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Gasdermins (GSDMs) are proteins cleaved by caspase (CASP) to trigger pyroptosis. In teleosts, pyroptosis is mediated by gasdermin E (GSDME). The Pufferfish, Takifugu rubripes, possesses two GSDME orthologs: named TrGSDMEa and TrGSDMEb. TrGSDMEa is cleaved by CASP3/7 to liberate the N-terminal (NT) domain that can trigger pyroptosis in mammalian cells. However, the biological function of TrGSDMEa in pufferfish is unknown, and TrGSDMEb is poorly studied. We found that TrGSDMEb was cleaved by CASP1/3/6/7/8, but the resulting NT domain, despite its similarity to TrGSDMEa-NT domain in sequence and structure, failed to induce pyroptosis. TrGSDMEa and TrGSDMEb exhibited similar expression patterns in pufferfish under normal physiological conditions but were up- and downregulated, respectively, in expression during Vibrio harveyi and Edwardsiella tarda infection. Bacterial infection induced the activation of TrGSDMEa and CASP3/7 in pufferfish cells, resulting in pyroptosis accompanied with IL-1ß production and maturation. Inhibition of TrGSDMEa-mediated pyroptosis via TrCASP3/7 reduced the death of pufferfish cells and augmented bacterial dissemination in fish tissues. Structure-oriented mutagenesis identified 16 conserved residues in teleost GSDMEa that were required for the pore formation or auto-inhibition of GSDMEa. This study illustrates the role of GSDMEa-mediated pyroptosis in teleost defense against bacterial pathogens and provides new insights into the structure-based function of vertebrate GSDME. Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-024-00237-x.

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Atherosclerosis remains a major challenge to global healthcare despite decades of research and constant trials of novel therapeutic approaches. One feature that makes atherosclerosis treatment so elusive is an insufficient understanding of its origins and the early stages of the pathological process, which limits our means of effective prevention of the disease. Macrovascular pericytes are cells with distinct shapes that are located in the arterial wall of larger vessels and are in many aspects similar to microvascular pericytes that maintain the functionality of small vessels and capillaries. This cell type combines the residual contractile function of smooth muscle cells with a distinct stellar shape that allows these cells to make numerous contacts between themselves and the adjacent endothelial layer. Moreover, pericytes can take part in the immune defense and are able to take up lipids in the course of atherosclerotic lesion development. In growing atherosclerotic plaques, the morphology and function of pericytes change dramatically due to phagocytic and synthetic phenotypes that are actively involved in lipid accumulation and extracellular matrix synthesis. In this review, we summarize our knowledge of this less-studied cell type and its role in atherosclerosis.

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Hypochlorous acid (HClO) is widely used in everyday life for bleaching and disinfecting tap water, and also in human metabolism, where it plays an important role in destroying foreign bacterial invaders and pathogens as well as immune defense and cellular functioning maintenance. Abnormal levels of hypochlorous acid have the potential to cause joint inflammation, neuronal degeneration, and even life-threatening cancer. Specific identification and effective detection of hypochlorous acid are important for monitoring human health and the environment. In recent years, organic fluorescent probes have attracted much attention because of their simple synthesis, easy operation, high sensitivity, and high specificity, and a variety of hypochlorous acid fluorescent probes based on low-cost, easy-to-operate, and rapid identification have been developed. In this paper, we review the fluorescent probes that have been developed in the past five years for the specific recognition of hypochlorous acid based on different fluorophores, such as triphenylamine, coumarin, 1,8-naphthalize, etc., as well as recognition units, such as N-N dimethyl thiosemicarbazone, and describe how the probes and hypochlorous acid interact for identification in the same manner as other fluorescent probes. In addition, the reaction mechanism between the probe and hypochlorous acid, the fluorescence change of the probe, and the detection limit are described to illustrate the progress in the detection of hypochlorous acid in recent years and to provide ideas for the development of hypochlorous acid fluorescent probes in the future.

