CX3CR1 as a respiratory syncytial virus receptor in pediatric human lung

Abstract

Author ContributionsEach author has met the Pediatric Research authorship requirements. CSA, EEW, and TJM conceptualized the study. CSA, TJM, CC, QW, EEW, JAM, YR, and GP designed the experiments. TJM, GP, and RM developed the cohort, and collected the specimens. CSA, KD, TJM, CC, JM, YR, and SB generated, analyzed and interpreted the data. CSA, CC, JAM, GP EEW and TJM wrote and/or revised the manuscript.• We showed that RSV demonstrated preferential infection of CX3CR1 positive pediatric epithelial cells• Blocking CX3CR1/RSV interaction significantly decreased productive viral infection in vitro• We found that CX3CR1 transcript are often expressed in both the upper (60%) and lower airways (36%) of pediatric subjects • CX3CR1 tissue localization and intracellular transcript in donor quality pediatric lung specimens, demonstrating an apical RSV receptor on pediatric airways for the first time.• These data demonstrate CX3CR1 is both present in the airways of pediatric subjects where it may serve as a receptor for RSV infection, and plays a mechanistic role in mediating viral infection of pediatric airway epithelial cells in vitro.. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. was not certified by peer review)

Identification of RSV Fusion Protein Interaction Domains on the Virus Receptor, Nucleolin

“…In this study, we have extended previous work of RSV-nucleolin interactions through ultrastructural confirmation of co-localization on the cell surface and show how recombinant proteins and standard biochemical assays, as well as peptide array technology, can be very useful in mapping protein-protein interactions when combined with regular verification of biological relevance using cell culture model systems. This work was done in MDCK and HEp-2 culture systems and will need to be further confirmed in human airway epithelial cultures, similarly to what has been done for studies of the RSV-G protein receptor CX3CR1 [14,21,22]. Our data show that RSV binds nucleolin through the RBD1,2 domain and more specifically involves two 12-mer stretches within RBD1,2 (Figure 7).…”

Bioinformatics analyses of significant genes, related pathways, and candidate diagnostic biomarkers and molecular targets in SARS-CoV-2/COVID-19

“…OAS1 was liable for progression of severe acute respiratory syndrome (SARS) viral infection [ Hamano et al, 2005 ], but this gene may be associated with development of SARS-CoV-2 infection. Enriched genes such as CCL4 [ Al-Afif et al, 2015 ], IFIT3 [ Ternette et al, 2011 ], CCR1 [ Miller et al, 2006 ], CXCL13 [ Chalin et al, 2018 ], CX3CR1 [ Anderson et al, 2020 ] and DUSP1 [ Robitaille et al, 2017 ] were associated with progression of respiratory syncytial virus infection, but these genes may be key for advancement of SARS-CoV-2 infection. The novel biomarkers (CARD16, MEFV (MEFV innate immunity regulator, pyrin), CYBB (cytochrome b -245 beta chain), GBP4, CARD6, CASP5, HLX (H2.0 like homeobox), IL2RA, IL2RG, IL18RAP, GZMB (granzyme B), UBE2L6, FCGR1B, TRIM38, EIF2AK2, TRIM34, KPNA5, WARS1, PIK3CG, PRKCB (protein kinase C beta), TIAM2, DOCK2, GNB4, PTPRC (protein tyrosine phosphatase receptor type C), POR (cytochrome p 450 oxidoreductase), SLC27A2, RPL21, RPL26, RPL27, RPL27A, RPL29, RPL31, RPL32, RPL34, RPL37, RPL39, RPL36A, RPLP0, RPLP1, RPLP2, RPS2, RPS3, RPS3A, RPS5, RPS7, RPS8, RPS9, RPS10, RPS14, RPS15, RPS15A, RPS16, RPS18, RPS21, RPS27, RPS28, RPS29, FAU (FAU ubiquitin like and ribosomal protein S30 fusion), RPL36, MRPL14, RPS10-NUDT3, RPL10A, RPL17-C18orf32, RPL35, RPL13A, RPL3, RPL6, RPL7, RPL7A, RPL8, RPL15, RPL19, FOS (Fos proto-oncogene, AP-1 transcription factor subunit), JUNB (JunB proto-oncogene, AP-1 transcription factor subunit), JUND (JunD proto-oncogene, AP-1 transcription factor subunit), RPS12, COX5A, UQCRC1, COX4I1, COX5B, COX6A1, COX7B, ATP5F1E, ATP6V0B, SLC25A6, SEPTIN5, UQCRQ (ubiquinol-cytochrome c reductase complex III subunit VII), CYC1, NDUFA2, NDUFA4, NDUFAB1, NDUFB2, NDUFB7, NDUFB10, NDUFC1, NDUFV1, NDUFS6, UQCR11, TUBB2A, TUBB4B, ARPC1A, ARF5, DNAI2, SSR4, PGLS (6-phosphogluconolactonase), TALDO1 and TKT (transketolase)) obtained from the pathway enrichment analysis are all may be associated in SARS-CoV-2 infection progression process, which suggesting that these novel biomarkers may serve as diagnostics biomarkers or therapeutic targets for this infection.…”

More Than Just a Barrier: The Immune Functions of the Airway Epithelium in Asthma Pathogenesis

“…An example for this is chemokine receptor CX3CR1 via which RSV can infect its host. In differentiated human airway epithelial cells this molecule is highly abundant on cilia (70,71). Another possibility is the preceding action of a door-opener such as HBoV1 which may pave the way for further viral infections.…”