Damage sensing through TLR9 Promotes Viral Clearance and Recovery During Influenza Infection
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ABSTRACT:
PROVIDER: PRJNA1131841 | ENA |
REPOSITORIES: ENA
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Project description:Toll-like receptor-9 is a pattern-recognition receptor that binds to the unmethylated CpG sequences in DNA. Its role in influenza infection is not well understood. Using mice deficient in TLR9, we demonstrated that these animals mounted a reduced inflammatory response during early infection on day 7, driven by the myeloid cells and associated cytokine responses. However, despite this diminished inflammation, TLR9-/- mice had increased viral burden on day 7 post-infection. To understand the cellular specificity and underlying mechanism of increased infection susceptibility in TLR9-/- mice, we performed single-cell RNA sequencing of lung tissues. scRNA sequencing data indicate that TLR9-/- immune cells, especially those of myeloid origin are highly susceptible to influenza infection. This susceptibility of TLR9-/- cells appeared to be independent of type I interferon signaling as the type I interferon pathway appeared the most upregulated pathway in TLR9-/- immune cells. We confirmed increased susceptibility of TLR9-/- myeloid cells using ex vivo murine alveolar macrophage and human peripheral blood monocyte cells. Despite the initial amelioration of the lung injury, the widespread infection of immune cells in TLR9-/- lungs upregulated both influenza and inflammatory responses in myeloid cells. This persistent inflammatory response manifested as the accumulation of both myeloid and lymphoid cells in the airways and increased injury markers in TLR9-/- on day 14. Elevated injury on day 14 delayed the weight loss recovery in TLR9-/- mice. Finally, we demonstrate elevated levels of TLR9 ligands during influenza infection in humans. These data demonstrate a key role of TLR9 in regulating host response to influenza infection.
2025-07-02 | GSE271505 | GEO
Project description:Host response aimed at eliminating the infecting pathogen, as well as the pathogen itself, can cause tissue injury. Tissue injury leads to the release of a myriad of cellular components including mitochondrial DNA, which the host senses through pattern recognition receptors. How the sensing of tissue injury by the host shapes the anti-pathogen response remains poorly understood. In this study, we utilized mice that are deficient in toll-like receptor-9 (TLR9), which binds to unmethylated CpG DNA sequences such as those present in bacterial and mitochondrial DNA. To avoid direct pathogen sensing by TLR9, we utilized the influenza virus, which lacks ligands for TLR9, to determine how damage sensing by TLR9 contributes to anti-influenza immunity. Our data show that TLR9-mediated sensing of tissue damage promotes an inflammatory response during early infection, driven by the myeloid cells and associated cytokine responses. Along with the diminished inflammatory response, the absence of damage sensing through TLR9 led to impaired viral clearance manifested as a higher and prolonged influenza burden in the lung. The absence of TLR9 led to extensive infection of myeloid cells including monocytes and macrophages rendering them highly inflammatory, despite having a low initial inflammatory response. The persistent inflammation driven by infected myeloid cells led to persistent lung injury and impaired recovery in influenza-infected TLR9-/- mice. Further, we show elevated circulating TLR9 ligands in the plasma samples of patients with influenza, demonstrating its clinical relevance. Overall, over data show an essential role of damage sensing through TLR9 in promoting anti-influenza immunity.
| S-EPMC10942338 | biostudies-literature
Project description:Formation of Memory Assemblies through the DNA Sensing Tlr9 Pathway
| PRJNA1071681 | ENA
Project description:As hippocampal neurons respond to diverse types of information a subset assembles into stable microcircuits representing a memory. Those neurons typically undergo energy-intensive molecular adaptations, which occasionally results in transient DNA damage. We found, however, discrete clusters of excitatory hippocampal CA1 neurons showing persistent dsDNA breaks, nuclear envelope ruptures, and perinuclear release of histone and dsDNA fragments for hours after learning. Following these early events, some neurons acquired an inflammatory phenotype involving activation of Toll-like receptor 9 (Tlr9) signaling and accumulation of centrosomal DNA damage repair (DDR) complexes. Neuron-specific knockdown of Tlr9 impaired memory while blunting CFC-induced changes of gene expression in specific clusters of excitatory CA1 neurons. Most notably, Tlr9 played an essential role in centrosome function, including DDR, ciliogenesis, and build-up of perineuronal nets (PNN). We demonstrate a novel cascade of learning-induced molecular events in discrete neuronal clusters undergoing dsDNA damage and Tlr9-mediated repair, resulting in their recruitment to memory circuits. With compromised Tlr9 function, this fundamental memory mechanism becomes a gateway to genomic instability and cognitive impairments, which have been implicated in accelerated senescence, psychiatric disorders, and neurodegenerative disorders. Maintaining the integrity of Tlr9 inflammatory signaling thus emerges as a promising preventive strategy for neurocognitive deficits.
