Genetic alteration of heparan sulfate in CD11c + immune cells inhibits inflammation and facilitates pathogen clearance during influenza A virus infection.
Genetic alteration of heparan sulfate in CD11c + immune cells inhibits inflammation and facilitates pathogen clearance during influenza A virus infection.
复制标题
CD11c +免疫细胞中硫酸乙酰肝素的遗传改变抑制炎症并促进甲型流感病毒感染期间的病原体清除。
DOI：
10.1038/s41598-022-09197-7
复制
发表时间：
2022-03-30
影响因子：
4.6
通讯作者：
Fuster MM
中科院分区：
文献类型：
--
作者：
Kim SY;Gupta P;Johns SC;Zuniga EI;Teijaro JR;Fuster MM
甲型流感病毒（IAV）感染的存活率在很大程度上取决于肺部病原体清除和免疫调节之间的复杂平衡。我们证明，通过Ndst 1f/f CD 11 cCre+突变，抑制主要抗原呈递细胞群中的硫酸乙酰肝素（HS）硫酸化，从而改变CD 11 c+细胞中的聚糖硫酸乙酰肝素（HS）的遗传改变，可减少小鼠中A/波多黎各/8/1934（H1N1）流感引起的肺部炎症。突变的特征还在于，在接种后（p.i.）9天，在晚期感染/效应期，CD 4+调节性T（Treg）细胞的肺浸润减少，在感染后的较早时间点（第5天），肺CD 8 + T细胞或Treg细胞没有显著差异。在模型树突状细胞系（DC 2.4）中通过Ndst 1沉默诱导低硫酸化HS导致抗病毒细胞因子干扰素β（IFN-β）相对于对照的基础表达上调。用TLR 9配体CpG刺激细胞导致Ndst 1沉默的DC 2. 4细胞中更高的核因子-κB（NFκB）磷酸化。虽然用CpG刺激细胞也适度增加IFN-β表达，但这并不导致IFN-β蛋白质产生的显著增加。在使用Ndst 1f/f CD 11 cCre+突变小鼠和Cre−对照小鼠的原代骨髓DC进行的进一步IFN-β蛋白应答研究中，虽然检测到对CpG的应答中存在痕量IFN-β蛋白，但用TLR 7配体R848刺激导致IFN-β产生稳健，且与DC Ndst 1突变相关的水平显著更高。在体内，在Ndst 1f/f CD 11 cCre+突变小鼠的病原体清除率提高，建议减少IAV AA 5 H核蛋白在肺检查在晚期/效应阶段。在感染过程的早期（感染后第5天），平均病毒载量，作为衡量病毒RNA，是没有显着差异的基因型。这些发现指出了DC HS在病毒感染期间的先天性和适应性免疫中的新的调节作用。这可能具有治疗潜力，并在IAV或其他呼吸道病毒的背景下指导DC靶向HS工程平台。
Survival from influenza A virus (IAV) infection largely depends on an intricate balance between pathogen clearance and immunomodulation in the lung. We demonstrate that genetic alteration of the glycan heparan sulfate (HS) in CD11c + cells via Ndst1f/f CD11cCre + mutation, which inhibits HS sulfation in a major antigen presenting cell population, reduces lung inflammation by A/Puerto Rico/8/1934(H1N1) influenza in mice. Mutation was also characterized by a reduction in lung infiltration by CD4+ regulatory T (Treg) cells in the late infection/effector phase, 9 days post inoculation (p.i.), without significant differences in lung CD8 + T cells, or Treg cells at an earlier point (day 5) following infection. Induction of under-sulfated HS via Ndst1 silencing in a model dendritic cell line (DC2.4) resulted in up-regulated basal expression of the antiviral cytokine interferon β (IFN-β) relative to control. Stimulating cells with the TLR9 ligand CpG resulted in greater nuclear factor-κB (NFκB) phosphorylation in Ndst1 silenced DC2.4 cells. While stimulating cells with CpG also modestly increased IFN-β expression, this did not lead to significant increases in IFN-β protein production. In further IFN-β protein response studies using primary bone marrow DCs from Ndst1f/f CD11cCre + mutant and Cre− control mice, while trace IFN-β protein was detected in response to CpG, stimulation with the TLR7 ligand R848 resulted in robust IFN-β production, with significantly higher levels associated with DC Ndst1 mutation. In vivo, improved pathogen clearance in Ndst1f/f CD11cCre + mutant mice was suggested by reduced IAV AA5H nucleoprotein in lung examined in the late/effector phase. Earlier in the course of infection (day 5 p.i.), mean viral load, as measured by viral RNA, was not significantly different among genotypes. These findings point to novel regulatory roles for DC HS in innate and adaptive immunity during viral infection. This may have therapeutic potential and guide DC targeted HS engineering platforms in the setting of IAV or other respiratory viruses.
登录
查看更多内容
影响因子：
6
作者：
Christian F;Smith EL;Carmody RJ
通讯作者：
Carmody RJ
影响因子：
4.2
作者：
Gessani S;Conti L;Del Cornò M;Belardelli F
通讯作者：
Belardelli F
影响因子：
20.3
作者：
Longman, Randy S.;Braun, Deborah;Albert, Matthew L.
通讯作者：
Albert, Matthew L.
影响因子：
2.2
作者：
Abram CL;Roberge GL;Hu Y;Lowell CA
通讯作者：
Lowell CA
DOI：
10.3390/ph10020044
发表时间：
2017-05-04
期刊：
Pharmaceuticals (Basel, Switzerland)
影响因子：
--
作者：
Kim SY;Li B;Linhardt RJ
通讯作者：
Linhardt RJ