Search Results (80)

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disorder characterized by the destruction of insulin-producing pancreatic beta cells, resulting in lifelong insulin dependence. While genetic susceptibility—particularly human leukocyte antigen (HLA) class II alleles—is a major risk factor, accumulating evidence implicates viral infections as potential environmental triggers in disease onset and progression. This narrative review synthesizes current findings on the role of viral pathogens in T1DM pathogenesis. Enteroviruses, especially Coxsackie B strains, are the most extensively studied and show strong epidemiological and mechanistic associations with beta-cell autoimmunity. Large prospective studies—including Diabetes Virus Detection (DiViD), The environmental determinans of diabetes in the young (TEDDY), Miljøfaktorer i utvikling av type 1 diabetes (MIDIA), and Diabetes Autoimmunity Study in the Young (DAISY)—consistently demonstrate correlations between enteroviral presence and the initiation or acceleration of islet autoimmunity. Other viruses—such as mumps, rubella, rotavirus, influenza A (H1N1), and SARS-CoV-2—have been investigated for their potential involvement through direct cytotoxic effects, immune activation, or molecular mimicry. Interestingly, certain viruses like varicella-zoster virus (VZV) and cytomegalovirus (CMV) may exert modulatory or even protective influences on disease progression. Proposed mechanisms include direct beta-cell infection, molecular mimicry, bystander immune activation, and dysregulation of innate and adaptive immunity. Although definitive causality remains unconfirmed, the complex interplay between genetic predisposition, immune responses, and viral exposure underscores the need for further mechanistic research. Elucidating these pathways may inform future strategies for targeted prevention, early detection, and vaccine or antiviral development in at-risk populations. Full article

Schizophrenia is a challenging multifactorial neuropsychiatric disease that involves interactions between genetic susceptibility and environmental insults. Increasing evidence implicates viral infections as significant environmental contributors, particularly during sensitive neurodevelopmental periods. This review synthesises current findings on the viral hypothesis of schizophrenia, encompassing a wide array of neurotropic viruses, including influenza viruses, herpesviruses (HSV-1 and 2, CMV, VZV, EBV, HHV-6 and 8), hepatitis B and C viruses, HIV, HERVs, HTLV, Zika virus, BoDV, coronaviruses (including SARS-CoV-2), and others. These pathogens can contribute to schizophrenia through mechanisms such as direct microinvasion, persistent central nervous system infection, immune-mediated neuroinflammation, molecular mimicry, and the disturbance of the blood–brain barrier. Prenatal exposure to viral infections can trigger maternal immune activation, resulting in cytokine-mediated alterations in the neurological development of the foetus that persist into adulthood. Genetic studies highlight the role of immune-related loci, including major histocompatibility complex polymorphisms, in modulating susceptibility to infection and neurodevelopmental outcomes. Clinical data also support the “mild encephalitis” hypothesis, suggesting that a subset of schizophrenia cases involve low-grade chronic neuroinflammation. Although antipsychotics have some immunomodulatory effects, adjunctive anti-inflammatory therapies show promise, particularly in treatment-resistant cases. Despite compelling associations, pathogen-specific links remain inconsistent, emphasising the need for longitudinal studies and integrative approaches such as viromics to unravel causal relationships. This review supports a “multi-hit” model in which viral infections interfere with hereditary and immunological susceptibilities, enhancing schizophrenia risk. Elucidating these virus–immune–brain interactions may facilitate the discovery of biomarkers, targeted prevention, and novel therapeutic strategies for schizophrenia. Full article