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Golden pompano (Trachinotus ovatus), a marine farmed fish, is economically valuable in China. Lysophosphatidic acid phosphatase type 6 (ACP6) is a type of histidine acid phosphatase and plays an important role in regulating host inflammatory responses and anti-cancer effects in mammals. However, its function in teleost remains unknown. The present study aimed to investigate ACP6 function in golden pompano. ACP6 from golden pompano was identified, cloned, and named TroACP6. The open reading frame of TroACP6 was 1275 bp in length, encoding 424 amino acids. The TroACP6 protein shared high sequence identity (43.32%-90.57 %) with the ACP6 of other species. It contained a histidine phosphatase domain with the active site motif "RHGART" and the catalytic dipeptide HD (histidine and aspartate). Meanwhile, TroACP6 mRNA was widely distributed in the various tissues of healthy golden pompano, with the maximum expression in the head kidney. The function of TroACP6 was analyzed both in vitro and in vivo, and the results revealed that the purified recombinant TroACP6 protein exhibited optimum phosphatase activity at pH 6.0 and 50 °C in vitro. Meanwhile, upon Edwardsiella tarda challenge, TroACP6 expression in tissues increased significantly in vivo. In addition, TroACP6 overexpression enhanced the respiratory burst activity and superoxide dismutase activity of head kidney macrophages in vivo. Furthermore, the overexpression and knockdown of TroACP6 in vivo had a significant effect on bacterial infection. In summary, the study findings indicate that TroACP6 in golden pompano is involved in host defense against bacterial infection.

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Procambarus clarkii is an economically important species in China; however, its high mortality rate due to pathogenic bacteria, particularly Vibrio parahaemolyticus, results in significant economic loss. This study aimed to understand the immune response of crayfish to bacterial infection by comparing and analyzing transcriptome data of hepatopancreatic tissue from P. clarkii challenged with V. parahaemolyticus or treated with PBS. Physiological indices (TP, Alb, ACP, and AKP) were analyzed, and tissue sections were prepared. After assembling and annotating the data, 18,756 unigenes were identified. A comparison of the expression levels of these unigenes between the control and V. parahaemolyticus groups revealed 4037 DEGs, with 2278 unigenes upregulated and 1759 downregulated in the V. parahaemolyticus group. GO (Gene Ontology) enrichment analysis shows that the DGEs are mainly enriched in cellular anatomical activity, bindinga and cellular process, enrichment analysis of KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways showed that DGEs were mainly enriched in Base excision repair, Phagosome and Longevity regulating pathway. At the same time, lysosome was also enriched. The phagosome and lysosome pathways play a crucial role in the immune defense of crayfish against V. parahaemolyticus injection that will be highlighted. In addition, the expression levels of six selected immune-related DEGs were measured using qRT-PCR, which validated the results of RNA-seq analysis. This study provides a new perspective on the immune system and defense mechanisms of P. clarkii and a valuable foundation for further investigation of the molecular immune mechanisms of this species.

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Interleukin (IL)-18 is synthesized as a precursor that requires intracellular processing to become functionally active. In human, IL-18 is processed by caspase 1 (CASP1). In teleost, the maturation and signal transduction mechanisms of IL-18 are unknown. We identified two IL-18 variants, IL-18a and IL-18b, in turbot. IL-18a, but not IL-18b, was processed by CASP6/8 cleavage. Mature IL-18a bound specifically to IL-18 receptor (IL-18R) α-expressing cells and induced IL-18Rα-IL-18Rß association. Bacterial infection promoted IL-18a maturation in a manner that required CASP6 activation and correlated with gasdermin E activation. The mature IL-18a induced proinflammatory cytokine expression and enhanced bacterial clearance. IL-18a-mediated immune response was suppressed by IL-18 binding protein (IL-18BP), which functioned as a decoy receptor for IL-18a. IL-18BP also functioned as a pathogen pattern recognition receptor and directly inhibited pathogen infection. Our findings revealed unique mechanism of IL-18 maturation and conserved mechanism of IL-18 signaling and regulation in turbot, and provided new insights into the regulation and function of IL-18 related immune signaling.

