Deficiency of C-reactive protein or human C-reactive protein transgenic treatment aggravates influenza A infection in mice.
Deficiency of C-reactive protein or human C-reactive protein transgenic treatment aggravates influenza A infection in mice.
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C反应蛋白或人C反应蛋白转基因治疗的缺乏会加剧小鼠流感A的感染。
DOI：
10.3389/fimmu.2022.1028458
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发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
C-反应蛋白（CRP）已被证明是一个潜在的候选目标，在免疫治疗的严重甲型流感感染。然而，目前尚不清楚CRP在流感感染中的发病机制。在此，我们使用甲型H1N1流感病毒CA 04分别感染人CRP转基因小鼠（KI）、CRP敲除小鼠（KO）和野生型小鼠（WT），并比较这些小鼠中病毒的致病性和相关免疫应答。结果显示，CA 04感染分别导致KO、KI和WT小鼠的100%、80%和60%死亡。与WT小鼠相比，CA 04感染导致KI小鼠在感染后第3天肺中较高的TCID 50，但在感染后第21天存活小鼠血清中HI抗体滴度降低。ELISA检测结果显示，感染后第7天，WT、KI、KO小鼠血清中IFN-γ浓度显著升高;感染后第3、7天，WT小鼠血清中IL-17浓度显著升高，KI小鼠血清中IL-17浓度显著降低，KO小鼠血清中IL-17浓度无显著变化。定量RT-PCR显示KI或KO小鼠感染后第3天或第7天肺中免疫检查点CTLA-4、LAIR-1、GITR、BTLA、TIM-3或PD-1 mRNA的相对表达水平呈下降趋势。相关性分析显示，WT小鼠中6种分子的mRNA表达水平与病毒的TICD 50呈正相关，而KI或KO小鼠中6种分子的mRNA表达水平与病毒的TCID 50呈负相关。然而，只有LAIR-1在WT、KI或KO小鼠的每个肺组织中与CA 07感染统计学上呈现显著相关性。免疫组化结果显示，CA 04感染的WT、KO、KI小鼠肺组织中均可见LAIR-1阳性细胞，阳性细胞主要分布于炎性致密区。我们的研究结果表明，缺乏CRP或人CRP转基因治疗加重了小鼠中的甲型流感病毒感染。CRP在流感病毒感染的免疫调节中是一把双刃剑，IL-17和免疫检查点可能参与其中。
C-reactive protein (CRP) has been shown to be a potential candidate target in the immunotherapy of severe influenza A infection. However, it is unclear on the pathogenesis associated with CRP in influenza infections. Here, we used influenza A H1N1 CA04 to infect human CRP transgenic mice (KI), CRP knockout mice (KO), and wild-type mice (WT), respectively, and compared the viral pathogenicity and associated immune response in those mice. The results showed that CA04 infection resulted in 100%, 80%, and 60% death in KO, KI, and WT mice, respectively. Compared to WT mice, CA04 infection resulted in higher TCID50 in lungs on day 3 after infection but lowered HI antibody titers in sera of survivors on day 21 after infection in KI mice. ELISA assay showed that IFN-γ concentration was significantly increased in sera of WT, KI, or KO mice on day 7 after infection, and IL-17 was remarkably increased in sera of WT mice but decreased in sera of KI mice while no significant change in sera of KO mice on day 3 or 7 after infection. Quantitative RT-PCR showed that the relative expression levels of immune checkpoint CTLA-4, LAIR-1, GITR, BTLA, TIM-3, or PD-1 mRNA in the lung presented decreased levels on day 3 or 7 after infection in KI or KO mice. The correlation analysis showed that mRNA expression levels of the 6 molecules positively correlated with viral TICD50 in WT mice but negatively correlated with viral TCID50 in KI or KO mice. However, only LAIR-1 presented a significant correlation in each lung tissue of WT, KI, or KO mice with CA07 infection statistically. IHC results showed that LAIR-1 positive cells could be found in WT, KO, or KI mice lung tissues with CA04 infection, and the positive cells were mainly distributed in an inflammatory dense area. Our results suggested that deficiency of CRP or human CRP transgenic treatment aggravates influenza A virus infection in mice. CRP is a double sword in immune regulation of influenza infection in which IL-17 and immune checkpoint may be involved.
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DOI：
10.1038/nrc3239
发表时间：
2012-03-22
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Pardoll DM
通讯作者：
Pardoll DM
影响因子：
9
作者：
Newton AH;Cardani A;Braciale TJ
通讯作者：
Braciale TJ
DOI：
10.1111/j.1749-6632.1982.tb22124.x
发表时间：
1982-01-01
影响因子：
5.2
作者：
KUSHNER, I
通讯作者：
KUSHNER, I
影响因子：
15.9
作者：
Pepys, MB;Hirschfield, GM
通讯作者：
Hirschfield, GM
影响因子：
11.4
作者：
CILIBERTO, G;ARCONE, R;RUTHER, U
通讯作者：
RUTHER, U