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

Ibtehaj Naqvi, Nicholas Giroux, Lyra Olson, Sarah Ahn Morrison, Telmo Llanga, Tolu O. Akinade, Yuefei Zhu, Yiling Zhong, Shree Bose, Stephanie Arvai, Karen Abramson, Lingye Chen, Loretta Que, Bryan Kraft, Xiling Shen, Jaewoo Lee, Kam W. Leong, Smita K. Nair, Bruce Sullenger

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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’ 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.

Original languageEnglish
Article number121393
JournalBiomaterials
Volume283
DOIs
StatePublished - Apr 2022

Keywords

  • Major-biological sciences
  • Minor-immunology and inflammation

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