RT Journal Article
SR Electronic
T1 Single-Cell Epitope-Transcriptomics Reveal Lung Stromal and Immune Cell Response Kinetics to Nanoparticle-delivered RIG-I and TLR4 Agonists
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.11.29.518316
DO 10.1101/2022.11.29.518316
A1 Keenum, M. Cole
A1 Chatterjee, Paramita
A1 Atalis, Alexandra
A1 Pandey, Bhawana
A1 Jimenez, Angela
A1 Roy, Krishnendu
YR 2022
UL http://biorxiv.org/content/early/2022/11/29/2022.11.29.518316.abstract
AB Lung-resident and circulatory lymphoid, myeloid, and stromal cells, expressing various pattern recognition receptors (PRRs), detect pathogen and danger-associated molecular patterns (PAMPs/DAMPs), and defend against respiratory pathogens and injuries. Here, we report the early responses of murine lungs to nanoparticle-delivered PAMPs, specifically the RIG-I agonist poly-U/UC (PUUC), with or without the TLR4 agonist monophosphoryl lipid A (MPLA). Using cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq), we characterized the responses at 4 and 24 hours after intranasal administration. Within 4 hours, ribosome-associated transcripts decreased in both stromal and immune cells, followed by widespread interferon-stimulated gene (ISG) expression. Using RNA velocity, we show that lung-neutrophils dynamically regulate the synthesis of cytokines like CXCL-10, IL-1α, and IL-1β. Co-delivery of MPLA and PUUC increased chemokine synthesis and upregulated antimicrobial binding proteins targeting iron, manganese, and zinc in many cell types, including fibroblasts, endothelial cells, and epithelial cells. Overall, our results elucidate the early PAMP-induced cellular responses in the lung and demonstrate that stimulation of the RIG-I pathway, with or without TLR4 agonists, induces a ubiquitous microbial defense state in lung stromal and immune cells. Nanoparticle-delivered combination PAMPs may have applications in intranasal antiviral and antimicrobial therapies and prophylaxis.Competing Interest StatementThe authors have declared no competing interest.