。与HPS相关的大量血管渗漏的机制尚不清楚，然而，免疫反应成分的失调通常被认为是可能的原因。肺泡巨噬细胞位于肺泡内，是许多空气传播病原体的第一道防线。为了确定肺泡巨噬细胞是否在HPS的发病机制中起作用，在一种与人类HPS非常相似的成年啮齿动物模型中，肺泡巨噬细胞被耗尽。叙利亚仓鼠接受气管内氯屈膦酸盐包裹的脂质体或对照脂质体治疗，然后用ANDV激发。使用氯屈膦酸脂质体治疗可显著减少肺泡巨噬细胞，但耗竭并不能阻止发病或延长疾病。耗竭也不能显著减少感染ANDV的金黄地鼠肺内病毒的数量，但改变了鼻腔攻击后早期中性粒细胞募集、MIP-1α和MIP-2趋化因子的表达以及金黄地鼠肺泡灌洗液中血管内皮生长因子的水平。这些数据表明，肺泡巨噬细胞在雾化吸入ANDV后早期可能起到有限的保护作用，但不直接参与HPS模型中汉坦病毒病的发病。重要性汉坦病毒继续在全球范围内引起疾病，目前还没有FDA许可的疫苗、有效的暴露后预防措施或治疗药物。这在很大程度上可以归因于对汉坦病毒病发病机制的了解不足。长期以来，汉坦病毒病一直被认为是一种免疫介导性疾病；然而，通过直接操纵叙利亚仓鼠模型，我们继续消除个别免疫细胞类型。作为呼吸道中数量最多的免疫细胞，肺泡巨噬细胞可以抵抗汉坦病毒的感染，但这些抗病毒反应也可能导致汉坦病毒病。在这里，我们证明，就像我们之前的T和B细胞研究一样，肺泡巨噬细胞既不能预防汉坦病毒感染，也不能引起汉坦病毒病。虽然这些研究反映了仓鼠模型的发病机制，但它们应该有助于我们排除特定的细胞类型，并促使我们考虑其他潜在的疾病机制，以努力改善人类HPS的结局。
Andes virus (ANDV) is associated with a lethal vascular leak syndrome in humans termed hantavirus pulmonary syndrome (HPS). The mechanism for the massive vascular leakage associated with HPS is poorly understood; however, dysregulation of components of the immune response is often suggested as a possible cause. Alveolar macrophages are found in the alveoli of the lung and represent the first line of defense to many airborne pathogens. To determine whether alveolar macrophages play a role in HPS pathogenesis, alveolar macrophages were depleted in an adult rodent model of HPS that closely resembles human HPS. Syrian hamsters were treated, intratracheally, with clodronate-encapsulated liposomes or control liposomes and were then challenged with ANDV. Treatment with clodronate-encapsulated liposomes resulted in significant reduction in alveolar macrophages, but depletion did not prevent pathogenesis or prolong disease. Depletion also did not significantly reduce the amount of virus in the lung of ANDV-infected hamsters but altered neutrophil recruitment, MIP-1α and MIP-2 chemokine expression, and vascular endothelial growth factor (VEGF) levels in hamster bronchoalveolar lavage (BAL) fluid early after intranasal challenge. These data demonstrate that alveolar macrophages may play a limited protective role early after exposure to aerosolized ANDV but do not directly contribute to hantavirus disease pathogenesis in the hamster model of HPS. IMPORTANCE Hantaviruses continue to cause disease worldwide for which there are no FDA-licensed vaccines, effective postexposure prophylactics, or therapeutics. Much of this can be attributed to a poor understanding of the mechanism of hantavirus disease pathogenesis. Hantavirus disease has long been considered an immune-mediated disease; however, by directly manipulating the Syrian hamster model, we continue to eliminate individual immune cell types. As the most numerous immune cells present in the respiratory tract, alveolar macrophages are poised to defend against hantavirus infection, but those antiviral responses may also contribute to hantavirus disease. Here, we demonstrate that, like in our prior T and B cell studies, alveolar macrophages neither prevent hantavirus infection nor cause hantavirus disease. While these studies reflect pathogenesis in the hamster model, they should help us rule out specific cell types and prompt us to consider other potential mechanisms of disease in an effort to improve the outcome of human HPS.