Crosstalk Between Innate Immunity and Autophagy in Viral Myocarditis Leading to Dilated Cardiomyopathy.

Viral myocarditis, characterised by inflammation of the heart muscle, presents a significant challenge to global public health, particularly affecting younger individuals and often progressing to dilated cardiomyopathy (DCM), a leading cause of heart failure. Despite ongoing research efforts, viable treatments for this condition remain elusive. Recent studies have shed light on the complex interplay between the innate immune response and autophagy mechanisms, revealing their pivotal roles in the pathogenesis of viral myocarditis and subsequent DCM development. This review aims to delve into the recent advancements in understanding the molecular mechanisms and pathways that intersect innate immunity and autophagy in the context of viral myocarditis. Furthermore, it explores the potential therapeutic implications of these findings, offering insights into promising avenues for the management and treatment of this debilitating condition.

Infectious viruses and neurodegenerative diseases: The mitochondrial defect hypothesis.

Global attention is riveted on neurodegenerative diseases due to their unresolved aetiologies and lack of efficacious therapies. Two key factors implicated include mitochondrial impairment and microglial ageing. Several viral infections, including Herpes simplex virus-1 (HSV-1), human immunodeficiency virus (HIV) and Epstein-Barr virus, are linked to heightened risk of these disorders. Surprisingly, numerous studies indicate viruses induce these aforementioned precipitating events. Epstein-Barr virus, Hepatitis C Virus, HIV, respiratory syncytial virus, HSV-1, Japanese Encephalitis Virus, Zika virus and Enterovirus 71 specifically impact mitochondrial function, leading to mitochondrial malfunction. These vital organelles govern various cell activities and, under specific circumstances, trigger microglial ageing. This article explores the role of viral infections in elucidating the pathogenesis of neurodegenerative ailments. Various viruses instigate microglial ageing via mitochondrial destruction, causing senescent microglia to exhibit activated behaviour, thereby inducing neuroinflammation and contributing to neurodegeneration.

The Role of the Nrf2 Pathway in Airway Tissue Damage Due to Viral Respiratory Infections.

Respiratory viruses constitute a significant cause of illness and death worldwide. Respiratory virus-associated injuries include oxidative stress, ferroptosis, inflammation, pyroptosis, apoptosis, fibrosis, autoimmunity, and vascular injury. Several studies have demonstrated the involvement of the nuclear factor erythroid 2-related factor 2 (Nrf2) in the pathophysiology of viral infection and associated complications. It has thus emerged as a pivotal player in cellular defense mechanisms against such damage. Here, we discuss the impact of Nrf2 activation on airway injuries induced by respiratory viruses, including viruses, coronaviruses, rhinoviruses, and respiratory syncytial viruses. The inhibition or deregulation of Nrf2 pathway activation induces airway tissue damage in the presence of viral respiratory infections. In contrast, Nrf2 pathway activation demonstrates protection against tissue and organ injuries. Clinical trials involving Nrf2 agonists are needed to define the effect of Nrf2 therapeutics on airway tissues and organs damaged by viral respiratory infections.

An Update on Viral Infection-Associated Collapsing Glomerulopathy.

The COVID-19 era has been a reminder to clinicians around the world of the important role that viral infections play in promoting glomerular disease. Several viral infections including human immunodeficiency virus (HIV), severe acute respiratory syndrome coronavirus 2, Epstein-Barr virus, cytomegalovirus, and parvovirus B19 can cause podocyte injury and present with a collapsing glomerulopathy (CG) variant of focal segmental glomerulosclerosis or minimal change disease. CG associated with COVID-19 has been termed COVID-19-associated nephropathy due to its striking resemblance to HIV-associated nephropathy. Host susceptibility is a major determinant of viral infection-associated CG, and the presence of two APOL1 risk variants explains most of the racial predilection to viral-associated CG observed in individuals of African ancestry. Interactions between APOL1 risk variants, viral genes, and the systemic inflammatory response to viral infection all contribute to kidney injury. This review will summarize our current knowledge of viral infection-associated CG, focusing primarily on the clinical presentation, histological features, mechanisms, and disease course of HIV-associated nephropathy and COVID-19-associated nephropathy.

