Tumor Progression Locus 2 Protects against Acute Respiratory Distress Syndrome in Influenza A Virus-Infected Mice.
Tumor Progression Locus 2 Protects against Acute Respiratory Distress Syndrome in Influenza A Virus-Infected Mice.
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DOI：
10.1128/spectrum.01136-22
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发表时间：
2022-10-26
影响因子：
3.7
通讯作者：
Watford, Wendy T.
中科院分区：
文献类型：
--
作者：
Latha, Krishna;Rao, Sanjana;Sakamoto, Kaori;Watford, Wendy T.
严重流感患者的过度炎症可能导致急性肺损伤，从而导致急性呼吸窘迫综合征（ARDS）。ARDS与严重损害气体交换的肺泡损伤和肺水肿相关，导致缺氧。由于目前还没有FDA批准的ARDS治疗方法，因此了解导致病毒诱导的ARDS发展的因素以改善预防、诊断和治疗非常重要。我们先前已经表明，丝氨酸-苏氨酸促分裂原活化蛋白激酶Tp 12（MAP 3 K8或COT）缺陷的小鼠死于典型的低致病性甲型流感病毒株（IAV; HKX 31，H3 N2 [x31]）感染。本研究的目的是评估甲型流感病毒感染的Tp 12 −/−小鼠的临床和组织病理学，以深入了解疾病机制。我们假设Tp 12 −/−小鼠死于IAV感染，原因是发生了ARDS样疾病和肺功能障碍。我们观察到感染后7 - 9天（dpi），IAV感染Tp 12 −/−小鼠肺中肺泡间隔坏死、透明膜、胸膜炎、水肿和乳酸脱氢酶（LDH）水平高于野生型（WT）小鼠。值得注意的是，WT小鼠显示出上皮再生的迹象，表明修复和恢复，这在Tpl 2 −/−小鼠中减少。此外，与人类ARDS病例相关的生物标志物在感染后7天在Tp 12 −/−小鼠中上调，表明Tp 12 −/−小鼠对IAV感染的反应具有ARDS样表型。重要性本研究证实了丝氨酸-苏氨酸丝裂原活化蛋白激酶Tp 12在流感病毒发病机制中的保护作用，并揭示了宿主Tp 12缺陷足以将低致病性甲型流感病毒感染转化为严重的流感疾病，其在组织病理学和转录上都类似于ARDS。因此，IAV感染的Tp 12 −/−小鼠代表了一种用于研究ARDS样疾病的新型小鼠模型，可以提高我们对这种侵袭性疾病的理解，并有助于设计更好的诊断和治疗方法。
Excessive inflammation in patients with severe influenza disease may lead to acute lung injury that results in acute respiratory distress syndrome (ARDS). ARDS is associated with alveolar damage and pulmonary edema that severely impair gas exchange, leading to hypoxia. With no existing FDA-approved treatment for ARDS, it is important to understand the factors that lead to virus-induced ARDS development to improve prevention, diagnosis, and treatment. We have previously shown that mice deficient in the serine-threonine mitogen-activated protein kinase, Tpl2 (MAP3K8 or COT), succumb to infection with a typically low-pathogenicity strain of influenza A virus (IAV; HKX31, H3N2 [x31]). The goal of the current study was to evaluate influenza A virus-infected Tpl2−/− mice clinically and histopathologically to gain insight into the disease mechanism. We hypothesized that Tpl2−/− mice succumb to IAV infection due to development of ARDS-like disease and pulmonary dysfunction. We observed prominent signs of alveolar septal necrosis, hyaline membranes, pleuritis, edema, and higher lactate dehydrogenase (LDH) levels in the lungs of IAV-infected Tpl2−/− mice compared to wild-type (WT) mice from 7 to 9 days postinfection (dpi). Notably, WT mice showed signs of regenerating epithelium, indicative of repair and recovery, that were reduced in Tpl2−/− mice. Furthermore, biomarkers associated with human ARDS cases were upregulated in Tpl2−/− mice at 7 dpi, demonstrating an ARDS-like phenotype in Tpl2−/− mice in response to IAV infection. IMPORTANCE This study demonstrates the protective role of the serine-threonine mitogen-activated protein kinase, Tpl2, in influenza virus pathogenesis and reveals that host Tpl2 deficiency is sufficient to convert a low-pathogenicity influenza A virus infection into severe influenza disease that resembles ARDS, both histopathologically and transcriptionally. The IAV-infected Tpl2−/− mouse thereby represents a novel murine model for studying ARDS-like disease that could improve our understanding of this aggressive disease and assist in the design of better diagnostics and treatments.
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发表时间：
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