Background: Protein kinase R (PKR) inhibits general mRNA translation by phosphorylating the alpha subunit of eukaryotic translation initiation factor 2 (eIF2). PKR also modulates NF-κB signaling during viral infections, but comparative studies of PKR-mediated NF-κB responses across mammalian species and their regulation by viral inhibitors remain largely unexplored. This study aimed to characterize the conserved antiviral and inflammatory roles of mammalian PKR orthologs and investigate their modulation by poxviral inhibitors. Methods: Using reporter gene assays and quantitative RT-PCR, we assessed the impact of 17 mammalian PKR orthologs on general translation inhibition, stress-responsive translation, and NF-κB-dependent induction of target genes. Congenic human and rabbit cell lines infected with a myxoma virus strain lacking PKR inhibitors were used to compare the effects of human and rabbit PKR on viral replication and inflammatory responses. Site-directed mutagenesis was employed to determine key residues responsible for differential sensitivity to the viral inhibitor M156. Results: All 17 mammalian PKR orthologs significantly inhibited general translation, strongly activated stress-responsive ATF4 translation, and robustly induced NF-κB target genes. Inhibition of these responses was specifically mediated by poxviral K3 orthologs that effectively suppressed PKR activation. Comparative analyses showed human and rabbit PKRs similarly inhibited virus replication and induced cytokine transcripts. Amino acid swaps between rabbit PKRs reversed their sensitivity to viral inhibitor M156 and NF-κB activation. Conclusions: Our data show that the tested PKR orthologs exhibit conserved dual antiviral and inflammatory regulatory roles, which can be antagonized by poxviral K3 orthologs that exploit eIF2α mimicry to modulate the PKR-NF-κB axis. Full article

The COVID-19 pandemic has revealed the profound and lasting impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on the nervous system. Beyond acute infection, SARS-CoV-2 acts as a potent immunomodulatory agent, disrupting immune homeostasis and contributing to persistent inflammation, autoimmunity, and neurodegeneration. Long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC), is characterized by a spectrum of neurological symptoms, including cognitive dysfunction, fatigue, neuropathy, and mood disturbances. These are linked to immune dysregulation involving cytokine imbalance, blood–brain barrier (BBB) disruption, glial activation, and T-cell exhaustion. Key biomarkers such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NFL) correlate with disease severity and chronicity. This narrative review examines the immunopathological mechanisms underpinning the neurological sequelae of long COVID, focusing on neuroinflammation, endothelial dysfunction, and molecular mimicry. We also assess the role of viral variants in shaping neuroimmune outcomes and explore emerging diagnostic and therapeutic strategies, including biomarker-guided and immune-targeted interventions. By delineating how SARS-CoV-2 reshapes neuroimmune interactions, this review aims to support the development of precision-based diagnostics and targeted therapies for long COVID-related neurological dysfunction. Emerging approaches include immune-modulatory agents (e.g., anti-IL-6), neuroprotective drugs, and strategies for repurposing antiviral or anti-inflammatory compounds in neuro-COVID. Given the high prevalence of comorbidities, personalized therapies guided by biomarkers and patient-specific immune profiles may be essential. Advancements in vaccine technologies and targeted biologics may also hold promise for prevention and disease modification. Finally, continued interdisciplinary research is needed to clarify the complex virus–immune–brain axis in long COVID and inform effective clinical management. Full article

Summary: COVID-19, caused by SARS-CoV-2, has been associated with a range of cardiovascular complications, including myocarditis. This review aims to systematically present the clinical manifestations, underlying pathophysiological mechanisms, diagnostic approaches, and management strategies for both COVID-19-associated myocarditis and myocarditis related to SARS-CoV-2 vaccination. We conducted a literature search using the PubMed database, covering studies published up to early 2024. Search terms included combinations of “COVID-19”, “Coronavirus”, “SARS-CoV-2”, and/or “vaccination” with “cardiac injury”, “cardiac inflammation”, “myocarditis”. The reported prevalence of COVID-19-associated myocarditis varies between 2.3% and 5.0%, though myocardial injury is more frequently observed than confirmed myocarditis. Pathophysiological mechanisms include direct viral damage, immune-mediated injury, and molecular mimicry. Clinically, patients may present with chest pain, dyspnea, and fever. Diagnostic workup includes electrocardiography (ECG), troponin measurement, echocardiography, cardiac magnetic resonance imaging (cMRI), and in selected cases, endomyocardial biopsy (EMB). The management and disposition of COVID-19-associated myocarditis varies according to severity, especially to allow targeted treatment of complications. Glucocorticoids are a mainstay of treatment in severe cases. Myocarditis following SARS-CoV-2 vaccination is rare, more frequently reported in males under 30 years, and is generally associated with a favorable prognosis. Despite this, the benefits of vaccination continue to outweigh the risks. COVID-19 is associated with an increased risk of heart failure and other cardiovascular complications, underlining the importance of long-term follow-up and preventive strategies. Further research is needed to better understand the pathogenesis and optimal management of myocarditis in the context of COVID-19, with the goal of developing evidence-based therapeutic algorithms. Full article