Molecular mechanisms of secretory autophagy and its potential role in diseases.

Autophagy is a cellular degradation system that recycles or degrades damaged organelles, viral particles, and aggregated proteins through the lysosomal pathway. Autophagy plays an indispensable role in cellular homeostasis and communication processes. An interesting aspect is that autophagy also mediates the secretion of cellular contents, a process known as secretory autophagy. Secretory autophagy differs from macroautophagy, which sequesters recruited proteins, organelles, or viral particles into autophagosomes and degrades these sequesters in lysosomes, while the secretory autophagy pathway participates in the extracellular export of cellular contents sequestered by autophagosomes through autophagy and endosomal modulators. Recent evidence reveals that secretory autophagy is pivotal in the occurrence and progression of diseases. In this review, we summarize the molecular mechanisms of secretory autophagy. Furthermore, we review the impact of secretory autophagy on diseases, including cancer, viral infectious diseases, neurodegenerative diseases, and cardiovascular diseases. Considering the pleiotropic actions of secretory autophagy on diseases, studying the mechanism of secretory autophagy may help to understand the relevant pathophysiological processes.

Eosinophil activation during immune responses: an ultrastructural view with an emphasis on viral diseases.

Eosinophils are cells of the innate immune system that orchestrate complex inflammatory responses. The study of the cell biology of eosinophils, particularly associated with cell activation, is of great interest to understand their immune responses. From a morphological perspective, activated eosinophils show ultrastructural signatures that have provided critical insights into the comprehension of their functional capabilities. Application of conventional transmission electron microscopy in combination with quantitative assessments (quantitative transmission electron microscopy), molecular imaging (immunoEM), and 3-dimensional electron tomography have generated important insights into mechanisms of eosinophil activation. This review explores a multitude of ultrastructural events taking place in eosinophils activated in vitro and in vivo as key players in allergic and inflammatory diseases, with an emphasis on viral infections. Recent progress in our understanding of biological processes underlying eosinophil activation, including in vivo mitochondrial remodeling, is discussed, and it can bring new thinking to the field.

Role of lymphatic endothelium specific hyaluronan receptor 1 in virus infection and associated diseases.

Lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) serves as a prominent marker for lymphatic endothelial cells (LECs) and is pivotal in the process of lymphangiogenesis, a critical factor in cancer development and metastasis. Overexpression of LYVE-1 has been observed in various cancers, where it is recognized as an adverse prognostic indicator. Targeting LYVE-1 has demonstrated inhibitory effects on tumor cell proliferation, migration, and the formation of lymph node metastases both in vitro and in vivo. While extensive research has focused on the role of LYVE-1 in cancer cells, its involvement in virus infection and associated diseases remains largely unexplored. This review consolidates recent findings regarding the expression of LYVE-1 and its functions in lymphangiogenesis during various viral infections and the development of related diseases, with a particular emphasis on Kaposi's sarcoma herpesvirus. Despite the limited available data, it is evident that further studies are essential to comprehensively understand the contribution of LYVE-1 to viral pathogenesis and oncogenesis.

Kidney double positive T cells have distinct characteristics in normal and diseased kidneys.

