Influenza viral neuraminidase primes bacterial coinfection through TGF-β-mediated expression of host cell receptors
Influenza viral neuraminidase primes bacterial coinfection through TGF-β-mediated expression of host cell receptors
复制标题
DOI：
10.1073/pnas.1414422112
复制
发表时间：
2015-01-06
影响因子：
11.1
通讯作者：
Wang, Beinan
中科院分区：
文献类型：
--
作者：
Li, Ning;Ren, Aihui;Wang, Beinan
流感感染使宿主易于继发细菌性肺炎，这是流感流行期间死亡的主要原因。细菌合并感染的分子机制仍然难以捉摸。甲型流感病毒（IAV）的神经氨酸酶（NA）增强细菌粘附并且还激活TGF-β。由于TGF-β可以上调宿主粘附分子，如纤连蛋白和整合素的细菌结合，我们假设在IAV感染过程中激活的TGF-β有助于通过上调这些宿主粘附分子继发性细菌感染。人肺上皮细胞系的流式细胞术分析表明，IAV感染或重组NA治疗后，纤连蛋白和α 5整合素的表达上调，并通过抑制TGF-β信号转导而逆转。IAV促进的A组链球菌（GAS）和其他需要纤连蛋白结合的共感染病原体的粘附通过TGF-β的抑制被显著阻止。然而，IAV没有促进乳酸乳球菌的粘附，除非该细菌表达GAS的纤连蛋白结合蛋白。小鼠实验表明，IAV感染增强了野生型动物肺中的GAS定植，但在TGF-β信号传导缺陷的小鼠肺中则没有。总之，这些结果揭示了一个以前未被认识的机制：IAV NA通过激活TGF-β增强细胞粘附素的表达，导致肺部细菌负荷增加。我们的研究结果表明，TGF-β和细胞粘附素可能是潜在的药物靶点，用于预防合并感染。
Influenza infection predisposes the host to secondary bacterial pneumonia, which is a major cause of mortality during influenza epidemics. The molecular mechanisms underlying the bacterial coinfection remain elusive. Neuraminidase (NA) of influenza A virus (IAV) enhances bacterial adherence and also activates TGF-beta. Because TGF-beta can up-regulate host adhesion molecules such as fibronectin and integrins for bacterial binding, we hypothesized that activated TGF-beta during IAV infection contributes to secondary bacterial infection by up-regulating these host adhesion molecules. Flow cytometric analyses of a human lung epithelial cell line indicated that the expression of fibronectin and alpha 5 integrin was up-regulated after IAV infection or treatment with recombinant NA and was reversed through the inhibition of TGF-beta signaling. IAV-promoted adherence of group A Streptococcus (GAS) and other coinfective pathogens that require fibronectin for binding was prevented significantly by the inhibition of TGF-beta. However, IAV did not promote the adherence of Lactococcus lactis unless this bacterium expressed the fibronectin-binding protein of GAS. Mouse experiments showed that IAV infection enhanced GAS colonization in the lungs of wild-type animals but not in the lungs of mice deficient in TGF-beta signaling. Taken together, these results reveal a previously unrecognized mechanism: IAV NA enhances the expression of cellular adhesins through the activation of TGF-beta, leading to increased bacterial loading in the lungs. Our results suggest that TGF-beta and cellular adhesins may be potential pharmaceutical targets for the prevention of coinfection.