DAMPs/PAMPs induce monocytic TLR activation and tolerance in COVID-19 patients; nucleic acid binding scavengers can counteract such TLR agonists.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • 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

Published Date

  • April 2022

Published In

Volume / Issue

  • 283 /

Start / End Page

  • 121393 -

PubMed ID

  • 35349874

Pubmed Central ID

  • PMC8797062

Electronic International Standard Serial Number (EISSN)

  • 1878-5905

Digital Object Identifier (DOI)

  • 10.1016/j.biomaterials.2022.121393

Language

  • eng

Conference Location

  • Netherlands