DAMPs/PAMPs induce monocytic TLR activation and tolerance in COVID-19 patients; nucleic acid binding scavengers can counteract such TLR agonists.
DAMPs/PAMPs induce monocytic TLR activation and tolerance in COVID-19 patients; nucleic acid binding scavengers can counteract such TLR agonists.
复制标题
DOI：
10.1016/j.biomaterials.2022.121393
复制
发表时间：
2022-04
期刊：
影响因子：
14
通讯作者：
Sullenger B
中科院分区：
文献类型：
--
作者：
Naqvi I;Giroux N;Olson L;Morrison SA;Llanga T;Akinade TO;Zhu Y;Zhong Y;Bose S;Arvai S;Abramson K;Chen L;Que L;Kraft B;Shen X;Lee J;Leong KW;Nair SK;Sullenger B
数以百万计的COVID-19患者死于呼吸道和全身炎症。Toll样受体（TLR）信号传导的过度刺激是病毒感染后免疫病理学的关键驱动因素。我们发现重症监护室（ICU）中的重症COVID-19患者显示出这种过度刺激的特征，其血液和肺部存在大量核酸感应TLR激动剂。这些含核酸的损伤和病原体相关分子模式（DAMP/PAMP）可以使用核酸结合微纤维来消除，以限制患者样品超活化这种先天免疫受体的能力。单细胞RNA测序显示，来自死亡但未恢复的ICU患者的CD 16+单核细胞在离体TLR刺激后表现出TLR耐受表型和抗病毒应答缺陷。血浆蛋白质组学证实了这种骨髓过度活化，并揭示了死亡患者中DAMP/PAMP载体的消耗。用MnO纳米颗粒处理这些COVID-19患者样本有效地中和了他们的肺和血液中存在的大量含核酸DAMP/PAMP对TLR的激活。最后，MnO纳米清除剂处理限制DAMP/PAMP诱导单核细胞中TLR耐受性的能力。因此，使用基于微纤维或纳米颗粒的DAMP/PAMP清除剂的治疗可能被证明可用于限制SARS-CoV-2诱导的过度炎症，预防单核细胞TLR耐受，并改善重症COVID-19患者的结局。
Millions of COVID-19 patients have succumbed to respiratory and systemic inflammation. Hyperstimulation of toll-like receptor (TLR) signaling is a key driver of immunopathology following infection by viruses. We found that severely ill COVID-19 patients in the Intensive Care Unit (ICU) display hallmarks of such hyper-stimulation with abundant agonists of nucleic acid-sensing TLRs present in their blood and lungs. These nucleic acid-containing Damage and Pathogen Associated Molecular Patterns (DAMPs/PAMPs) can be depleted using nucleic acid-binding microfibers to limit the patient samples’ ability to hyperactivate such innate immune receptors. Single-cell RNA-sequencing revealed that CD16+ monocytes from deceased but not recovered ICU patients exhibit a TLR-tolerant phenotype and a deficient anti-viral response after ex vivo TLR stimulation. Plasma proteomics confirmed such myeloid hyperactivation and revealed DAMP/PAMP carrier consumption in deceased patients. Treatment of these COVID-19 patient samples with MnO nanoparticles effectively neutralizes TLR activation by the abundant nucleic acid-containing DAMPs/PAMPs present in their lungs and blood. Finally, MnO nanoscavenger treatment limits the ability of DAMPs/PAMPs to induce TLR tolerance in monocytes. Thus, treatment with microfiber- or nanoparticle-based DAMP/PAMP scavengers may prove useful for limiting SARS-CoV-2 induced hyperinflammation, preventing monocytic TLR tolerance, and improving outcomes in severely ill COVID-19 patients.
登录
查看更多内容
影响因子：
64.5
作者：
Chevrier N;Mertins P;Artyomov MN;Shalek AK;Iannacone M;Ciaccio MF;Gat-Viks I;Tonti E;DeGrace MM;Clauser KR;Garber M;Eisenhaure TM;Yosef N;Robinson J;Sutton A;Andersen MS;Root DE;von Andrian U;Jones RB;Park H;Carr SA;Regev A;Amit I;Hacohen N
通讯作者：
Hacohen N
影响因子：
5.8
作者：
Fertig, Elana J.;Ding, Jie;Ochs, Michael F.
通讯作者：
Ochs, Michael F.
影响因子：
8
作者：
Eppensteiner, John;Kwun, Jean;Lee, Jaewoo
通讯作者：
Lee, Jaewoo
影响因子：
5.5
作者：
Gauss, Katherine A.;Nelson-Overton, Laura K.;Quinn, Mark T.
通讯作者：
Quinn, Mark T.
影响因子：
32.4
作者：
Cros J;Cagnard N;Woollard K;Patey N;Zhang SY;Senechal B;Puel A;Biswas SK;Moshous D;Picard C;Jais JP;D'Cruz D;Casanova JL;Trouillet C;Geissmann F
通讯作者：
Geissmann F