Transforming growth factor-β: activation by neuraminidase and role in highly pathogenic H5N1 influenza pathogenesis.
Transforming growth factor-β: activation by neuraminidase and role in highly pathogenic H5N1 influenza pathogenesis.
复制标题
DOI：
10.1371/journal.ppat.1001136
复制
发表时间：
2010-10-07
期刊：
影响因子：
6.7
通讯作者：
Schultz-Cherry S
中科院分区：
文献类型：
--
作者：
Carlson CM;Turpin EA;Moser LA;O'Brien KB;Cline TD;Jones JC;Tumpey TM;Katz JM;Kelley LA;Gauldie J;Schultz-Cherry S
转化生长因子 -β（TGF -β）是一种调节多种免疫过程的多功能细胞因子，几乎所有细胞都以一种无生物学活性的分子形式表达，称为潜伏性TGF -β（LTGF -β）。我们先前已经表明，在小鼠流感病毒感染期间，TGF -β活性增加，并提出神经氨酸酶（NA）蛋白介导这种激活作用。在当前的研究中，我们通过迁移率变动和酶抑制试验确定了来自流感病毒A/灰水鸭/澳大利亚/2/1979的NA激活LTGF -β的机制。我们还研究了通过复制缺陷型腺病毒载体给予外源性TGF -β是否能对H5N1流感发病机制提供保护，以及在病毒感染期间TGF -β的耗竭是否会增加小鼠的发病率。我们发现流感和细菌的NA都通过从LTGF -β上去除唾液酸基序来激活LTGF -β，每种NA对所切割的唾液酸连接具有特异性。此外，NA可能主要通过其酶活性激活LTGF -β，但蛋白酶也可能在这个过程中起作用。除了高致病性的H5N1毒株外，几种甲型流感病毒亚型（H1N1、H1N2、H3N2、H5N9、H6N1和H7N3）在体外和体内都能激活LTGF -β。在H5N1流感病毒感染的小鼠中添加外源性TGF -β可延迟死亡并降低病毒滴度，而在H5N1和2009年大流行的H1N1感染期间中和TGF -β会增加发病率。总之，这些数据表明微生物相关的NAs能够直接激活LTGF -β，并且TGF -β在保护宿主免受流感发病机制影响方面起着关键作用。
转化生长因子 -β（TGF -β）是一种多功能蛋白质，通过控制炎症反应的起始和消退作为免疫的全局调节因子。一种能够调节TGF -β激活的病原体可以在其宿主内为自身促进一种免疫特权状态。实际上，多种寄生虫、细菌和真菌病原体通过调节TGF -β成功地逃避了免疫反应。我们证明来自甲型流感病毒和产气荚膜梭菌的神经氨酸酶蛋白将无生物学活性的TGF -β转化为其活性形式。重要的是，在流感感染期间对TGF -β活性的调节影响小鼠中的病毒滴度和疾病结果，这表明TGF -β在流感发病机制中，特别是在感染期间保护宿主方面起着重要作用。这些研究表明来自不同微生物的神经氨酸酶可能能够直接调节TGF -β，这反过来可能在疾病中起重要作用。
Transforming growth factor-beta (TGF-β), a multifunctional cytokine regulating several immunologic processes, is expressed by virtually all cells as a biologically inactive molecule termed latent TGF-β (LTGF-β). We have previously shown that TGF-β activity increases during influenza virus infection in mice and suggested that the neuraminidase (NA) protein mediates this activation. In the current study, we determined the mechanism of activation of LTGF-β by NA from the influenza virus A/Gray Teal/Australia/2/1979 by mobility shift and enzyme inhibition assays. We also investigated whether exogenous TGF-β administered via a replication-deficient adenovirus vector provides protection from H5N1 influenza pathogenesis and whether depletion of TGF-β during virus infection increases morbidity in mice. We found that both the influenza and bacterial NA activate LTGF-β by removing sialic acid motifs from LTGF-β, each NA being specific for the sialic acid linkages cleaved. Further, NA likely activates LTGF-β primarily via its enzymatic activity, but proteases might also play a role in this process. Several influenza A virus subtypes (H1N1, H1N2, H3N2, H5N9, H6N1, and H7N3) except the highly pathogenic H5N1 strains activated LTGF-β in vitro and in vivo. Addition of exogenous TGF-β to H5N1 influenza virus–infected mice delayed mortality and reduced viral titers whereas neutralization of TGF-β during H5N1 and pandemic 2009 H1N1 infection increased morbidity. Together, these data show that microbe-associated NAs can directly activate LTGF-β and that TGF-β plays a pivotal role protecting the host from influenza pathogenesis. Transforming growth factor-beta (TGF-β) is a multifunctional protein that serves as a global regulator of immunity by controlling the initiation and resolution of inflammatory responses. A pathogen that can regulate TGF-β activation could promote an immune-privileged state for itself within its host. Indeed, multiple parasitic, bacterial, and fungal pathogens successfully evade immune responses by regulating TGF-β. We demonstrate that the neuraminidase proteins from influenza A viruses and Clostridium perfringens convert biologically inactive TGF-β to its active form. Importantly, modulation of TGF-β activity during influenza infection affects viral titers and disease outcome in mice, suggesting that TGF-β plays an important role in influenza pathogenesis, particularly in protecting the host during infection. These studies suggest that neuraminidases from diverse microbes may be able to directly regulate TGF-β, which may in turn play an important role in disease.
登录
查看更多内容
影响因子：
2.9
作者：
ABE, M;HARPEL, JG;RIFKIN, DB
通讯作者：
RIFKIN, DB
影响因子：
5.6
作者：
LAWRENCE, DA;PIRCHER, R;JULLIEN, P
通讯作者：
JULLIEN, P
影响因子：
6
作者：
Gauldie, J;Galt, T;Warburton, D
通讯作者：
Warburton, D
影响因子：
5.4
作者：
Jones, Jeremy C.;Turpin, Elizabeth A.;Schultz-Cherry, Stacey
通讯作者：
Schultz-Cherry, Stacey
影响因子：
3.7
作者：
Aung, H;Wu, M;Toossi, Z
通讯作者：
Toossi, Z