Chronic tissue inflammation causes progressive tissue damage, organ dysfunction, and increased susceptibility to inflammatory diseases. Viral infections are major drivers of this process, but the molecular mechanisms linking antiviral immune responses to persistent inflammation and tissue pathology remain poorly understood. The function of TRIM47 was examined using primary macrophages and mouse models of RNA virus infection. Alveolar macrophages, peritoneal macrophages, and bone marrow–derived macrophages (BMDM) from wild-type and Trim47-deficient (Trim47-KO) mice were treated with RNA viruses or RNA mimics, and antiviral cytokine production was quantified. Sublethal reovirus and influenza A virus infection mouse models were used to evaluate survival, cytokine responses, and viral titers in vivo. Liquid chromatography-tandem mass spectrometry (LC-MS) was used to identify TRIM47-interacting proteins. Molecular and biochemical assays were used to examine post-translational modification, aggregation and activation of mitochondrial antiviral-signaling protein (MAVS). TRIM47 was highly expressed in macrophages, and TRIM47 deficiency in BMDM markedly reduced type I interferon (IFN-I) production following RNA virus infection or RNA mimics stimulation. In sublethal RNA virus infection mouse models, Trim47-KO mice exhibited reduced survival, impaired IFN-I responses, higher viral titers, increased inflammatory cell infiltration and tissue inflammation including myocarditis compared to wild-type mice. Mechanistically, TRIM47 interacted with MAVS and promoted SUMO1-mediated MAVS SUMOylation at K297 and K348, thereby enhancing MAVS aggregation and activation and driving robust IFN-I, IL-1β and IL-18 production in macrophages. These findings establish TRIM47 as a molecular switch of MAVS activation and antiviral cytokine responses in macrophages, highlighting its role in restricting RNA virus infection and mitigating inflammation. This study provides mechanistic insight into host pathways that may be therapeutically leveraged in chronic viral inflammation.

Abstract Introduction Inflammatory bowel diseases (IBDs) are becoming an increasingly significant public health problem, with roughly 1 in 100 Americans currently affected. Intestinal epithelial cells (IECs) serve as the first line of defense against intestinal pathogens and play a pivotal role in the initiation of colitis. TRIM68, an E3 ligase, is highly expressed in IECs, but its function in intestinal inflammation remains unclear. Methods To investigate its role, we specifically generate TRIM68 totally knockout (Trim68-/-) and IEC conditionally knockout (Trim68IEC-KO) mice. Colitis was induced using dextran sodium sulfate (DSS), and disease severity was evaluated through body weight changes, histopathological scoring, and cytokine expression analysis. Results Following dextran sodium sulfate (DSS) administration, TRIM68-deficient mice exhibited pronounced body weight loss, more severe histopathological damage, and elevated IL-6 and IL-1β expression compared with control mice. Notably, Trim68IEC-KO mice exhibited almost identical responses to Trim68-/- mice, highlighting the essential contribution of IEC expressed TRIM68. Mechanistically, TRIM68 binds to TGF-β—activated kinase 1—binding protein 2 (TAB2), an essential upstream adaptor of NF-κB signaling responsible for inducing IL-6 and IL-1β. This interaction promotes ubiquitination and degradation of TAB2, thereby dampening downstream proinflammatory cytokine induction. Conclusion Our findings reveal that TRIM68 acts as a novel negative regulator in the host innate immune response to colitis specifically within IECs. These results expand the understanding of colitis pathogenesis and suggest TRIM68 as a potential therapeutic target. Funding Source 1R56AI148215, R01AI155488 Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)

Antiviral innate immunity is a decisive determinant of whether cardiotropic viral infection resolves or progresses to myocarditis and deadly heart failure. Viral myocarditis (VM) remains a leading cause of sudden death in children and young adults, yet its human pathophysiological mechanisms remain incompletely understood and effective therapies are limited. In this Review, we map the cellular and molecular logic of cardiac antiviral innate immunity from first sensing to therapeutic opportunity and synthesize how these responses set the myocardial 'inflammatory set point' across cardiac-resident cells and recruited innate immune cells. We highlight RNA- and DNA-sensing immune signaling pathways that detect cardiotropic RNA and DNA viruses to collectively shape viral control and heart injury during VM. Finally, we connect mechanisms to translation by summarizing emerging biomarkers and clinical trials and by proposing a phase- and etiology-guided therapeutic framework that pairs antiviral immunomodulation with timely restraint of innate proinflammatory amplifiers to limit heart damage and prevent progression from VM to heart failure. This review will provide a roadmap of antiviral innate immunity to accelerate mechanistic discovery and targeted therapy for VM and virus-associated cardiovascular diseases.