Multiple types of T cells have been described and assigned pathophysiologic functions in the kidneys. However, the existence and functions of TCR+CD4+CD8+ (double positive; DP) T cells are understudied in normal and diseased murine and human kidneys. We studied kidney DPT cells in mice at baseline and after ischemia reperfusion (IR) and cisplatin injury. Additionally, effects of viral infection and gut microbiota were studied. Human kidneys from patients with renal cell carcinoma were evaluated. Our results demonstrate that DPT cells expressing CD4 and CD8 co-receptors constitute a minor T cell population in mouse kidneys. DPT cells had significant Ki67 and PD1 expression, effector/central memory phenotype, proinflammatory cytokine (IFNγ, TNFα and IL-17) and metabolic marker (GLUT1, HKII, CPT1a and pS6) expression at baseline. IR, cisplatin and viral infection elevated DPT cell proportions, and induced distinct functional and metabolic changes. scRNA-seq analysis showed increased expression of Klf2 and Ccr7 and enrichment of TNFα and oxidative phosphorylation related genes in DPT cells. DPT cells constituted a minor population in both normal and cancer portion of human kidneys. In conclusion, DPT cells constitute a small population of mouse and human kidney T cells with distinct inflammatory and metabolic profile at baseline and following kidney injury.

Cell-type dependence of necroptosis pathways triggered by viral infection.

Necroptosis, a potent host defense mechanism, limits viral replication and pathogenesis through three distinct initiation pathways. Toll-like receptor 3 (TLR3) via TIR-domain-containing adapter-inducing interferon-ß (TRIF), Z-DNA-binding protein 1 (ZBP1) and tumor necrosis factor (TNF)α mediate necroptosis, with ZBP1 and TNF playing pivotal roles in controlling viral infections, with the role of TLR3-TRIF being less clear. ZBP1-mediated necroptosis is initiated when host ZBP1 senses viral Z-form double stranded RNA and recruits receptor-interacting serine/threonine-protein kinase 3 (RIPK3), driving a mixed lineage kinase domain-like pseudokinase (MLKL)-dependent necroptosis pathway, whereas TNF-mediated necroptosis is initiated by TNF signaling, which drives a RIPK1-RIPK3-MLKL pathway, resulting in necroptosis. Certain viruses (cytomegalovirus, herpes simplex virus and vaccinia) have evolved to produce proteins that compete with host defense systems, preventing programmed cell death pathways from being initiated. Two engineered viruses deficient of active forms of these proteins, murine cytomegalovirus M45mutRHIM and vaccinia virus E3∆Zα, trigger ZBP1-dependent necroptosis in mouse embryonic fibroblasts. By contrast, when bone-marrow-derived macrophages are infected with the viruses, necroptosis is initiated predominantly through the TNF-mediated pathway. However, when the TNF pathway is blocked by RIPK1 inhibitors or a TNF blockade, ZBP1-mediated necroptosis becomes the prominent pathway in bone-marrow-derived macrophages. Overall, these data implicate a cell-type preference for either TNF-mediated or ZBP1-mediated necroptosis pathways in host responses to viral infections. These preferences are important to consider when evaluating disease models that incorporate necroptosis because they may contribute to tissue-specific reactions that could alter the balance of inflammation versus control of virus, impacting the organism as a whole.

Dengue virus infection induces selective expansion of Vγ4 and Vγ6TCR γδ T cells in the small intestine and a cytokine storm driving vascular leakage in mice.

Dengue is a major health problem in tropical and subtropical regions. Some patients develop a severe form of dengue, called dengue hemorrhagic fever, which can be fatal. Severe dengue is associated with a transient increase in vascular permeability. A cytokine storm is thought to be the cause of the vascular leakage. Although there are various research reports on the pathogenic mechanism, the complete pathological process remains poorly understood. We previously reported that dengue virus (DENV) type 3 P12/08 strain caused a lethal systemic infection and severe vascular leakage in interferon (IFN)-α/ß and γ receptor knockout mice (IFN-α/ß/γRKO mice), and that blockade of TNF-α signaling protected mice. Here, we performed transcriptome analysis of liver and small intestine samples collected chronologically from P12/08-infected IFN-α/ß/γRKO mice in the presence/absence of blockade of TNF-α signaling and evaluated the cytokine and effector-level events. Blockade of TNF-α signaling mainly protected the small intestine but not the liver. Infection induced the selective expansion of IL-17A-producing Vγ4 and Vγ6 T cell receptor (TCR) γδ T cells in the small intestine, and IL-17A, together with TNF-α, played a critical role in the transition to severe disease via the induction of inflammatory cytokines such as TNF-α, IL-1ß, and particularly the excess production of IL-6. Infection also induced the infiltration of neutrophils, as well as neutrophil collagenase/matrix metalloprotease 8 production. Blockade of IL-17A signaling reduced mortality and suppressed the expression of most of these cytokines, including TNF-α, indicating that IL-17A and TNF-α synergistically enhance cytokine expression. Blockade of IL-17A prevented nuclear translocation of NF-κB p65 in stroma-like cells and epithelial cells in the small intestine but only partially prevented recruitment of immune cells to the small intestine. This study provides an overall picture of the pathogenesis of infection in individual mice at the cytokine and effector levels.

