NK cells and monocytes modulate primary HTLV-1 infection

PLoS Pathogens, Journal Year: 2022, Volume and Issue: 18(4), P. e1010416 - e1010416

Published: April 4, 2022

We investigated the impact of monocytes, NK cells, and CD8 + T-cells in primary HTLV-1 infection by depleting cell subsets exposing macaques to either wild type (HTLV-1 WT ) or p12KO mutant unable infect replete animals due a single point mutation orf-I that inhibits its expression. The orf- I encoded p8/p12 proteins counteract cytotoxic favor viral DNA persistence monocytes. Double depletion alone accelerated seroconversion all exposed . In contrast, infectivity was fully restored only when cells were also depleted, demonstrating critical role infection. Monocyte/macrophage resulted , but antibody titers virus low not sustained. Seroconversion did occur most p12KO. vitro experiments human monocytes THP-1 comparing demonstrated expression is associated with inhibition inflammasome activation increased CD47 “don’t-eat-me” signal surface infected decreased monocyte engulfment cells. Collectively, our data demonstrate for innate suggest dual On one hand, increases chances transmission sparing from efferocytosis, on other may protect engulfed modulating activation. These that, once established, stoichiometry contribute chronic inflammation observed efferocytosis.

Language: Английский

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Host Cell Restriction Factors Blocking Efficient Vector Transduction: Challenges in Lentiviral and Adeno-Associated Vector Based Gene Therapies

Cells, Journal Year: 2023, Volume and Issue: 12(5), P. 732 - 732

Published: Feb. 24, 2023

Gene therapy relies on the delivery of genetic material to patient’s cells in order provide a therapeutic treatment. Two currently most used and efficient systems are lentiviral (LV) adeno-associated virus (AAV) vectors. vectors must successfully attach, enter uncoated, escape host restriction factors (RFs), before reaching nucleus effectively deliver instructions cell. Some these RFs ubiquitously expressed mammalian cells, while others cell-specific, still only upon induction by danger signals as type I interferons. Cell have evolved protect organism against infectious diseases tissue damage. These can be intrinsic, directly acting vector, or related with innate immune response system, indirectly through interferons, but both intertwined. The immunity is first line defense pathogens and, such derived from myeloid progenitors (but not only), well equipped detect pathogen-associated molecular patterns (PAMPs). In addition, some non-professional epithelial endothelial fibroblasts, play major roles pathogen recognition. Unsurprisingly, foreign DNA RNA molecules among detected PAMPs. Here, we review discuss identified that block LV AAV vector transduction, hindering their efficacy.

Language: Английский

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RNA sensing at the crossroads of autoimmunity and autoinflammation

RNA, Journal Year: 2025, Volume and Issue: unknown, P. rna.080304.124 - rna.080304.124

Published: Jan. 8, 2025

Immune-mediated diseases are common in humans. The immune system is a complex host defense that evolved to protect us from pathogens, but also plays an important role homeostatic processes, removing dead or senescent cells, and participating tumor surveillance. human has two arms: the older innate system, newer adaptive system. Sensing of foreign RNA critical system’s ability recognize especially viral infections. However, sensors strongly implicated autoimmune autoinflammatory diseases, highlighting importance balancing pathogen recognition with tolerance RNAs can resemble their counterparts. We describe how bind ligands, this binding coupled upregulation Type I interferon-stimulated genes, ways which mutations genes play roles homeostasis have been linked diseases.

Language: Английский

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SAMHD1 enhances HIV-1-induced apoptosis in monocytic cells via the mitochondrial pathway

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 10, 2025

SUMMARY Sterile alpha motif (SAM) and histidine-aspartate (HD) domain-containing protein 1 (SAMHD1) inhibits HIV-1 replication in non-dividing cells by reducing the intracellular dNTP pool. SAMHD1 enhances spontaneous apoptosis cells, but its effects on HIV-1-induced underlying mechanisms remain unknown. Here we uncover a new mechanism which monocytic through mitochondrial pathway. We found that endogenous levels induced infection dividing THP-1 cells. Mechanistically, expression decreases membrane potential promotes cytochrome c release thereby enhancing apoptotic SAMHD1-enhanced is associated with increased of pro-apoptotic BCL-2-interacting killer (BIK) further demonstrated BIK contributes to during infection. Overall, our results reveal an unappreciated regulatory via pathway

Language: Английский

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Integrated Approach for Biomarker Discovery and Mechanistic Insights into the Co-Pathogenesis of Type 2 Diabetes Mellitus and Non-Hodgkin Lymphoma

Diabetes Metabolic Syndrome and Obesity, Journal Year: 2025, Volume and Issue: Volume 18, P. 267 - 282

Published: Jan. 1, 2025

Type 2 diabetes mellitus (T2DM) is associated with an increased risk of non-Hodgkin lymphoma (NHL), but the underlying mechanisms remain unclear. This study aimed to identify potential biomarkers and elucidate molecular co-pathogenesis T2DM NHL. Microarray datasets NHL were downloaded from Gene Expression Omnibus database. Subsequently, a protein-protein interaction network was constructed based on common differentially expressed genes (DEGs) between explore regulatory interactions. Functional analyses performed mechanisms. Topological analysis machine learning algorithms applied refine hub gene selection. Finally, quantitative real-time polymerase chain reaction validate in clinical samples. Intersection DEGs identified 81 shared genes. suggested that immune-related pathways played significant role three genes: GZMM, HSPG2, SERPING1. Correlation revealed correlations these immune cells, underscoring importance dysregulation pathogenesis. The expression successfully validated pivotal as key contributors. These findings provide insight into complex interplay

Language: Английский

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Coevolution of Lentiviral Vif with Host A3F and A3G: Insights from Computational Modelling and Ancestral Sequence Reconstruction