2024-03-01 | GSE254780 | GEO
Project description:Studies of mucosal infections have mainly focused on the acute phase at single timepoints, whilst little is known about the host recovery phase. We characterised temporal changes to colonic epithelial cells during the late steady-state, clearance and recovery phases of Citrobacter rodentium infection in C57BL/6 mice. Changes to immuno-metabolism and innate immunity peaked at 10-13 days post infection (DPI) and recovered from 17 DPI. Multiple DNA sensing receptors (ZBP1, STING), pyroptotic (Caspase-1 and -8, GSDMD) and necroptotic (RIPK3, MLKL) proteins were enriched; Ripk3, but not Mlkl, knockout mice presented exacerbated diarrhoea and pathology at 10 DPI. We defined a new “host recovery” phase, characterised by IFN responses and manifested by high abundance of the immunoproteasome and MHC class II subunits, which is unresolved 4 weeks following pathogen clearance. These findings represent a paradigm shift in our understanding of mucosal surfaces recovery from infection.
2022-01-05 | PXD022230 | Pride
Project description:Dendritic cells (DCs) rely on Toll-like receptor 9 (TLR9) to detect unmethylated CpG motifs in microbial DNA, triggering essential immune responses. While the downstream signaling pathways of TLR9 activation are well characterized, their impact on S-palmitoylation is unknown. S-palmitoylation, involving the reversible attachment of palmitic acid to cysteine residues, plays a crucial role in regulating protein function and is catalyzed by the ZDHHC family of palmitoyl-acyltransferases (PATs). In this study, we investigated the S-palmitoylated proteome of bone marrow-derived GM-CSF DCs (GM-DCs) at resting and following TLR9 activation with CpGB. Using the click-chemistry compatible analog 17-octadecynoic acid (17-ODYA) and mass spectrometry-(MS)-based proteomics, we characterized dynamic remodeling of S-palmitoylation in response to TLR9 activation. This included enrichment of targets involved in immune and metabolic pathways. Transcriptomic analysis of mice and human DCs revealed TLR9-driven modulation of ZDHHC genes. Subsequently, we explored the contribution of ZDHHC9 to the regulation of S-palmitoylation in DCs. We found that Zdhhc9 deficiency affects the S-palmitoylation of specific proteins, revealing potential ZDHHC9 substrates. Interestingly, modulation of Zdhhc9 expression alone did not influence DC maturation, suggesting that other PATs might compensate for its activity. Together, our findings reveal a novel layer of regulation in TLR9 signaling mediated by S-palmitoylation.
2025-08-25 | PXD066223 | Pride
Project description:CXCL4 is a cationic peptide that binds to TLR9-ligand oligonucleotide, resulting in an inhibition of TLR9 response in B cells
2023-06-27 | GSE227639 | GEO
Project description:Although apoptotic cells (ACs) contain nucleic acids that can be recognized by Toll-like receptors (TLRs), engulfment of ACs does not initiate inflammation in healthy organisms. To better understand this phenomenon, we identified and characterized macrophage populations that continually engulf ACs in several distinct tissues. These macrophages share characteristics compatible with immunologically silent clearance of ACs, including high expression of AC recognition receptors, low expression of TLR9, and reduced TLR responsiveness to nucleic acids. When removed from tissues, these macrophages lose many of these characteristics and generate inflammatory responses to AC-derived nucleic acids, suggesting that cues from the tissue microenvironment are required to program macrophages for silent AC clearance. We show that KLF2 and KLF4 control expression of many genes within this AC clearance program. Coordinated expression of AC receptors with genes that limit responses to nucleic acids may represent a central feature of tissue macrophages that ensures maintenance of homeostasis.
2017-11-15 | GSE93820 | GEO
Project description:We show here that the antimicrobial peptide RNase 7 enables human pDCs to recognize self-DNA, and promotes their rapid sensing of bacterial DNA.
2017-09-07 | GSE103522 | GEO