Self/non-self-discrimination is a fundamental aspect of adaptive immunity, which helps prevent harmful autoimmune responses. However, infectious agents can also act as environmental catalysts for autoimmune diseases. In this study, we investigated the role of molecular mimicry to self-antigens in epitope recognition in relation to infectious and autoimmune diseases. To this end, we performed BLAST searches against the human proteome, utilizing known virus-specific B and T cell peptide epitopes identified in association with autoimmune or infectious diseases in humans as our queries. Additionally, similar control analyses were carried out using non-B and non-T cell epitopes, consisting of random viral peptide sequences. Overall, our results endorsed a major role of molecular mimicry in instigating or sustaining autoimmunity associated with viral infections and challenged the prevailing view on self/non-self-discrimination for T cells. Additionally, we uncovered many virus-specific epitopes among those identified in association with infectious diseases with high similarity to self-antigens, which are primarily derived from human coronaviruses and various flaviviruses. Recognition of these epitopes could lead to autoimmunity against human proteins that are in cellular components concerning cell motility, cell membrane projections, and cellular synapses. Full article

Neuropathic pain has emerged as a significant concern for patients dealing with persistent post-COVID-19 symptoms. Small fiber neuropathy (SFN) has been identified as a potential underlying mechanism contributing to long-term pain in these patients. Despite an increasing body of evidence associating post-COVID-19 SFN with immune dysregulation and neuroinflammation, the exact pathophysiology and optimal treatment remains unclear. This review aims to explore the pathophysiology, diagnosis, proposed mechanisms, and treatment of post-COVID-19 SFN. A comprehensive literature review was conducted, examining studies on SFN, as well as SFN in the context of COVID-19, including clinical manifestations, diagnostic criteria, and potential treatment modalities. Evidence was gathered from case studies, observational reports, and clinical trials addressing post-COVID-19 neuropathy and SFN. SFN in long COVID presents a heterogeneous range of sensory and autonomic symptoms. Diagnosis relies on clinical evaluation, quantitative sensory testing, and confirmatory skin biopsy. Proposed mechanisms include autoimmune dysregulation, molecular mimicry, direct viral invasion of neural structures, and inflammatory responses. Pharmacological treatments—such as gabapentin, antidepressants, and corticosteroids—have demonstrated symptom relief, while immunomodulatory therapies show promise in immune-mediated cases. Non-pharmacological strategies warrant further investigation. Post-COVID-19 SFN represents a complex and multifactorial condition requiring a multidisciplinary approach to diagnosis and management. While merging evidence supports immune-mediated pathogenesis, further research is needed to establish definitive mechanisms and optimize targeted therapeutic strategies. Continued investigation into post-COVID-19 SFN will be crucial in addressing the long-term neurological sequelae of SARS-CoV-2 infection. Full article

HIV-1 integrase (IN), an essential viral protein that catalyzes integration, also influences non-integration functions such as particle production and morphogenesis. The mechanism by which non-integration functions are mediated is not completely understood. Several factors influence these non-integration functions, including the ability of IN to bind to viral RNA. INI1 is an integrase-binding host factor that influences HIV-1 replication at multiple stages, including particle production and particle morphogenesis. IN mutants defective for binding to INI1 are also defective for particle morphogenesis, similar to RNA-binding-defective IN mutants. Studies have indicated that the highly conserved Repeat (Rpt) 1, the IN-binding domain of INI1, structurally mimics TAR RNA, and that Rpt1 and TAR RNA compete for binding to IN. Based on the RNA mimicry, we propose that INI1 may function as a “place-holder” for viral RNA to facilitate proper ribonucleoprotein complex formation required during the assembly and particle morphogenesis of the HIV-1 virus. These studies suggest that drugs that target IN/INI1 interaction may lead to dual inhibition of both IN/INI1 and IN/RNA interactions to curb HIV-1 replication. Full article