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Animal aggression is one of the most conserved behaviors. Excessive and inappropriate aggression was a serious social concern across species. After long-term selection under strict stress conditions, Henan gamecock serves as a good model for studying aggressive behavior. In this research, we constructed a Henan game chicken backcross population containing 25% Rhode Island Red (RIR), and conducted brain transcriptomics and serum metabolomics analyses on Henan gamecock (HGR) through its comparison with its female encounters (HGH) and the male backcross birds (BGR). The study revealed that seven differential metabolites in serum and 172 differentially expressed genes in the brain were commonly shared in both HGR vs. HGH and HGR vs. BGR comparisons. They exhibited the same patterns of modulation in Henan gamecocks, following either HGH < HGR > BGR or HGH > HGR < BGR style. Therein, some neurological genes involving in serotonergic and dopaminergic signaling were upregulated, while the levels of many genes related with neuro-immune function were decreased in Henan gamecock. In addition, many unknown genes specifically or highly expressed in the brain of the Henan gamecock were identified. These genes are potentially key candidates for enhancing the bird's aggression. Multi-omics joint analysis revealed that tyrosine metabolism and neuroactive ligand-receptor interaction were commonly affected. Overall, our results propose that the aggressiveness of Henan gamecocks can be heightened by the activation of the serotonergic-dopaminergic metabolic process in the brain, which concurrently impairs the neuroimmune system. Further research is needed to identify the function of these unknown genes on the bird's aggressive behavior.

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Infections are one of the most significant healthcare and economic burdens across the world as underscored by the recent coronavirus pandemic. Moreover, with the increasing incidence of antimicrobial resistance, there is an urgent need to better understand host-pathogen interactions to design effective treatment strategies. The complement system is a key arsenal of the host defense response to pathogens and bridges both innate and adaptive immunity. However, in the contest between pathogens and host defense mechanisms, the host is not always victorious. Pathogens have evolved several approaches, including co-opting the host complement regulators to evade complement-mediated killing. Furthermore, deficiencies in the complement proteins, both genetic and therapeutic, can lead to an inefficient complement-mediated pathogen eradication, rendering the host more susceptible to certain infections. On the other hand, overwhelming infection can provoke fulminant complement activation with uncontrolled inflammation and potentially fatal tissue and organ damage. This review presents an overview of critical aspects of the complement-pathogen interactions during infection and discusses perspectives on designing therapies to mitigate complement dysfunction and limit tissue injury.

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HIV-1 replication is tightly regulated in host cells, and various restriction factors have important roles in inhibiting viral replication. SAMHD1, a well-known restriction factor, suppresses HIV-1 replication by hydrolyzing intracellular dNTPs, thereby limiting the synthesis of viral cDNA in quiescent cells. In this study, we revealed an additional and distinct mechanism of SAMHD1 inhibition during the postviral cDNA synthesis stage. Using immunoprecipitation and mass spectrometry analysis, we demonstrated the interaction between SAMHD1 and MX2/MxB, an interferon-induced antiviral factor that inhibits HIV-1 cDNA nuclear import. The disruption of endogenous MX2 expression significantly weakened the ability of SAMHD1 to inhibit HIV-1. The crucial region within SAMHD1 that binds to MX2 has been identified. Notably, we found that SAMHD1 can act as a sensor that recognizes and binds to the incoming HIV-1 core, subsequently delivering it to the molecular trap formed by MX2, thereby blocking the nuclear entry of the HIV-1 core structure. SAMHD1 mutants unable to recognize the HIV-1 core showed a substantial decrease in antiviral activity. Certain mutations in HIV-1 capsids confer resistance to MX2 inhibition while maintaining susceptibility to suppression by the SAMHD1-MX2 axis. Overall, our study identifies an intriguing antiviral pattern wherein two distinct restriction factors, SAMHD1 and MX2, collaborate to establish an alternative mechanism deviating from their actions. These findings provide valuable insight into the complex immune defense networks against exogenous viral infections and have implications for the development of targeted anti-HIV therapeutics. IMPORTANCE: In contrast to most restriction factors that directly bind to viral components to exert their antiviral effects, SAMHD1, the only known deoxynucleotide triphosphate (dNTP) hydrolase in eukaryotes, indirectly inhibits viral replication in quiescent cells by reducing the pool of dNTP substrates available for viral cDNA synthesis. Our study provides a novel perspective on the antiviral functions of SAMHD1. In addition to its role in dNTP hydrolysis, SAMHD1 cooperates with MX2 to inhibit HIV-1 nuclear import. In this process, SAMHD1 acts as a sensor for incoming HIV-1 cores, detecting and binding to them, before subsequently delivering the complex to the molecular trap formed by MX2, thereby immobilizing the virus. This study not only reveals a new antiviral pathway for SAMHD1 but also identifies a unique collaboration and interaction between two distinct restriction factors, establishing a novel line of defense against HIV-1 infection, which challenges the traditional view of restriction factors acting independently. Overall, our findings further indicate the intricate complexity of the host immune defense network and provide potential targets for promoting host antiviral immune defense.

