Vaccines are the most effective agents to control infections. In addition to the pathogen antigens, vaccines contain adjuvants that are used to enhance protective immune responses. However, the molecular mechanism of action of most adjuvants is ill-known, and a better understanding of adjuvanticity is needed to develop improved adjuvants based on molecular targets that further enhance vaccine efficacy. This is particularly important for tuberculosis, malaria, AIDS, and other diseases for which protective vaccines do not exist. Release of endogenous danger signals has been linked to adjuvanticity; however, the role of extracellular ATP during vaccination has never been explored. Here, we tested whether ATP release is involved in the immune boosting effect of four common adjuvants: aluminum hydroxide, calcium phosphate, incomplete Freund's adjuvant, and the oil-in-water emulsion MF59. We found that intramuscular injection is always associated with a weak transient release of ATP, which was greatly enhanced by the presence of MF59 but not by all other adjuvants tested. Local injection of apyrase, an ATP-hydrolyzing enzyme, inhibited cell recruitment in the muscle induced by MF59 but not by alum or incomplete Freund's adjuvant. In addition, apyrase strongly inhibited influenza-specific T-cell responses and hemagglutination inhibition titers in response to an MF59-adjuvanted trivalent influenza vaccine. These data demonstrate that a transient ATP release is required for innate and adaptive immune responses induced by MF59 and link extracellular ATP with an enhanced response to vaccination.
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http://dx.doi.org/10.1073/pnas.1319784110 | DOI Listing |
Int Immunopharmacol
December 2024
Department of Orthopaedic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250012, PR China. Electronic address:
Rheumatoid arthritis (RA) is a chronic inflammatory disease that leads to joint deformity and ultimately disability. The metabolite of quercetin, 4-Methylcatechol (4-MC), has been acknowledged for its anti-inflammatory and antioxidant properties; however, the protective effects of 4-MC on RA and its underlying mechanisms remain incompletely elucidated. In a collagen-induced arthritis (CIA) model, we observed that 4-MC effectively mitigated joint inflammation and bone destruction in CIA mice.
View Article and Find Full Text PDFTheory Biosci
December 2024
Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology Delhi, Hauz Khas, New Delhi, 110016, India.
Can mathematical proofs be employed for the solution of fundamental molecular-level problems in biology? Recently, I mathematically tackled complex mechanistic problems arising during the synthesis of the universal biological currency, adenosine triphosphate (ATP) by the FF-ATP synthase, nature's smallest rotary molecular motor, using graph-theoretical and combinatorial approaches for the membrane-bound F and water-soluble F domains of this fascinating molecule (see Nath in Theory Biosci 141:249‒260, 2022 and Theory Biosci 143:217‒227, 2024). In the third part of this trilogy, I investigate another critical aspect of the molecular mechanism-that of coupling between the F and F domains of the ATP synthase mediated by the central γ-subunit of nanometer diameter. According to Nath's torsional mechanism of energy transduction and ATP synthesis the γ-subunit twists during ATP synthesis and the release of stored torsional energy in the central γ-stalk causes conformational changes in the catalytic sites that lead to ATP synthesis, with 1 ATP molecule synthesized per discrete 120° rotation.
View Article and Find Full Text PDFJ Physiol
December 2024
Department of Cell Biology & Anatomy, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
In recent years, evidence supporting non-ionotropic signalling by the NMDA receptor (niNMDAR) has emerged, including roles in long-term depression (LTD). Here, we investigated whether niNMDAR-pannexin-1 (Panx1) contributes to LTD at the CA3-CA1 hippocampal synapse. Using whole-cell, patch clamp electrophysiology in rat hippocampal slices, we show that a low-frequency stimulation (3 Hz) of the Schaffer collaterals produces LTD that is blocked by continuous but not transient application of the NMDAR competitive antagonist, MK-801.
View Article and Find Full Text PDFBiochem Biophys Res Commun
December 2024
Laboratory of Molecular and Cellular Biochemistry, Meiji Pharmaceutical University, Kiyose, Tokyo, 204-8588, Japan. Electronic address:
WD repeat domain 74 (WDR74) is a nucleolar protein involved in the early stages of pre-60S maturation in the ribosome biogenesis pathway. In later stages, WDR74 interacts with MTR4, an RNA helicase that functions with the exosome nuclease complex, and is dissociated upon ATP hydrolysis by the chaperone-like nuclear VCP-like 2 (NVL2) AAA-ATPase. We previously reported that ATP hydrolysis-defective NVL2 causes aberrant accumulation of WDR74 on the MTR4-exosome complex at the nucleolar periphery and in the nucleoplasm and that this nuclear redistribution of WDR74 leads to the unusual cleavage of the early rRNA precursor within the internal transcribed spacer 1 sequence.
View Article and Find Full Text PDFMethods Mol Biol
December 2024
Department of Physics, University of California San Diego, La Jolla, CA, USA.
Viral DNA packaging is a required step in the assembly of many dsDNA viruses. A molecular motor fueled by ATP hydrolysis packages the viral genome to near crystalline density inside a pre-formed prohead shell in ~5 min at room temperature in vitro. We describe procedures for measuring the packaging of single DNA molecules into single viral proheads with optical tweezers.
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