@article{bd74250572dc4b35aef035861529feef,
title = "DAMPs/PAMPs induce monocytic TLR activation and tolerance in COVID-19 patients; nucleic acid binding scavengers can counteract such TLR agonists",
abstract = "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{\textquoteright} 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.",
keywords = "Major-biological sciences, Minor-immunology and inflammation",
author = "Ibtehaj Naqvi and Nicholas Giroux and Lyra Olson and Morrison, {Sarah Ahn} and Telmo Llanga and Akinade, {Tolu O.} and Yuefei Zhu and Yiling Zhong and Shree Bose and Stephanie Arvai and Karen Abramson and Lingye Chen and Loretta Que and Bryan Kraft and Xiling Shen and Jaewoo Lee and Leong, {Kam W.} and Nair, {Smita K.} and Bruce Sullenger",
note = "Funding Information: Development of methods used in the project was funded by: Funding Information: This study was funded by: Funding Information: Discretionary funds from Duke Department of Surgery.Department of Defense Breast Cancer Research Program award W81XWH-16-1-0354 (SKN), W81XWH-19-1-0463 (KWL) and National Institutes of Health (NIH) grant R01AR073935 (BAS and KWL).We are extremely grateful to David Montefiori, PhD for helpful discussions, resources and infrastructure support and Guido Ferrari, MD for helpful discussions and advice. We would like to acknowledge David Boczkowski for his help in flow cytometry and PBMC isolation and stimulation. We would also like to acknowledge John Yi and the Duke Immune Profiling Core, Department of Surgery, without whom our immune profiling would have been impossible. We would also like to acknowledge Matthew Foster and the Duke Proteomics Core for their help in processing the plasma samples and aiding our team in acquiring the data. We thank Simon Gregory, PhD for discussions related to single-cell RNAseq. This work used a high-performance computing facility partially supported by grants 2016-IDG-1013 and 2020-IIG-2109 from the North Carolina Biotechnology Center. Publisher Copyright: {\textcopyright} 2022 Elsevier Ltd",
year = "2022",
month = apr,
doi = "10.1016/j.biomaterials.2022.121393",
language = "English",
volume = "283",
journal = "Biomaterials",
issn = "0142-9612",
}