Concern over COVID-19’s long-term influence on women’s reproductive health is growing, with emerging research suggesting potential links to ovarian dysfunction, menstrual irregularities, fertility challenges, and adverse pregnancy outcomes. Post-viral immune dysregulation is linked to both the development and exacerbation of autoimmune diseases, including multiple sclerosis (MS). Long COVID has been associated with immunological dysfunction, hormonal imbalances, and chronic inflammation, all of which may worsen autoimmune disorders and reproductive health issues. Long COVID is characterized by symptoms persisting for weeks or months beyond the acute infection phase. There are indications that prolonged COVID may contribute to autoimmune disease development through mechanisms such as immune hyperactivation, molecular mimicry, and dysregulated cytokine responses. Although this research field is still emerging, growing evidence suggests that SARS-CoV-2 infection may have lasting effects on women’s health, highlighting the need for further studies into its underlying mechanisms and long-term clinical outcomes. This review compiles recent findings on the long-term impact of COVID-19 on women’s reproductive health and its potential association with autoimmune disorders, particularly MS. Full article

Cross-kingdom infections, where pathogens from one kingdom infect organisms of another, were historically regarded as rare anomalies with minimal concern. However, emerging evidence reveals their increasing prevalence and potential to disrupt the delicate balance between plant, animal, and human health systems. Traditionally recognized as plant-specific, a subset of phytopathogens, including certain fungi, bacteria, viruses, and nematodes, have demonstrated the capacity to infect non-plant hosts, particularly immunocompromised individuals. These pathogens exploit conserved molecular mechanisms, such as immune evasion strategies, stress responses, and effector proteins, to breach host-specific barriers and establish infections. Specifically, fungal pathogens like Fusarium spp. and Colletotrichum spp. employ toxin-mediated cytotoxicity and cell-wall-degrading enzymes, while bacterial pathogens, such as Pseudomonas syringae, utilize type III secretion systems to manipulate host immune responses. Viral and nematode phytopathogens also exhibit molecular mimicry and host-derived RNA silencing suppressors to facilitate infections beyond plant hosts. This review features emerging cases of phytopathogen-driven animal and human infections and dissects the key molecular and ecological determinants that facilitate such cross-kingdom transmission. It also highlights critical drivers, including pathogen plasticity, horizontal gene transfer, and the convergence of environmental and anthropogenic stressors that breach traditional host boundaries. Furthermore, this review focuses on the underlying molecular mechanisms that enable host adaptation and the evolutionary pressures shaping these transitions. To address the complex threats posed by cross-kingdom phytopathogens, a comprehensive One Health approach that bridges plant, animal, and human health strategies is advocated. Integrating molecular surveillance, pathogen genomics, AI-powered predictive modeling, and global biosecurity initiatives is essential to detect, monitor, and mitigate cross-kingdom infections. This interdisciplinary approach not only enhances our preparedness for emerging zoonoses and phytopathogen spillovers but also strengthens ecological resilience and public health security in an era of increasing biological convergence. Full article

Viruses manipulate host cellular machinery to propagate their life cycle, with one key strategy being the mimicry of short linear motifs (SLiMs) found in host proteins. While databases continue to expand with virus–host protein–protein interaction (vhPPI) data, accurately predicting viral mimicry remains challenging due to the inherent degeneracy of SLiMs. In this study, we investigate how viral genomic composition influences motif mimicry and the mechanisms through which viruses hijack host cellular functions. We assessed domain–motif interaction (DMI) enrichment differences, and also predicted new DMIs based on known viral motifs with varying stringency levels, using SLiMEnrich v.1.5.1. Our findings reveal that dsDNA viruses capture significantly more known DMIs compared to other viral groups, with dsRNA viruses also exhibiting higher DMI enrichment than ssRNA viruses. Additionally, we identified new vhPPIs mediated via SLiMs, particularly within different viral genomic contexts. Understanding these interactions is vital for elucidating viral strategies to hijack host functions, which could inform the development of targeted antiviral therapies. Full article