T cells have a remarkable capacity to clonally expand, a process that is intricately linked to their effector activities. As vigorously proliferating T cell also incur substantial DNA lesions, how the dividing T cells safeguard their genomic integrity to allow the generation of T effector cells remains largely unknown. Here we report the identification of the apurinic/apyrimidinic endonuclease-1 (Apex1) as an indispensable molecule for the induction of cytopathic T effectors in mouse models. We demonstrate that conditional deletion of Apex1 in T cells resulted in a remarkable accumulation of baseless DNA sites in the genome of proliferating T cells, which further led to genomic instability and apoptotic cell death. Consequently, Apex1-deleted T cells failed to acquire any effector features after activation and failed to mediate autoimmune diseases and allergic tissue damages. Detailed mutational analyses pinpointed the importance of its endonuclease domain in the generation of T effector cells. We provide further evidence that inhibiting the base repair activities of Apex1 with chemical inhibitors similarly abrogated the induction of autoimmune diseases. Collectively, our study suggests that Apex1 serves as a gatekeeper for the generation of cytopathic T cells and that therapeutically targeting Apex1 may have important clinical implications in the treatment of autoimmune diseases.

Introduction: Myocarditis, defined as an inflammatory injury to the myocardium, is irreversible with a 20% fatality rate in 2 years and a 50% fatality rate in 5 years. The most common causes of myocarditis are viruses, such as influenza A (IAV). IAV is a cardiotropic virus that can disseminate from the lungs to infect heart tissue, particularly during severe infections. Despite the implications for public health, little is known about the underlying mechanisms by which IAV causes heart pathology. Methods: To investigate the role of the novel E3 ligase TRIM47 in IAV-induced myocarditis, we utilized both in vitro and in vivo approaches. In vivo , wild-type (WT) and TRIM47 knockout (KO) mice were challenged intranasally with IAV to induce myocarditis. Survival, heart function (echocardiography), and cardiac pathology (histology, viral load by RT-PCR, cytokine levels by ELISA) were evaluated. In vitro , bone marrow-derived macrophages (BMDM) from WT and TRIM47 KO mice were infected with IAV and interferon production was detected by ELISA. To elucidate molecular mechanisms, co-immunoprecipitation and Western blotting were used to confirm TRIM47-MAVS interaction and ubiquitination patterns. Furthermore, recombinant protein expression, mutagenesis, and co-expression studies were used to map binding sites and identify specific ubiquitination types and sites on MAVS. Results: TRIM47 KO mice exhibited significantly reduced survival rates compared to WT controls following IAV infection, along with higher viral loads, diminished type I interferon levels, and increased histopathological damage in lungs and hearts. Consistently, TRIM47 KO BMDMs produced substantially lower interferon levels upon IAV challenge. Mechanistically, TRIM47 was found to directly bind MAVS at an endogenous level and promoted the ubiquitination of MAVS, facilitating its aggregation and subsequent activating downstream antiviral signaling pathways. Conclusions: Our findings establish macrophage expressed TRIM47 as a critical regulator of the innate immune response to IAV-induced myocarditis. This study provides the first in vivo evidence of TRIM47’s role in controlling IAV-induced myocarditis and highlights the TRIM47- MAVS axis as a promising therapeutic target for viral-associated cardiovascular diseases.

Ovarian cancer ranks as the seventh most common malignancy and the eighth leading cause of cancer-related death in women worldwide. Most patients are diagnosed at an advanced stage, resulting in poor survival outcomes. The standard treatment is primary debulking surgery (PDS) with platinum-based chemotherapy, however interval debulking surgery (IDS) following neoadjuvant chemotherapy (NACT) is an alternative for select cases. In this review, we summarize recent advancements in the therapeutic landscape of ovarian cancer, focusing on targeted therapies, immunotherapy, and novel drug delivery systems. Poly (ADP-ribose) polymerase (PARP) inhibitors have markedly improved progression-free survival in BRCA-mutated and homologous recombination deficiency (HRD)-positive patients. Antibody-drug conjugates (ADCs), immune checkpoint inhibitors (ICIs), chimeric antigen receptor T (CAR-T) cell therapy, and tumor vaccines are emerging strategies, but they face challenges due to treatment resistance and tumor microenvironment suppression. Future research should focus on combination therapies, ADCs optimization, and immunotherapy refinement, while also integrating nanotechnology and 3D organoid models to enhance treatment precision to improve survival outcomes and quality of life for ovarian cancer patients.

