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The innate immune system senses infection by detecting either evolutionarily conserved molecules essential for the survival of microbes or the abnormal location of molecules. Here we demonstrate the existence of a previously unknown innate detection mechanism induced by fusion between viral envelopes and target cells. Virus-cell fusion specifically stimulated a type I interferon response with expression of interferon-stimulated genes, in vivo recruitment of leukocytes and potentiation of signaling via Toll-like receptor 7 (TLR7) and TLR9. The fusion-dependent response was dependent on the stimulator of interferon genes STING but was independent of DNA, RNA and viral capsid. We suggest that membrane fusion is sensed as a danger signal with potential implications for defense against enveloped viruses and various conditions of giant-cell formation.
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http://dx.doi.org/10.1038/ni.2350 | DOI Listing |
Microbiol Spectr
August 2025
Jiangsu Key Laboratory of Sericultural and Animal Biotechnology, School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, China.
Unlabelled: Enveloped viruses initiate host cell entry through membrane fusion mediated by viral fusion proteins. In group I alphabaculoviruses, the class III membrane fusion protein GP64 mediates virus-cell fusion under acidic conditions. In Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV), three key histidine residues in GP64 function as pH sensors.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
June 2025
Department of Microbiology & Immunology, University of Michigan Medical School, Ann Arbor, MI 48109.
HIV-1 has been observed to enter target cells at both the plasma membrane and endosomes. However, which pathways mediate its entry into primary CD4 T cells, the major targets of this virus, remains unclear. Here, we show that HIV-1 can enter primary CD4 T cells through macropinocytosis, a form of endocytosis.
View Article and Find Full Text PDFAAPS PharmSciTech
May 2025
Ingenious Biopharma-Engineered Drugs and Biologics Delivery Laboratory (Ibd2 Lab), Department of Pharmaceutical Sciences, Mercer University, Atlanta, Georgia, 30341, USA.
COVID- 19, caused by the coronavirus SARS-CoV- 2, has arisen as a global health epidemic, claiming the lives of millions of people throughout the world. Combating the pandemic has involved developing and approving vaccines and antiviral products. Camostat Mesylate (Camo) is a TMPRSS2 inhibitor that inhibits virus-cell membrane fusion and, thereby, viral multiplication.
View Article and Find Full Text PDFJ Virol
June 2025
Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China.
Coronavirus entry into host cells enables the virus to initiate its replication cycle efficiently while evading host immune response. Cell entry is intricately associated with pH levels in the cytoplasm or endosomes. In this study, we observed that the sodium hydrogen exchanger 3 (Na/H exchanger 3 or NHE3), which is strongly activated by dexamethasone (Dex) to promote cell membrane Na/H exchange, was critical for cytoplasmic and endosomal acidification.
View Article and Find Full Text PDFJ Virol
May 2025
Molecular and Cellular Biophysics Program, Department of Biological Sciences, University of Denver, Denver, Colorado, USA.
To become infectious, assembling enveloped viruses must acquire viral glycoproteins to mediate downstream infection events. Human immunodeficiency virus-1 (HIV-1) envelope glycoproteins (Env) are well characterized to function as trimers for membrane fusion and entry; however, we sought to understand whether the trimeric structure of Env is required for incorporation into virus particles. Using superresolution live-cell imaging and biochemical assays, we demonstrate that a monomeric receptor chimera containing the Env cytoplasmic tail (Env-CT), known to regulate Env incorporation, is sufficient for lattice trapping and incorporation into virus assembly sites.
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