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The accumulation of excessive reactive oxygen species (ROS) and recurrent infections with drug-resistant bacteria pose significant challenges in diabetic wound infections, often leading to impediments in wound healing. Addressing this, there is a critical demand for novel strategies dedicated to treating and preventing diabetic wounds infected with drug-resistant bacteria. Herein, 2D tantalum carbide nanosheets (Ta4C3 NSs) have been synthesized through an efficient and straightforward approach, leading to the development of a new, effective nanoplatform endowed with notable photothermal properties, biosafety, and diverse ROS scavenging capabilities, alongside immunogenic attributes for diabetic wound treatment and prevention of recurrent drug-resistant bacterial infections. The Ta4C3 NSs exhibit remarkable photothermal performance, effectively eliminating methicillin-resistant Staphylococcus aureus (MRSA) and excessive ROS, thus promoting diabetic wound healing. Furthermore, Ta4C3 NSs enhance dendritic cell activation, further triggering T helper 1 (TH1)/TH2 immune responses, leading to pathogen-specific immune memory against recurrent MRSA infections. This nanoplatform, with its significant photothermal and immunomodulatory effects, holds vast potential in the treatment and prevention of drug-resistant bacterial infections in diabetic wounds.

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The aim of this study was to investigate the effects of melatonin (MT) feed supplementation on the antioxidant capacity, immune defense, and intestinal flora in Procambarus clarkii (P. clarkii). Six groups of P. clarkii were fed test feeds containing different levels of MT: 0 mg/kg (control), 22.5, 41.2, 82.7, 165.1, and 329.2 mg/kg for a duration of 2 months. The specific growth rate, hepatosomatic index, and condition factor were recorded highest in the test group of shrimp fed an MT concentration of 165.1 mg/kg. Compared to the control group, the rate of apoptosis was lower in hepatopancreas cells of P. clarkii supplemented with high concentrations of MT. Analyses of antioxidant capacity and immune-response-related enzymes in the hepatopancreas indicated that dietary supplementation of MT significantly augmented both the antioxidant system and immune responses. Dietary MT supplementation significantly increased the expression levels of antioxidant-immunity-related genes and decreased the expression levels of genes linked to apoptosis. Dietary MT was associated with an elevation in the abundance of the Firmicutes and a reduction in the abundance of the Proteobacteria in the intestines; besides, resulting in an increase in the abundance of beneficial bacteria, such as Lactobacilli. The broken-line model indicated that the suitable MT concentration was 154.09-157.09 mg/kg. MT supplementation enhanced the growth performance of P. clarkii, exerting a positive influence on the intestinal microbiota, and bolstered both immune response and disease resistance. Thus, this study offered novel perspectives regarding the application of dietary MT supplementation within the aquaculture field.

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In this article for the Highlights of 2023 Series, we consider the growing understanding of mast cell heterogeneity and interactions that has developed from single cell RNA sequencing studies. We also discuss novel concepts concerning mast cell interactions with the central nervous system and evidence for their role in host defense against SARS-CoV-2 infection.

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Most studies in comparative immunology involve investigations into the detailed mechanisms of the immune system of a nonmodel organism. Although this approach has been insightful, it has promoted a deep understanding of only a handful of species, thus inhibiting the recognition of broad taxonomic patterns. Here, we call for investigating the immune defenses of numerous species within a pointillist framework, that is, the meticulous, targeted collection of data from dozens of species and investigation of broad patterns of organismal, ecological, and evolutionary forces shaping those patterns. Without understanding basic immunological patterns across species, we are limited in our ability to extrapolate and/or translate our findings to other organisms, including humans. We illustrate this point by focusing predominantly on the biological scaling literature with some integrations of the pace of life literature, as these perspectives have been the most developed within this framework. We also highlight how the more traditional approach in comparative immunology works synergistically with a pointillist approach, with each approach feeding back into the other. We conclude that the pointillist approach promises to illuminate comprehensive theories about the immune system and enhance predictions in a wide variety of domains, including host-parasite dynamics and disease ecology.

