Entry Inhibition and Modulation of Pro-Inflammatory Immune Response Against Influenza A Virus by a Recombinant Truncated Surfactant Protein D.
Entry Inhibition and Modulation of Pro-Inflammatory Immune Response Against Influenza A Virus by a Recombinant Truncated Surfactant Protein D.
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DOI：
10.3389/fimmu.2018.01586
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发表时间：
2018
影响因子：
7.3
通讯作者：
Kishore U
中科院分区：
文献类型：
--
作者：
Al-Ahdal MN;Murugaiah V;Varghese PM;Abozaid SM;Saba I;Al-Qahtani AA;Pathan AA;Kouser L;Nal B;Kishore U
表面活性蛋白D（SP-D）在肺的粘膜分泌物中表达，并有助于宿主对多种病原体（包括甲型流感病毒（IAV））的先天防御。SP-D可抑制IAV的血凝作用和感染性，并通过其糖识别结构域（CRD）与IAV的神经氨酸酶（NA）和血凝素（HA）上的糖模式（N-连接甘露糖基化）结合而降低NA的活性。在这里，我们证明，重组片段的人SP-D（rfhSP-D），含有同源三聚体的颈部和CRD区域，作为一个进入抑制剂的IAV和下调M1的表达相当大的A549细胞与IAV的H1N1和H3 N2亚型在2小时的治疗挑战。此外，rfhSP-D还能下调TNF-α、IFN-α、IFN-β、IL-6和RANTES的mRNA水平，尤其是在IAV感染A549细胞的初始阶段。rfhSP-D还通过HA结合来干扰Madin达比犬肾（MDCK）细胞的IAV感染。此外，发现rfhSP-D可以降低H1+N1假型慢病毒颗粒转导的MDCK细胞中的荧光素酶报告基因活性，其中10 µg/ml rfhSP-D观察到50%的降低，这表明rfhSP-D作为进入抑制剂的关键作用针对IAV感染性。多重细胞因子阵列显示，IAV攻击的A549细胞的rfhSP-D处理导致关键促炎细胞因子和趋化因子的显著抑制。在pH 1 N1的情况下，TNF-α、IFN-α、IL-10、IL-12（p40）、VEGF、GM-CSF和eotaxin在24 h时被rfhSP-D处理显著抑制。然而，在H3 N2亚型的情况下，除了TNF-α、IFN-α和GM-CSF之外，这些对IL-10、VEGF、eotaxin和IL-12（p40）的抑制作用不那么明显。这些数据似乎表明，SP-D对宿主细胞的免疫调节作用的程度可以以IAV亚型特异性方式显著变化。因此，rfhSP-D治疗可以下调由IAV促进的促炎环境，否则会引起异常的炎性细胞募集，导致细胞死亡和肺损伤。
Surfactant protein D (SP-D) is expressed in the mucosal secretion of the lung and contributes to the innate host defense against a variety of pathogens, including influenza A virus (IAV). SP-D can inhibit hemagglutination and infectivity of IAV, in addition to reducing neuraminidase (NA) activity via its carbohydrate recognition domain (CRD) binding to carbohydrate patterns (N-linked mannosylated) on NA and hemagglutinin (HA) of IAV. Here, we demonstrate that a recombinant fragment of human SP-D (rfhSP-D), containing homotrimeric neck and CRD regions, acts as an entry inhibitor of IAV and downregulates M1 expression considerably in A549 cells challenged with IAV of H1N1 and H3N2 subtypes at 2 h treatment. In addition, rfhSP-D downregulated mRNA levels of TNF-α, IFN-α, IFN-β, IL-6, and RANTES, particularly during the initial stage of IAV infection of A549 cell line. rfhSP-D also interfered with IAV infection of Madin Darby canine kidney (MDCK) cells through HA binding. Furthermore, rfhSP-D was found to reduce luciferase reporter activity in MDCK cells transduced with H1+N1 pseudotyped lentiviral particles, where 50% of reduction was observed with 10 µg/ml rfhSP-D, suggestive of a critical role of rfhSP-D as an entry inhibitor against IAV infectivity. Multiplex cytokine array revealed that rfhSP-D treatment of IAV challenged A549 cells led to a dramatic suppression of key pro-inflammatory cytokines and chemokines. In the case of pH1N1, TNF-α, IFN-α, IL-10, IL-12 (p40), VEGF, GM-CSF, and eotaxin were considerably suppressed by rfhSP-D treatment at 24 h. However, these suppressive effects on IL-10, VEGF, eotaxin and IL-12 (p40) were not so evident in the case of H3N2 subtype, with the exception of TNF-α, IFN-α, and GM-CSF. These data seem to suggest that the extent of immunomodulatory effect of SP-D on host cells can vary considerably in a IAV subtype-specific manner. Thus, rfhSP-D treatment can downregulate pro-inflammatory milieu encouraged by IAV that otherwise causes aberrant inflammatory cell recruitment leading to cell death and lung damage.
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影响因子：
7.3
作者：
Nayak A;Dodagatta-Marri E;Tsolaki AG;Kishore U
通讯作者：
Kishore U
影响因子：
3.7
作者：
Rossman JS;Lamb RA
通讯作者：
Lamb RA
影响因子：
--
作者：
Ng WC;Tate MD;Brooks AG;Reading PC
通讯作者：
Reading PC
流感A的解剖病毒内吞途径揭示了大型细胞增多症作为替代入口途径。
影响因子：
6.7
作者：
de Vries E;Tscherne DM;Wienholts MJ;Cobos-Jiménez V;Scholte F;García-Sastre A;Rottier PJ;de Haan CA
通讯作者：
de Haan CA
影响因子：
5.4
作者：
Mitnaul, LJ;Matrosovich, MN;Kawaoka, Y
通讯作者：
Kawaoka, Y