Alpha-synuclein in Parkinson's disease: a villain or tragic hero? A critical view of the formation of α-synuclein aggregates induced by dopamine metabolites and viral infection.

INTRODUCTION: Since the discovery of the presynaptic protein α-synuclein (aSyn) as a central player in Parkinson's disease (PD), several key questions on the function of the protein in neurodegeneration processes remain unclear, including: is there a synergy between dopamine metabolism and the formation of toxic aSyn species in neurons? What is the role of aSyn in the immunological system? AREAS COVERED: Herein, the authors revisit the intricate pathways related to dopamine metabolism and how it impacts on aSyn aggregation/function. Additionally, they discuss the importance of aSyn in the immune response to viral infections as well as the current findings on the possible protective role of certain virus vaccines against PD and other neuropathologies. EXPERT OPINION: The physiological function of aSyn seems to cover different pathways, such as immune response against infections and a neuroprotective role, besides the already-established regulation of synaptic vesicle trafficking. Clinical studies with monoclonal antibodies against aSyn aggregates have shown disappointing results in patients with early-stage PD. Alternatively, we could consider, as immunological target, specific neurotoxic oligomers of aSyn formed in the presence of dopamine metabolites, such as DOPAL. Nevertheless, the crucial question remains as to whether removing these protein deposits will affect the clinical course of the disease.

Signatures for viral infection and inflammation in the proximal olfactory system in familial Alzheimer's disease.

Alzheimer's disease (AD) is characterized by deficits in olfaction and olfactory pathology preceding diagnosis of dementia. Here we analyzed differential gene and protein expression in the olfactory bulb (OB) and tract (OT) of familial AD (FAD) individuals carrying the autosomal dominant presenilin 1 E280A mutation. Compared to control, FAD OT had increased immunostaining for ß-amyloid (Aß) and CD68 in high and low myelinated regions, as well as increased immunostaining for Iba1 in the high myelinated region. In FAD samples, RNA sequencing showed: (1) viral infection in the OB; (2) inflammation in the OT that carries information via entorhinal cortex from the OB to hippocampus, a brain region essential for learning and memory; and (3) decreased oligodendrocyte deconvolved transcripts. Interestingly, spatial proteomic analysis confirmed altered myelination in the OT of FAD individuals, implying dysfunction of communication between the OB and hippocampus. These findings raise the possibility that viral infection and associated inflammation and dysregulation of myelination of the olfactory system may disrupt hippocampal function, contributing to acceleration of FAD progression.

Neutrophil Functional Heterogeneity and Implications for Viral Infections and Treatments.

Evidence suggests that neutrophils exert specialized effector functions during infection and inflammation, and that these cells can affect the duration, severity, and outcome of the infection. These functions are related to variations in phenotypes that have implications in immunoregulation during viral infections. Although the complexity of the heterogeneity of neutrophils is still in the process of being uncovered, evidence indicates that they display phenotypes and functions that can assist in viral clearance or augment and amplify the immunopathology of viruses. Therefore, deciphering and understanding neutrophil subsets and their polarization in viral infections is of importance. In this review, the different phenotypes of neutrophils and the roles they play in viral infections are discussed. We also examine the possible ways to target neutrophil subsets during viral infections as potential anti-viral treatments.

