Influenza A Virus Infection Causes Chronic Lung Disease Linked to Sites of Active Viral RNA Remnants.
Influenza A Virus Infection Causes Chronic Lung Disease Linked to Sites of Active Viral RNA Remnants.
复制标题
DOI：
10.4049/jimmunol.1800671
复制
发表时间：
2018-10-15
期刊：
影响因子：
--
通讯作者：
Holtzman MJ
中科院分区：
文献类型：
--
作者：
Keeler SP;Agapov EV;Hinojosa ME;Letvin AN;Wu K;Holtzman MJ
临床和实验观察表明，慢性肺部疾病与呼吸道病毒感染有关。然而，这种关系的长期方面还没有使用在人类和相应的动物模型中以适当的高水平复制的病毒来定义。在这里，我们发现甲型流感病毒感染使小鼠肺部病毒载量增加1×106倍，急性疾病的严重程度呈剂量依赖性。此外，这些事件发生后，负链和正链病毒RNA残留持续15周，慢性肺部疾病至少持续26周。该疾病的表现是细支气管化和粘液产生的局灶性区域，与肺部未受累区域相比，这些区域沿着病毒RNA残留物以及粘蛋白Muc 5 ac和Il 13 mRNA水平升高。过度的粘液产生和相关的气道高反应性（但不是纤维化或肺气肿）随着IL-13产生或信号传导的丧失而部分减弱（使用具有IL-13或STAT 6缺陷的小鼠）。这些缺陷导致肺中l17 a mRNA和嗜中性粒细胞的相互增加，然而，与IL-13缺陷相比，IL-13-IL-17 a或与STAT 6缺陷相比，这些疾病终点都没有改变。这些结果确定了一种有效的人类呼吸道病毒在活性病毒RNA残留部位局部产生慢性肺病的能力，这可能反映了病毒复制的位置，重新编程了该区域。疾病的病毒剂量依赖性还暗示高水平病毒复制和急性感染的严重程度是慢性肺部疾病（如哮喘和COPD）的决定因素，具有IL-13依赖性和IL-13/IL-17非依赖性机制。
Clinical and experimental observations suggest that chronic lung disease is linked to respiratory viral infection. However, the long-term aspect of this relationship is not yet defined using a virus that replicates at properly high levels in humans and a corresponding animal model. Here we show that influenza A virus infection achieves 1×106-fold increases in viral load in the lung and dose-dependent severity of acute illness in mice. Moreover, these events are followed by persistence of negative- and positive-strand viral-RNA remnants for 15 weeks and chronic lung disease for at least 26 weeks after infection. The disease is manifested by focal areas of bronchiolization and mucus production that contain increased levels of viral-RNA remnants along with mucin Muc5ac and Il13 mRNA compared to uninvolved areas of the lung. Excess mucus production and associated airway hyper-reactivity (but not fibrosis or emphysema) are partially attenuated with loss of IL-13 production or signaling (using mice with IL-13- or STAT6-deficiency). These deficiencies cause reciprocal increases in l17a mRNA and neutrophils in the lung, however, none of these disease endpoints are changed with IL-13–IL-17a-compared to IL-13-deficiency or STAT6-IL-17a-compared to STAT6-deficiency. The results establish the capacity of a potent human respiratory virus to produce chronic lung disease focally at sites of active viral-RNA remnants, likely reflecting locations of viral replication that reprogram the region. Viral dose-dependency of disease also implicates high-level viral replication and severity of acute infection as determinants of chronic lung diseases such as asthma and COPD with IL-13-dependent and IL-13/IL-17-independent mechanisms.
登录
查看更多内容
影响因子：
14.2
作者：
Castro, Mario;Schweiger, Toni;Yin-DeClue, Huiquing;Ramkumar, Thiruvamoor P.;Christie, Chandrika;Zheng, Jie;Cohen, Rebecca;Schechtman, Kenneth B.;Strunk, Robert;Bacharier, Leonard B.
通讯作者：
Bacharier, Leonard B.
DOI：
10.4049/jimmunol.1100500
发表时间：
2011-07-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Ather JL;Ckless K;Martin R;Foley KL;Suratt BT;Boyson JE;Fitzgerald KA;Flavell RA;Eisenbarth SC;Poynter ME
通讯作者：
Poynter ME
影响因子：
9.6
作者：
Byers, Derek E.;Wu, Kangyun;Holtzman, Michael J.
通讯作者：
Holtzman, Michael J.
DOI：
10.1165/2009-0122rc
发表时间：
2009-10-01
影响因子：
6.4
作者：
Agapov, Eugene;Battaile, John T.;Holtzman, Michael J.
通讯作者：
Holtzman, Michael J.
影响因子：
3.7
作者：
Empey, Kerry M.;Orend, Jacob G.;Kolls, Jay K.
通讯作者：
Kolls, Jay K.