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In this study, we present the first cloning and identification of perforin (MsPRF1) in largemouth bass (Micropterus salmoides). The full-length cDNA of MsPRF1 spans 1572 base pairs, encoding a 58.88 kDa protein consisting of 523 amino acids. Notably, the protein contains MACPF and C2 structural domains. To evaluate the expression levels of MsPRF1 in various healthy largemouth bass tissues, real-time quantitative PCR was employed, revealing the highest expression in the liver and gut. After the largemouth bass were infected by Nocardia seriolae, the mRNA levels of MsPRF1 generally increased within 48 h. Remarkably, the recombinant protein MsPRF1 exhibits inhibitory effects against both Gram-negative and Gram-positive bacteria. Additionally, the largemouth bass showed a higher survival rate in the N. seriolae challenge following the intraperitoneal injection of rMsPRF1, with observed reductions in the tissue bacterial loads. Moreover, rMsPRF1 demonstrated a significant impact on the phagocytic and bactericidal activities of largemouth bass MO/MΦ cells, concurrently upregulating the expression of pro-inflammatory factors. These results demonstrate that MsPRF1 has a potential role in the immune response of largemouth bass against N. seriolae infection.

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The stingless bee Melipona scutellaris performs buzz pollination, effectively pollinating several wild plants and crops with economic relevance. However, most research has focused on honeybees, leaving a significant gap in studies concerning native species, particularly regarding the impacts of pesticide combinations on these pollinators. Thus, this study aimed to evaluate the sublethal effects of imidacloprid (IMD), pyraclostrobin (PYR), and glyphosate (GLY) on the behavior and fat body cell morphology and physiology of M. scutellaris. Foragers were orally exposed to the different pesticides alone and in combination for 48 h. Bees fed with contaminated solution walked less, moved slower, presented morphological changes in the fat body, including vacuolization, altered cell shape and nuclei morphology, and exhibited a higher count of altered oenocytes and trophocytes. In all exposed groups, alone and in combination, the number of cells expressing caspase-3 increased, but the TLR4 number of cells expressing decreased compared to the control groups. The intensity of HSP70 immunolabeling increased compared to the control groups. However, the intensity of the immunolabeling of HSP90 decreased in the IMD, GLY, and I + G (IMD + GLY) groups but increased in I + P-exposed bees (IMD + PYR). Alternatively, exposure to PYR and P + G (PYR + GLY) did not affect the immunolabeling intensity. Our findings demonstrate the hazardous effects and environmental consequences of isolated and combined pesticides on a vital neotropical pollinator. Understanding how pesticides impact the fat body can provide crucial insights into the overall health and survival of native bee populations, which can help develop more environmentally friendly approaches to agricultural practices.

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INTRODUCTION: Coronavirus disease 2019 caused by coronavirus-2 (SARS-CoV-2) has emerged as an aggressive viral pandemic. Health care providers confront a challenging task for rapid development of effective strategies to combat this and its long-term after effects. Virus entry into host cells involves interaction between receptor-binding domain (RBD) of spike (S) protein S1 subunit with angiotensin converting enzyme present on host cells. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a moonlighting enzyme involved in cellular glycolytic energy metabolism and micronutrient homeostasis. It is deployed in various cellular compartments and the extra cellular milieu. Though it is known to moonlight as a component of mammalian innate immune defense machinery, till date its role in viral restriction remains unknown. METHOD: Recombinant S protein, the RBD, and human GAPDH protein were used for solid phase binding assays and biolayer interferometry. Pseudovirus particles expressing four different strain variants of S protein all harboring ZsGreen gene as marker of infection were used for flow cytometry-based infectivity assays. RESULTS: Pseudovirus entry into target cells in culture was significantly inhibited by addition of human GAPDH into the extracellular medium. Binding assays demonstrated that human GAPDH binds to S protein and RBD of SARS-CoV-2 with nanomolar affinity. CONCLUSIONS: Our investigations suggest that this interaction of GAPDH interferes in the viral docking with hACE2 receptors, thereby affecting viral ingress into mammalian cells.