A genome-wide association study in a large community-based cohort identifies multiple loci associated with susceptibility to bacterial and viral infections.

There is limited data on host-specific genetic determinants of susceptibility to bacterial and viral infections. Genome-wide association studies using large population cohorts can be a first step towards identifying patients prone to infectious diseases and targets for new therapies. Genetic variants associated with clinically relevant entities of bacterial and viral infections (e.g., abdominal infections, respiratory infections, and sepsis) in 337,484 participants of the UK Biobank cohort were explored by genome-wide association analyses. Cases (n = 81,179) were identified based on ICD-10 diagnosis codes of hospital inpatient and death registries. Functional annotation was performed using gene expression (eQTL) data. Fifty-seven unique genome-wide significant loci were found, many of which are novel in the context of infectious diseases. Some of the detected genetic variants were previously reported associated with infectious, inflammatory, autoimmune, and malignant diseases or key components of the immune system (e.g., white blood cells, cytokines). Fine mapping of the HLA region revealed significant associations with HLA-DQA1, HLA-DRB1, and HLA-DRB4 locus alleles. PPP1R14A showed strong colocalization with abdominal infections and gene expression in sigmoid and transverse colon, suggesting causality. Shared significant loci across infections and non-infectious phenotypes in the UK Biobank cohort were found, suggesting associations for example between SNPs identified for abdominal infections and CRP, rheumatoid arthritis, and diabetes mellitus. We report multiple loci associated with bacterial and viral infections. A better understanding of the genetic determinants of bacterial and viral infections can be useful to identify patients at risk and in the development of new drugs.

TBK1-METTL3 axis facilitates antiviral immunity.

mRNA m6A modification is heavily involved in modulation of immune responses. However, its function in antiviral immunity is controversial, and how immune responses regulate m6A modification remains elusive. We here find TBK1, a key kinase of antiviral pathways, phosphorylates the core m6A methyltransferase METTL3 at serine 67. The phosphorylated METTL3 interacts with the translational complex, which is required for enhancing protein translation, thus facilitating antiviral responses. TBK1 also promotes METTL3 activation and m6A modification to stabilize IRF3 mRNA. Type I interferon (IFN) induction is severely impaired in METTL3-deficient cells. Mettl3fl/fl-lyz2-Cre mice are more susceptible to influenza A virus (IAV)-induced lethality than control mice. Consistently, Ythdf1-/- mice show higher mortality than wild-type mice due to decreased IRF3 expression and subsequently attenuated IFN production. Together, we demonstrate that innate signals activate METTL3 via TBK1, and METTL3-mediated m6A modification secures antiviral immunity by promoting mRNA stability and protein translation.

Special Issue "Emerging Virus Infections in Adverse Pregnancy Outcomes".

Dear contributors and readers, [...].

Neutrophil subsets and their differential roles in viral respiratory diseases.

Neutrophils play significant roles in immune homeostasis and as neutralizers of microbial infections. Recent evidence further suggests heterogeneity of neutrophil developmental and activation states that exert specialized effector functions during inflammatory disease conditions. Neutrophils can play multiple roles during viral infections, secreting inflammatory mediators and cytokines that contribute significantly to host defense and pathogenicity. However, their roles in viral immunity are not well understood. In this review, we present an overview of neutrophil heterogeneity and its impact on the course and severity of viral respiratory infectious diseases. We focus on the evidence demonstrating the crucial roles neutrophils play in the immune response toward respiratory infections, using influenza as a model. We further extend the understanding of neutrophil function with the studies pertaining to COVID-19 disease and its neutrophil-associated pathologies. Finally, we discuss the relevance of these results for future therapeutic options through targeting and regulating neutrophil-specific responses.

A systematic review and meta-analysis of the aetiological agents of non-malarial febrile illnesses in Africa.

