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Subsequent transcriptome and gene expression analyses reveal an induction of autophagy-related genes and an elevated LC3-II/LC3-I ratio in neutrophils following P. plecoglossicida infection. [...]the application of the autophagy inhibitor 3-Methyladenine (3-MA) is shown to suppress NETosis, highlighting the essential role of autophagy in the NETosis process induced by P. plecoglossicida infection. IgM is a crucial immunoglobulin in fish.Huang et al.observed that largemouth bass (Micropterus salmoides) survived from largemouth bass ranavirus (LMBRaV) infection exhibit a higher survival rate during the second infection compared to wild-type M. salmoides, indicating the role of adaptive immune response in viral elimination. Given the distinct environmental conditions between aquatic animals and humans, it is worth investigating potential differences in autophagy and cell death between these groups, as well as the evolutionary trajectory of these processes from aquatic animals to humans.

The cGAS-STING pathway, well-known to elicit interferon (IFN) responses, is also a key inducer of autophagy upon virus infection or other stimuli. Whereas the mediators for cGAS-induced IFN responses are well characterized, much less is known about how cGAS elicits autophagy. Here, we report that TRIM23, a unique TRIM protein harboring both ubiquitin E3 ligase and GTPase activity, is crucial for cGAS-STING-dependent antiviral autophagy. Genetic ablation of TRIM23 impairs autophagic control of HSV-1 infection. HSV-1 infection or cGAS-STING stimulation induces TBK1-mediated TRIM23 phosphorylation at S39, which triggers TRIM23 autoubiquitination and GTPase activity and ultimately elicits autophagy. Fibroblasts from a patient with herpes simplex encephalitis heterozygous for a dominant-negative, kinase-inactivating TBK1 mutation fail to activate autophagy by TRIM23 and cGAS-STING. Our results thus identify the cGAS-STING-TBK1-TRIM23 axis as a key autophagy defense pathway and may stimulate new therapeutic interventions for viral or inflammatory diseases. The cGAS-STING pathway senses cytosolic DNA to activate interferon responses, but has also been implicated in autophagy induction. Here the authors show that, during herpes simplex virus infection, cGAS-induced autophagy is mediated by TBK1-induced TRIM23 phosphorylation and downstream signaling events to assist in antiviral immunity.

Sensing of viral pathogens by RIG-I-like receptors (RLRs) requires their priming via dephosphorylation mediated by the protein phosphatase 1 regulatory subunit 12 C (R12C), which is activated upon virus-induced actin rearrangements. Here, we show that the HIV-1 accessory protein Nef prevents R12C-mediated RLR priming, thereby suppressing viral sensing. HIV-1 variants containing single point mutations in Nef (F/R191A) that ablate its ability to bind the actin-modulating kinase PAK2 trigger increased interferon (IFN) responses in primary CD4 T cells, macrophages, and dendritic cells. Neutralization of IFN suppresses innate immune activation and enhances the replication of Nef-mutated HIV-1. We further demonstrate that HIV-1 encoding Nef F/R191A is sensed by MDA5 after proviral integration in an R12C-dependent manner. Mechanistically, PAK2 binding by Nef promotes actin repair and stabilization, thereby preventing re-localization of R12C to MDA5 and RIG-I and their subsequent dephosphorylation. Our data identify Nef as an antagonist of actin-R12C-mediated RLR priming, enabling HIV-1 to escape immune control.

Viral myocarditis, an inflammatory disease of the heart, causes significant morbidity and mortality. Type I interferon (IFN)-mediated antiviral responses protect against myocarditis, but the mechanisms are poorly understood. We previously identified A Disintegrin And Metalloproteinase domain 9 (ADAM9) as an important factor in viral pathogenesis. ADAM9 is implicated in a range of human diseases, including inflammatory diseases; however, its role in viral infection is unknown. Here, we demonstrate that mice lacking ADAM9 are more susceptible to encephalomyocarditis virus (EMCV)-induced death and fail to mount a characteristic type I IFN response. This defect in type I IFN induction is specific to positive-sense, single-stranded RNA (+ ssRNA) viruses and involves melanoma differentiation-associated protein 5 (MDA5)—a key receptor for +ssRNA viruses. Mechanistically, ADAM9 binds to MDA5 and promotes its oligomerization and thereby downstream mitochondrial antiviral-signaling protein (MAVS) activation in response to EMCV RNA stimulation. Our findings identify a role for ADAM9 in the innate antiviral response, specifically MDA5-mediated IFN production, which protects against virus-induced cardiac damage, and provide a potential therapeutic target for treatment of viral myocarditis. Mice lacking A Disintegrin and Metalloproteinase 9 (ADAM9) do not mount Type 1 interferon responses against encephalomyocarditis infection. Here, Bazzone et al show that ADAM9 regulates innate immune responses via by MDA5.