Infections by enteric virus and intestinal inflammation are recognized as a leading cause of deadly gastroenteritis, and NLRP6 and NLRP9b signaling control these infection and inflammation. However, the regulatory mechanisms of the NLRP6 and NLRP9b signaling in enteric viral infection remain unexplored. In this study, we found that the E3 ligase TRIM29 suppressed type III interferon (IFN-λ) and interleukin-18 (IL-18) production by intestinal epithelial cells (IECs) when exposed to polyinosinic:polycytidylic acid (poly I:C) and enteric RNA viruses. Knockout of TRIM29 in IECs was efficient to restrict intestinal inflammation triggered by the enteric RNA viruses, rotavirus in suckling mice, and the encephalomyocarditis virus (EMCV) in adults. This attenuation in inflammation was attributed to the increased production of IFN-λ and IL-18 in the IECs and more recruitment of intraepithelial protective Ly6A+CCR9+CD4+ T cells in small intestines from TRIM29-deficient mice. Mechanistically, TRIM29 promoted K48-linked ubiquitination, leading to the degradation of NLRP6 and NLRP9b, resulting in decreased IFN-λ and IL-18 secretion by IECs. Our findings reveal that enteric viruses utilize TRIM29 to inhibit IFN-λ and inflammasome activation in IECs, thereby facilitating viral-induced intestinal inflammation. This indicates that targeting TRIM29 could offer a promising therapeutic strategy for alleviating gut diseases.

Allergic asthma, a chronic disorder marked by lung inflammation, is associated with significant interleukin-33 (IL-33) production. Alveolar epithelial cells (AECs) are the primary cells damaged by inflammation and initially respond to allergic pathogens. TRIM68, a TRIM family E3 ligase, exhibits high expression in AECs. We found that this highly expression of TRIM68 was significantly inhibited in the lungs of allergic asthma patients. To investigate TRIM68’s role in allergic asthma, we specifically generated TRIM68 totally knockout (Trim68-/-) and AEC conditionally knockout (Trim68f/f, Nkx2-Cre) mice. Upon house dust mite (HDM) extract challenges, TRIM68 depletion markedly enhanced IL-33 production as well as Th2 response related cytokine production in mice. Compared with wild type mice, Trim68-/- mice showed stronger inflammatory infiltration and lung tissue damage upon HDM induction. Notably, Trim68f/f, Nkx2-Cre mice exhibited almost identical responses to Trim68-/- mice, underscoring the critical role of TRIM68 in AECs. Mechanistically, TRIM68 binds to caspase recruitment domain 9 (CARD9) which is the key adaptor in the HDM sensing pathway capable of inducing proinflammatory cytokines. Through this interaction, TRIM68 promotes CARD9 ubiquitination and degradation, consequently reducing IL-33 production. Overall, our findings suggest TRIM68 as a negative regulator in AEC-mediated HDM responses, offering insights into asthma pathogenesis and potential therapies. 1R56AI148215, R01AI155488 Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)

Herpes simplex keratitis (HSK), caused by herpes simplex virus type I (HSV-1) ocular infection, is a leading cause of visual morbidity worldwide, and although cases of HSK can be managed with current medications, new developments are required to make treatments more effective and satisfactory. Current evidence suggests that corneal scarring and vascularization result from chronic inflammation triggered by HSV-1 antigens. The pathogenesis of HSK remains complex and incompletely understood, but there have been many recent advancements have improved our knowledge of HSV-1 and its interactions with the host immune system, particularly in regard to various signaling pathways and regulators. In this review, we discuss the roles of innate immunity in corneal epithelial cells and innate immune cells, DNA sensors and regulators of DNA sensing pathways in HSK caused by acute and recurrent HSV-1 ocular infection and present potential immune-based therapeutic targets for novel HSK treatments.