The pathogenesis of primary biliary cholangitis (PBC) is not fully understood. Despite recent progress, many aspects require further clarification. Thus, PBC is regarded as an autoimmune disease, but immunosuppressive treatment, which is effective in other autoimmune diseases, is not working in the case of PBC. Moreover, there are controversies over the pathogenetic role of anti-mitochondrial antibodies as mitochondria are present in all cells but only cholangiocytes are damaged. In this review, all the proposed models and factors that have been involved in the pathogenesis of PBC are presented. They include mechanisms such as dysregulated autophagy, senescence, apoptosis, impairment of the protective bicarbonate umbrella, immunological abnormalities, the dysbiosis of gut microbiota, and the role of bile acids. Genetics of PBC and epigenetic transcriptional modifications are also presented. Data supporting molecular mimicry and the viral etiology of PBC are analyzed. Finally, an integrated model is proposed based on interactions of the factors that may participate in PBC pathogenesis. Therefore, the purpose of this review is to provide a unifying presentation of the various aspects of PBC pathophysiology, which will allow for a better understanding of this multifaceted disease. New treatment targets may also be identified in such a holistic model. Full article

Repeating sequences of DNA, or repetitive elements (REs), are common features across both prokaryotic and eukaryotic genomes. Unlike many of their protein-coding counterparts, the functions of REs in host cells remained largely unknown and have often been overlooked. While there is still more to learn about their functions, REs are now recognized to play significant roles in both beneficial and pathological processes in their hosts at the cellular and organismal levels. Therefore, in this review, we discuss the various types of REs and review what is known about their evolution. In addition, we aim to classify general mechanisms by which REs promote processes that are variously beneficial and harmful to host cells/organisms. Finally, we address the emerging role of REs in cancer, aging, and neurological disorders and provide insights into how RE modulation could provide new therapeutic benefits for these specific conditions. Full article

Polymyositis is a rarely reported complication of COVID-19 illness, especially in children. Molecular mimicry may be a cause of hyperactivated autoimmunity, leading to various clinical manifestations, including myopathies. Symptoms vary from mild muscle weakness to severe rhabdomyolysis. We review the literature on post-COVID myositis and report a case of severe polymyositis in a 7-year-old boy, following undefined viral infection 3 weeks before the onset of muscle pain. Patient’s condition deteriorated from physical activity-associated pain in the lower limbs to severe muscle weakness leading to dysphagia and mechanical ventilation. As antibodies against SARS-CoV-2 were detected and other possible conditions causing myositis were excluded, the diagnosis of post-COVID polymyositis was considered as the most likely. The patient was treated with high doses of methylprednisolone and cyclophosphamide, resulting in improvement. Although COVID-19 is becoming a seasonal disease, the infection itself and post-viral disorders, such as polymyositis, are still of great interest and require better investigation to ensure appropriate management for each individual. Our experience suggests that aggressive immunosuppressive therapy might be a solution for severe post-COVID-related diseases. This literature review is provided in addition to the case report presented at the 29th European Paediatric Rheumatology Congress; the abstract is available online in the Proceedings of the 29th European Paediatric Rheumatology Congress. Full article

Endogenous retroviruses (ERVs) are the remnants of retroviral germline infections and are highly abundant in the genomes of vertebrates. At one time considered to be nothing more than inert ‘junk’ within genomes, ERVs have been tolerated within host genomes over vast timescales, and their study continues to reveal complex co-evolutionary histories within their respective host species. For example, multiple instances have been characterized of ERVs having been ‘borrowed’ for normal physiology, from single copies to ones involved in various regulatory networks such as innate immunity and during early development. Within the cell, the accessibility of ERVs is normally tightly controlled by epigenetic mechanisms such as DNA methylation or histone modifications. However, these silencing mechanisms of ERVs are reversible, and epigenetic alterations to the chromatin landscape can thus lead to their aberrant expression, as is observed in abnormal cellular environments such as in tumors. In this review, we focus on ERV transcriptional control and draw parallels and distinctions concerning the loss of regulation in disease, as well as their precise regulation in early development. Full article