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TFF3 is a typical secretory poplypeptide of mucous epithelia belonging to the trefoil factor family (TFF) of lectins. In the intestine, respiratory tract, and saliva, TFF3 mainly exists as a high-molecular-mass complex with IgG Fc binding protein (FCGBP), which is indicative of a role in mucosal innate immunity. For the first time, we identified different forms of TFF3 in the endocervix, i.e., monomeric and homodimeric TFF3, as well as a high-molecular-mass TFF3-FCGBP complex; the latter also exists in a hardly soluble form. Immunohistochemistry co-localized TFF3 and FCGBP. Expression analyses of endocervical and post-menopausal vaginal specimens revealed a lack of mucin and TFF3 transcripts in the vaginal specimens. In contrast, genes encoding other typical components of the innate immune defense were expressed in both the endocervix and vagina. Of note, FCGBP is possibly fucosylated. Endocervical specimens from transgender individuals after hormonal therapy showed diminished expression, particularly of FCGBP. Furthermore, mucus swabs from the endocervix and vagina were analyzed concerning TFF3, FCGBP, and lysozyme. It was the aim of this study to illuminate several aspects of the cervico-vaginal innate immune barrier, which is clinically relevant as bacterial and viral infections are also linked to infertility, pre-term birth and cervical cancer.

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The ability of Aedes aegypti mosquitoes to transmit vertebrate pathogens depends on multiple factors, including the mosquitoes' life history traits, immune response, and microbiota (i.e., the microbes associated with the mosquito throughout its life). The microsporidium Edhazardia aedis is an obligate intracellular parasite that specifically infects Ae. aegypti mosquitoes and severely affects mosquito survival and other life history traits critical for pathogen transmission. In this work, we investigated how E. aedis impacts bacterial infection with Serratia marcescens in Ae. aegypti mosquitoes. We measured development, survival, and bacterial load in both larval and adult stages of mosquitoes. In larvae, E. aedis exposure was either horizontal or vertical and S. marcescens was introduced orally. Regardless of the route of transmission, E. aedis exposure resulted in significantly higher S. marcescens loads in larvae. E. aedis exposure also significantly reduced larval survival but subsequent exposure to S. marcescens had no effect. In adult females, E. aedis exposure was only horizontal and S. marcescens was introduced orally or via intrathoracic injection. In both cases, E. aedis infection significantly increased S. marcescens bacterial loads in adult female mosquitoes. In addition, females infected with E. aedis and subsequently injected with S. marcescens suffered 100% mortality which corresponded with a rapid increase in bacterial load. These findings suggest that exposure to E. aedis can influence the establishment and/or replication of other microbes in the mosquito. This has implications for understanding the ecology of mosquito immune defense and potentially disease transmission by mosquito vector species. IMPORTANCE: The microsporidium Edhazardia aedis is a parasite of the yellow fever mosquito, Aedes aegypti. This mosquito transmits multiple viruses to humans in the United States and around the world, including dengue, yellow fever, and Zika viruses. Hundreds of millions of people worldwide will become infected with one of these viruses each year. E. aedis infection significantly reduces the lifespan of Ae. aegypti and is therefore a promising novel biocontrol agent. Here, we show that when the mosquito is infected with this parasite, it is also significantly more susceptible to infection by an opportunistic bacterial pathogen, Serratia marcescens. This novel discovery suggests the mosquito's ability to control infection by other microbes is impacted by the presence of the parasite.

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Eukaryotic translation initiation factors have long been recognized for their critical roles in governing the translation of coding RNAs into peptides/proteins. However, whether they harbor functional activities at the post-translational level remains poorly understood. Here, we demonstrate that eIF3f1 (eukaryotic translation initiation factor 3 subunit f1), which encodes an archetypal deubiquitinase, is essential for the antimicrobial innate immune defense of Drosophila melanogaster. Our in vitro and in vivo evidence indicate that the immunological function of eIF3f1 is dependent on the N-terminal JAMM (JAB1/MPN/Mov34 metalloenzymes) domain. Mechanistically, eIF3f1 physically associates with dTak1 (Drosophila TGF-beta activating kinase 1), a key regulator of the IMD (immune deficiency) signaling pathway, and mediates the turnover of dTak1 by specifically restricting its K48-linked ubiquitination. Collectively, these results provide compelling insight into a noncanonical molecular function of a translation initiation factor that controls the post-translational modification of a target protein.

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