BACKGROUND: The awareness of non-malarial febrile illnesses (NMFIs) has been on the rise over the last decades. Therefore, we undertook a systematic literature review and meta-analysis of causative agents of non-malarial fevers on the African continent. METHODOLOGY: We searched for literature in African Journals Online, EMBASE, PubMed, Scopus, and Web of Science databases to identify aetiologic agents that had been reported and to determine summary estimates of the proportional morbidity rates (PMr) associated with these pathogens among fever patients. FINDINGS: A total of 133 studies comprising 391,835 patients from 25 of the 54 African countries were eligible. A wide array of aetiologic agents were described with considerable regional differences among the leading agents. Overall, bacterial pathogens tested from blood samples accounted for the largest proportion. The summary estimates from the meta-analysis were low for most of the agents. This may have resulted from a true low prevalence of the agents, the failure to test for many agents or the low sensitivity of the diagnostic methods applied. Our meta-regression analysis of study and population variables showed that diagnostic methods determined the PMr estimates of typhoidal Salmonella and Dengue virus. An increase in the PMr of Klebsiella spp. infections was observed over time. Furthermore, the status of patients as either inpatient or outpatient predicted the PMr of Haemophilus spp. infections. CONCLUSION: The small number of epidemiological studies and the variety of NMFI agents on the African continent emphasizes the need for harmonized studies with larger sample sizes. In particular, diagnostic procedures for NMFIs should be standardized to facilitate comparability of study results and to improve future meta-analyses. Reliable NMFI burden estimates will inform regional public health strategies.

PANoptosis in Viral Infection: The Missing Puzzle Piece in the Cell Death Field.

In the past decade, emerging viral outbreaks like SARS-CoV-2, Zika and Ebola have presented major challenges to the global health system. Viruses are unique pathogens in that they fully rely on the host cell to complete their lifecycle and potentiate disease. Therefore, programmed cell death (PCD), a key component of the host innate immune response, is an effective strategy for the host cell to curb viral spread. The most well-established PCD pathways, pyroptosis, apoptosis and necroptosis, can be activated in response to viruses. Recently, extensive crosstalk between PCD pathways has been identified, and there is evidence that molecules from all three PCD pathways can be activated during virus infection. These findings have led to the emergence of the concept of PANoptosis, defined as an inflammatory PCD pathway regulated by the PANoptosome complex with key features of pyroptosis, apoptosis, and/or necroptosis that cannot be accounted for by any of these three PCD pathways alone. While PCD is important to eliminate infected cells, many viruses are equipped to hijack host PCD pathways to benefit their own propagation and subvert host defense, and PCD can also lead to the production of inflammatory cytokines and inflammation. Therefore, PANoptosis induced by viral infection contributes to either host defense or viral pathogenesis in context-specific ways. In this review, we will discuss the multi-faceted roles of PCD pathways in controlling viral infections.

ViMIC: a database of human disease-related virus mutations, integration sites and cis-effects.

Molecular mechanisms of virus-related diseases involve multiple factors, including viral mutation accumulation and integration of a viral genome into the host DNA. With increasing attention being paid to virus-mediated pathogenesis and the development of many useful technologies to identify virus mutations (VMs) and viral integration sites (VISs), much research on these topics is available in PubMed. However, knowledge of VMs and VISs is widely scattered in numerous published papers which lack standardization, integration and curation. To address these challenges, we built a pilot database of human disease-related Virus Mutations, Integration sites and Cis-effects (ViMIC), which specializes in three features: virus mutation sites, viral integration sites and target genes. In total, the ViMIC provides information on 31 712 VMs entries, 105 624 VISs, 16 310 viral target genes and 1 110 015 virus sequences of eight viruses in 77 human diseases obtained from the public domain. Furthermore, in ViMIC users are allowed to explore the cis-effects of virus-host interactions by surveying 78 histone modifications, binding of 1358 transcription regulators and chromatin accessibility on these VISs. We believe ViMIC will become a valuable resource for the virus research community. The database is available at http://bmtongji.cn/ViMIC/index.php.