To uncover the genomic basis of bats' resistance to viral diseases, the authors used long-read-sequencing and genome-assembly techniques to analyse ten bat species, with a focus on those known to harbour viruses that can be passed to humans. How bats counteract the potentially damaging inflammation that is driven by metabolic stress remains mostly unknown. Integrating genomic data with cutting-edge approaches - such as single-cell transcriptomics to catalogue the RNA transcripts expressed in individual cells, and comparative proteomics analyses to assess the differences in protein expression between bats and humans - could unveil molecular targets for alleviating excessive inflammation in humans.

Three-dimensional maps of glacier surfaces across Greenland reveal that cracks are growing rapidly where land ice meets the sea — and climate change is to blame. Cracks in Greenland's glaciers deepened by climate change.

Bats carry viral pathogens that typically do not lead to severe disease in the bats themselves but can be lethal to humans. Adaptations in certain immune genes might contribute to this resistance. Comparative genomics reveals how virus-carrying bats resist disease.

The rainfall changes in East Asian summer monsoon (EASM) regions on the orbital timescale remain controversial due to the lack of reliable rainfall records. Here, we present new multiproxy records ( δ 18 O, δ 13 C, Sr/Ca and Mg/Ca) of a 230 Th-dated stalagmite from Hulu Cave in central eastern China. Multiproxy records reconstruct a regional hydroclimate history from 340 to 261 kyr BP (thousand years before present), approximately covering the antepenultimate glacial period. The δ 18 O record is dominated by the precessional cycles, suggesting that EASM responds to changes in Northern Hemisphere summer insolation (NHSI) on the orbital timescale. Significant correlations amongst the δ 13 C, Sr/Ca and Mg/Ca suggest that a common factor, i.e., the local hydrological cycle, controlled their variability, and their leading principal component can be used as a proxy linked to regional rainfall. This composite record bears a good similarity to those from the Chinese Loess Plateau, showing a gradually decreasing rainfall during the antepenultimate glacial period, consistent with changes in global ice volume. Superimposed on the long-term trend, three relative wetter intervals were responding to the higher NHSI periods, suggesting that EASM rainfall variability was induced by integrated effects of global ice volume and NHSI. The increased ice sheets and lower NHSI resulted in an increased meridional temperature gradient and southward shift of the westerlies, which shortened the duration of Meiyu and midsummer rainfall. The differences between the rainfall record and the stalagmite δ 18 O record indicate that the latter represents the overall EASM intensity linked to monsoon circulation, but does not directly reflect the rainfall changes at the cave sites.

The posttranslational modification (PTM) of innate immune sensor proteins by ubiquitin or ubiquitin-like proteins is crucial for regulating antiviral host responses. The cytoplasmic dsRNA receptor melanoma differentiation-associated protein 5 (MDA5) undergoes several PTMs including ISGylation within its first caspase activation and recruitment domain (CARD), which promotes MDA5 signaling. However, the relevance of MDA5 ISGylation for antiviral immunity in an infected organism has been elusive. Here, we generated knock-in mice ( ) in which the two major ISGylation sites, K23 and K43, in MDA5 were mutated. Primary cells derived from mice exhibited abrogated endogenous MDA5 ISGylation and an impaired ability of MDA5 to form oligomeric assemblies leading to blunted cytokine responses to MDA5 RNA-agonist stimulation or infection with encephalomyocarditis virus (EMCV) or West Nile virus. Phenocopying mice, the mice infected with EMCV displayed increased mortality, elevated viral titers, and an ablated induction of cytokines and chemokines compared to WT mice. Molecular studies identified human HERC5 (and its functional murine homolog HERC6) as the primary E3 ligases responsible for MDA5 ISGylation and activation. Taken together, these findings establish the importance of CARD ISGylation for MDA5-mediated RNA virus restriction, promoting potential avenues for immunomodulatory drug design for antiviral or anti-inflammatory applications.