Viruses, Journal Year: 2025, Volume and Issue: 17(3), P. 393 - 393

Published: March 10, 2025

The evolutionary arms race between host restriction factors and viral antagonists provides crucial insights into immune system evolution adaptation. This study investigates the structural dynamics of double-domain A3F A3G their inhibitor, Vif, across diverse primate species. By constructing 3D homology models integrating ancestral sequence reconstruction (ASR), we identified patterns diversity, conservation, functional Inactive CD1 (Catalytic Domain 1) domains displayed greater diversity more positive surface charges than active CD2 domains, aiding nucleotide chain binding intersegmental transfer. Despite variability, DNA-binding grooves remained structurally consistent with conserved residues maintaining critical functions. diverged in loop 7’ interaction strategies, utilising distinct molecular interactions to facilitate roles. Vif exhibited charge variation linked species, reflecting its coevolution A3 proteins. These findings illuminate how adaptations enable both adapt selective pressures. Our results emphasize importance studying host–virus interactions, implications for understanding defense mechanisms, zoonotic risks, evolution. work establishes a foundation further exploration factor

Language: Английский

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Prime Editing in Dividing and Quiescent Cells

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(8), P. 3596 - 3596

Published: April 11, 2025

Prime editing is a method of genome based on reverse transcription. Recent results have shown its elevated efficiency in dividing cells, which raises some questions regarding the mechanism this effect, because prime does not employ homology-driven repair. This mini review aims to identify reason for phenomenon and find possible solution problems that it poses. In takes advantage high levels dNTPs active endonuclease ligase machinery, such as FEN1 LIG1 ligase, but DNA mismatch repair, closely associated with replication, works against editing. relies retroviral transcription, so mechanisms intrinsic anti-retroviral defense should also work One factors drastically reduce translation SAMHD1, maintains low non-dividing cells. aimed at mitigation SAMHD1 function demonstrated significant increase efficiency.

Language: Английский

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The HD-Domain Metalloprotein Superfamily: An Apparent Common Protein Scaffold with Diverse Chemistries

Catalysts, Journal Year: 2020, Volume and Issue: 10(10), P. 1191 - 1191

Published: Oct. 15, 2020

The histidine-aspartate (HD)-domain protein superfamily contains metalloproteins that share common structural features but catalyze vastly different reactions ranging from oxygenation to hydrolysis. This chemical diversion is afforded by (i) their ability coordinate most biologically relevant transition metals in mono-, di-, and trinuclear configurations, (ii) sequence insertions or the addition of supernumerary ligands active sites, (iii) auxiliary substrate specificity residues vicinal catalytic site, (iv) additional domains allosterically regulate activities have sensory roles, (v) work with partners. More than 500 structures HD-domain proteins are available date lay out unique which may be indicative function. In this respect, we describe three known classes (hydrolases, oxygenases, lyases) identify apparent traits aim portray differences molecular details responsible for functional divergence reconcile existing notions will help assign functions yet-to-be characterized proteins. present review collects data exemplify how nature tinkers scaffold afford chemistries provides insight into factors can selectively modulate catalysis.

Language: Английский

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The host antiviral protein SAMHD1 suppresses NF-κB activation by interacting with the IKK complex during inflammatory responses and viral infection

Journal of Biological Chemistry, Journal Year: 2023, Volume and Issue: 299(6), P. 104750 - 104750

Published: April 24, 2023

Sterile alpha motif and histidine-aspartate (HD) domain–containing protein 1 (SAMHD1) inhibits HIV-1 replication in nondividing cells by reducing the intracellular dNTP pool. SAMHD1 also suppresses NF-κB activation induced inflammatory stimuli viral infections. Specifically, SAMHD1-mediated reduction of inhibitory (IκBα) phosphorylation is important for suppression activation. However, while inhibitors kinase subunit beta (IKKα IKKβ) regulate IκBα phosphorylation, mechanism which regulates remains unclear. Here, we report that IKKα/β/γ via interaction with IKKα IKKβ, thus inhibiting subsequent monocytic THP-1 differentiated cells. We show knockout enhanced IKKα, IKKγ treated activator lipopolysaccharide or infected Sendai virus reconstitution inhibited virus–infected demonstrate endogenous interacted IKKβ recombinant bound to purified directly in vitro. Mapping these interactions showed HD domain interacts both ubiquitin-like are required their SAMHD1, respectively. Moreover, found disrupts between upstream TAK1 IKKβ. Our findings identify a new regulatory

Language: Английский

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A user-friendly, high-throughput tool for the precise fluorescent quantification of deoxyribonucleoside triphosphates from biological samples

Nucleic Acids Research, Journal Year: 2020, Volume and Issue: 48(8), P. e45 - e45

Published: Feb. 17, 2020

Abstract Cells maintain a fine-tuned, dynamic concentration balance in the pool of deoxyribonucleoside 5′-triphosphates (dNTPs). This is essential for physiological processes including cell cycle control or antiviral defense. Its perturbation results increased mutation frequencies, replication arrest and may promote cancer development. An easily accessible relatively high-throughput method would greatly accelerate exploration diversified consequences dNTP imbalances. The incorporation based, fluorescent TaqMan-like assay published by Wilson et al. has aforementioned advantages over mass spectrometry, radioactive chromatography based quantification methods. Nevertheless, failed to produce reliable data several biological samples. Therefore, we applied enzyme kinetics analysis on curves found that Taq polymerase exhibits independent exonuclease activity decouples signal generation from incorporation. Furthermore, both polymerization activities are unpredictably inhibited sample matrix. To resolve these issues, established which identifies generated We automated process nucleoTIDY software enables even inexperienced user calculate final accurate amounts 96-well-plate setup within minutes.

Language: Английский

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