COVID-19 plasma exosomes promote proinflammatory immune responses in peripheral blood mononuclear cells.
COVID-19 plasma exosomes promote proinflammatory immune responses in peripheral blood mononuclear cells.
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DOI：
10.1038/s41598-022-26457-8
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发表时间：
2022-12-16
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
--
作者：
COVID-19患者血清细胞因子产生升高与疾病进展和严重程度相关。然而，在患者中启动细胞因子产生的刺激仍有待充分揭示。病毒感染的细胞释放与病毒相关的外泌体，即内吞起源的细胞外囊泡，进入血液，递送能够调节免疫反应的病毒货物。在这里，我们报道了COVID-19患者的血浆外泌体含有SARS-CoV-2双链RNA (dsRNA)，并刺激人外周血单核细胞大量产生白细胞介素-6 （IL-6）、IL-8、肿瘤坏死因子-α (TNF-α)和其他炎症细胞因子和趋化因子。外泌体耗尽消除了这些受刺激的反应。COVID-19血浆外泌体在CD4+ T细胞、CD8+ T细胞和CD14+单核细胞中诱导促炎反应，但在调节性T细胞、Th17 T细胞或中枢记忆T细胞中不显著。COVID-19血浆外泌体保护SARS-CoV-2 dsRNA货物免受RNase的侵害，并将dsRNA运送到受体细胞中。这些外泌体显著增加外周T细胞和单核细胞中内体toll样受体3 （TLR3）、TLR7、TLR8和TLR9的表达。TLR3的药理学抑制剂可显著降低CD4+和CD8+ T细胞产生的细胞因子和趋化因子，但CD14+单核细胞却不能，这突出了免疫细胞对COVID-19血浆外泌体反应的不同信号通路。我们的研究结果确定了SARS-CoV-2感染后细胞间串扰的新模型，该模型唤起了与COVID-19进展、严重程度和长期症状相关的细胞因子产生升高的免疫反应。
Elevated serum cytokine production in COVID-19 patients is associated with disease progression and severity. However, the stimuli that initiate cytokine production in patients remain to be fully revealed. Virus-infected cells release virus-associated exosomes, extracellular vesicles of endocytic origin, into the blood to deliver viral cargoes able to regulate immune responses. Here, we report that plasma exosomes of COVID-19 patients contain SARS-CoV-2 double stranded RNA (dsRNA) and stimulate robust production of interleukin-6 (IL-6), IL-8, tumor necrosis factor-α (TNF-α), and other inflammatory cytokines and chemokines by human peripheral mononuclear cells. Exosome depletion abolished these stimulated responses. COVID-19 plasma exosomes induced proinflammatory responses in CD4+ T cells, CD8+ T cells, and CD14+ monocytes but not significantly in regulatory T cells, Th17 T cells, or central memory T cells. COVID-19 plasma exosomes protect the SARS-CoV-2 dsRNA cargo from RNase and deliver the dsRNA into recipient cells. These exosomes significantly increase expression of endosomal toll-like receptor 3 (TLR3), TLR7, TLR8, and TLR9 in peripheral T cells and monocytes. A pharmacological inhibitor of TLR3 considerably reduced cytokine and chemokine production by CD4+ and CD8+ T cells but not by CD14+ monocytes, highlighting divergent signaling pathways of immune cells in response to COVID-19 plasma exosomes. Our results identify a novel model of intercellular crosstalk following SARS-CoV-2 infection that evoke immune responses positioned to contribute to elevated cytokine production associated with COVID-19 progression, severity, and long-haul symptoms.
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PELI1促进了TRIF依赖性Toll样受体信号传导和促炎性细胞因子的产生。
影响因子：
30.5
作者：
通讯作者：
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影响因子：
64.8
作者：
Alexopoulou, L;Holt, AC;Flavell, RA
通讯作者：
Flavell, RA
DOI：
10.1016/s2213-2600(20)30370-2
发表时间：
2020-12
期刊：
The Lancet. Respiratory medicine
影响因子：
--
作者：
Grasselli G;Tonetti T;Protti A;Langer T;Girardis M;Bellani G;Laffey J;Carrafiello G;Carsana L;Rizzuto C;Zanella A;Scaravilli V;Pizzilli G;Grieco DL;Di Meglio L;de Pascale G;Lanza E;Monteduro F;Zompatori M;Filippini C;Locatelli F;Cecconi M;Fumagalli R;Nava S;Vincent JL;Antonelli M;Slutsky AS;Pesenti A;Ranieri VM;collaborators
通讯作者：
collaborators
影响因子：
4.6
作者：
Brennan, K.;Martin, K.;Mc Gee, M. M.
通讯作者：
Mc Gee, M. M.
影响因子：
82.9
作者：
Del Valle DM;Kim-Schulze S;Huang HH;Beckmann ND;Nirenberg S;Wang B;Lavin Y;Swartz TH;Madduri D;Stock A;Marron TU;Xie H;Patel M;Tuballes K;Van Oekelen O;Rahman A;Kovatch P;Aberg JA;Schadt E;Jagannath S;Mazumdar M;Charney AW;Firpo-Betancourt A;Mendu DR;Jhang J;Reich D;Sigel K;Cordon-Cardo C;Feldmann M;Parekh S;Merad M;Gnjatic S
通讯作者：
Gnjatic S