The interplay between host innate immunity and pathogen evasion is a dynamic battle shaping infection outcomes. The Topical Collection “Regulation of Antiviral and Antimicrobial Innate Immunity and Immune Evasion” synthesizes findings from thirteen recent studies to elucidate the molecular mechanisms of innate immune signaling and pathogen countermeasures. Host pattern-recognition receptors (PRRs), including Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), and DNA sensor cyclic GMP-AMP synthase (cGAS), drive type I interferon (IFN-I) and interferon-stimulated genes (ISGs) responses, alongside processes like autophagy and inflammasome activation, to combat viral and bacterial infections. Pathogens, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), cytomegalovirus, and porcine reproductive and respiratory syndrome virus, deploy sophisticated strategies to target immune sensors and adaptors, enabling replication and persistence. Novel insights, including the roles of ISG15, autophagy protein ATG7, and host factors such as THAP11 and PSMB4, highlight complex interactions influencing viral replication and host defense. These studies propose targeted therapeutic strategies, such as inflammasome modulation for human immunodeficiency viruses (HIV), and prostaglandin E2 regulation for foot-and-mouth disease virus vaccine production, offering promising avenues to enhance host immunity and counter pathogen evasion.

Viral myocarditis, an inflammatory disease of the myocardium, is a significant cause of sudden death in children and young adults. The current coronavirus disease 19 pandemic emphasizes the need to understand the pathogenesis mechanisms and potential treatment strategies for viral myocarditis. Here, we found that TRIM29 was highly induced by cardiotropic viruses and promoted protein kinase RNA-like endoplasmic reticulum kinase (PERK)-mediated endoplasmic reticulum (ER) stress, apoptosis, and reactive oxygen species (ROS) responses that promote viral replication in cardiomyocytes in vitro. TRIM29 deficiency protected mice from viral myocarditis by promoting cardiac antiviral functions and reducing PERK-mediated inflammation and immunosuppressive monocytic myeloid-derived suppressor cells (mMDSC) in vivo. Mechanistically, TRIM29 interacted with PERK to promote SUMOylation of PERK to maintain its stability, thereby promoting PERK-mediated signaling pathways. Finally, we demonstrated that the PERK inhibitor GSK2656157 mitigated viral myocarditis by disrupting the TRIM29-PERK connection, thereby bolstering cardiac function, enhancing cardiac antiviral responses, and curbing inflammation and immunosuppressive mMDSC in vivo. Our findings offer insight into how cardiotropic viruses exploit TRIM29-regulated PERK signaling pathways to instigate viral myocarditis, suggesting that targeting the TRIM29-PERK axis could mitigate disease severity. Knowledge of pathogenesis mechanisms and effective treatments for viral myocarditis is lacking. Here, Wang et al show that loss of TRIM29 and PERK inhibitor mitigate viral myocarditis by attenuating PERK-driven ER stress and ROS responses in male mice.

Viral myocarditis, an inflammatory disease of the myocardium, is a significant cause of sudden death in children and young adults. The current coronavirus disease 19 pandemic emphasizes the need to understand the pathogenesis mechanisms and potential treatment strategies for viral myocarditis. Here, we found that TRIM29 was highly induced by cardiotropic viruses and promoted protein kinase RNA-like endoplasmic reticulum kinase (PERK)-mediated endoplasmic reticulum (ER) stress, apoptosis, and reactive oxygen species (ROS) responses that promote viral replication in cardiomyocytes in vitro . TRIM29 deficiency protected mice from viral myocarditis by promoting cardiac antiviral functions and reducing PERK-mediated inflammation and immunosuppressive monocytic myeloid-derived suppressor cells (mMDSC) in vivo . Mechanistically, TRIM29 interacted with PERK to promote SUMOylation of PERK to maintain its stability, thereby promoting PERK-mediated signaling pathways. Finally, we demonstrated that the PERK inhibitor GSK2656157 mitigated viral myocarditis by disrupting the TRIM29-PERK connection, thereby bolstering cardiac function, enhancing cardiac antiviral responses, and curbing inflammation and immunosuppressive mMDSC in vivo . Our findings offer insight into how cardiotropic viruses exploit TRIM29-regulated PERK signaling pathways to instigate viral myocarditis, suggesting that targeting the TRIM29-PERK axis could mitigate disease severity.

Introduction: Viral myocarditis is an inflammatory disease of the myocardium that significantly contributes to sudden death in children and young adults. The COVID-19 pandemic underscores the critical need to understand the pathogenesis and develop effective treatment strategies for viral myocarditis. Methods: To investigate the role of the novel E3 ligase TRIM29 in viral myocarditis, we used wild-type and TRIM29 knockout mice infected with coxsackievirus B3 (CVB3) and encephalomyocarditis virus (EMCV), to induce the myocarditis. Additionally, wild-type mice infected with CVB3 were treated with the protein kinase RNA-like endoplasmic reticulum kinase (PERK) inhibitor GSK2656157 or a DMSO control to evaluate potential therapeutic interventions. Mice survival and heart function were monitored using transthoracic echocardiography, and hearts were harvested for histological and immunohistochemical analysis. Techniques including real-time PCR, western blotting, co-immunoprecipitation, enzyme-linked immunoassay, flow cytometry, over-expression, and knockdown were employed to elucidate the pathogenic mechanisms by which TRIM29 regulates the endoplasmic reticulum stress response after viral infection. Results: We found that TRIM29 was highly induced by cardiotropic viruses, including CVB3 and EMCV, and promoted PERK-mediated endoplasmic reticulum (ER) stress, apoptosis, and reactive oxygen species (ROS) responses, which restricted viral replication in cardiomyocytes in vitro . TRIM29 deficiency protected mice from viral myocarditis by enhancing cardiac antiviral functions and reducing PERK-mediated inflammation and immunosuppressive cells in vivo . Mechanistically, TRIM29 interacted with PERK to catalyze the SUMOylation of PERK, maintaining its stability and thereby promoting PERK-mediated signaling pathways. Furthermore, we demonstrated that the PERK inhibitor GSK2656157 mitigated viral myocarditis by disrupting the TRIM29-PERK interaction, which improved cardiac function, enhanced cardiac antiviral responses, and reduced inflammation and immunosuppressive cells in vivo . Conclusions: Our findings provide the first evidence that the TRIM29-PERK signaling axis can be targeted for the treatment of viral myocarditis. This suggests that targeting the TRIM29-PERK axis could effectively mitigate viral myocarditis and associated cardiovascular diseases.

Abstract In the past half century, there have been multiple RNA virus pandemics (influenza 1957, 1968 and 2009; SARS-CoV and COVID-19), inhabiting 44% of all emerging contagious diseases. Innate immunity is the first line of defense against viral infection. Here we found that TRIM47, a member of the TRIM family E3 ligase, plays a pivotal role in positively regulating host innate immunity in response to Influenza A virus (IAV). Among immune cells, TRIM47 is highly expressed in macrophages. Compared with wild type, TRIM47 deficient bone marrow derived macrophages exhibited a significantly lower level of type I interferon (IFN-I) following RNA mimics infection, encompassing IAV and poly I: C. After in vivo IAV infection, TRIM47 knockout mice showed an extremely lower survival rate, along with a lower level of IFN-I, higher viral load and more inflammatory cell infiltration in lungs compared to wild-type mice. Mechanistically, TRIM47 induces K68-linked ubiquitination of mitochondrial antiviral-signaling protein (MAVS), a key adaptor in RNA-sensing pathway, leading to robust IFN-I production. This K68-linked ubiquitination by TRIM47 is essential for MAVS aggregation and activation in macrophage. These findings provide compelling evidence that TRIM47 interacts with MAVS, enhancing IFN-I production to effectively restrict IAV infection in macrophages. This research not only advances our understanding of influenza pathogenesis but also opens avenues for potential therapeutic interventions.

EDITORIAL article Front. Immunol., 04 January 2024Sec. Viral Immunology Volume 14 - 2023 | https://doi.org/10.3389/fimmu.2023.1358542

RNA viruses cause numerous infectious diseases in humans and animals. The crosstalk between RNA viruses and the innate DNA sensing pathways attracts increasing attention. Recent studies showed that the cGAS-STING pathway plays an important role in restricting RNA viruses via mitochondria DNA (mtDNA) mediated activation. However, the mechanisms of cGAS mediated innate immune evasion by RNA viruses remain unknown. Here, we report that seneca valley virus (SVV) protease 3C disrupts mtDNA mediated innate immune sensing by cleaving porcine cGAS (pcGAS) in a species-specific manner. Mechanistically, a W/Q motif within the N-terminal domain of pcGAS is a unique cleavage site recognized by SVV 3C. Three conserved catalytic residues of SVV 3C cooperatively contribute to the cleavage of pcGAS, but not human cGAS (hcGAS) or mouse cGAS (mcGAS). Additionally, upon SVV infection and poly(dA:dT) transfection, pcGAS and SVV 3C colocalizes in the cells. Furthermore, SVV 3C disrupts pcGAS-mediated DNA binding, cGAMP synthesis and interferon induction by specifically cleaving pcGAS. This work uncovers a novel mechanism by which the viral protease cleaves the DNA sensor cGAS to evade innate immune response, suggesting a new antiviral approach against picornaviruses.

EDITORIAL article Front. Immunol., 01 December 2023Sec. Viral Immunology Volume 14 - 2023 | https://doi.org/10.3389/fimmu.2023.1341193