The Role of Circular RNAs in Coxsackievirus B3 Infection: Insights and Implications

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Coxsackievirus B3 (CVB3), an RNA virus from the Enterovirus genus of the Picornaviridae family, stands as a prominent agent in the onset of viral myocarditis (VM), a condition with global prevalence. While infections often present as asymptomatic or mild, severe cases, particularly in newborns and children, can manifest as pancreatitis, myocarditis, encephalitis, and type 1 diabetes. This highlights the critical nature of understanding CVB3 pathogenesis and the molecular mechanisms involved in its infection process.

Circular RNAs: Novel Regulators in Viral Infections

Among the non-coding RNAs (ncRNAs), circular RNAs (circRNAs) have emerged as significant players in the post-transcriptional regulation of gene expression. These molecules, characterized by their covalently closed loop structures, escape degradation by exonucleases, thus providing a stable platform for regulating protein translation and miRNA sequestration. CircRNAs have been implicated in various biological processes, including those related to viral infections, acting predominantly as miRNA sponges to modulate gene expression indirectly.

Recent studies have highlighted the role of specific circRNAs in influencing the replication and pathogenesis of various viruses. For example, circBACH1, circSIAE, and circEAF2 have been shown to regulate hepatitis B virus, CVB3, and Epstein–Barr virus replication, respectively, through distinct miRNA-targeted mechanisms. These findings underscore the importance of circRNAs in viral disease processes, pointing towards their potential as therapeutic targets.

circDDX17: A Key Player in CVB3 Infection

The focus of our study is hsa_circ_0063331, also known as circDDX17, which is derived from the DDX17 gene and significantly downregulated following CVB3 infection. The DDX17 protein, part of the DEAD-box helicase family, is crucial for RNA processes such as folding, splicing, and translation, and has been implicated in the replication cycles of various viruses. However, its role in CVB3 infection, particularly through the circDDX17 isoform, was previously unexplored.

Our research demonstrates that circDDX17 facilitates CVB3 replication by acting as a miRNA sponge for miR-1248. This interaction downregulates miR-1248 levels, leading to the derepression of its target, NOTCH Receptor 2 (NOTCH2), which subsequently influences the expression of methyltransferase-like protein 3 (METTL3). METTL3, a key component in the N6-methyladenosine (m6A) modification pathway, is known to play roles in the replication of various viruses, adding another layer to the complex interplay between circRNAs, miRNAs, and viral infection mechanisms.

Implications for CVB3 Infection and Beyond

This study sheds light on the intricate molecular interactions that facilitate CVB3 infection, highlighting the potential of targeting circRNAs and their associated miRNA networks as a novel therapeutic strategy. By unraveling the function of circDDX17 in CVB3 replication, we open new avenues for research into the mechanisms of viral diseases and their treatment. Furthermore, the implications of our findings extend beyond CVB3, suggesting a broader role for circRNAs in the pathogenesis of infectious diseases.

The discovery of circDDX17’s role in promoting CVB3 replication through miR-1248 and NOTCH2 highlights the complexity of viral infection mechanisms and the potential of circRNAs as targets for therapeutic intervention. Our findings contribute to the growing body of literature on the significance of ncRNAs in viral infections, paving the way for future studies aimed at exploiting these molecules for disease management and treatment strategies.

Coxsackievirus B3 and the Intricate Role of Circular RNAs in Myocarditis

Coxsackievirus B3 (CVB3), a leading cause of both acute and chronic myocarditis, poses a significant threat to heart health, potentially leading to myocardial fibrosis and dilated cardiomyopathy if not adequately controlled. The virus’s entry and replication in cardiomyocytes prompt cell damage and initiate host immune responses, which, when unresolved, result in chronic myocardial inflammation. Research has highlighted the importance of microRNAs (miRNAs) in regulating CVB3 replication, such as miR-324-3p’s inhibitory effect on the virus by targeting specific cellular pathways. However, the regulatory role of circular RNAs (circRNAs) in CVB3 replication has been less studied, despite their potential as miRNA sponges to modulate gene expression and influence viral infection outcomes.

Recent studies have unearthed circDDX17 as a novel regulator of CVB3 replication, marking a significant advance in understanding the virus’s pathogenesis. circDDX17 influences CVB3 replication negatively by interacting with miR-1248, which itself targets the NOTCH2 gene. NOTCH2 is known for its roles in cardiac fibrosis, heart development, and antiviral immune responses, and mutations within NOTCH2 have been implicated in various cardiac and vascular diseases. This interaction chain underscores the multifaceted regulatory mechanisms involving circRNAs and miRNAs in viral myocarditis, pointing to the broader implications of RNA modifications, like m6A methylation, in viral RNA metabolism and host-virus interactions.

The m6A modification, a conserved RNA modification found in eukaryotic nuclear RNAs, plays a pivotal role in RNA metabolism, including splicing, export, and decay. This modification is dynamically regulated by the “writers” complex, which includes METTL3 and METTL14. In the context of CVB3 infection, both METTL3 and METTL14 expression levels are modulated, indicating a sophisticated mechanism through which circDDX17 may enhance viral replication indirectly by affecting the m6A landscape within host cells. Specifically, METTL3’s interaction with NOTCH2, as demonstrated through co-immunoprecipitation analyses, suggests a direct link between m6A modification machinery and key regulatory pathways in viral replication.

This detailed exploration of circDDX17’s role in CVB3 infection expands our understanding of circRNAs’ function in viral diseases, offering novel insights into potential therapeutic targets. The interaction between circDDX17, miR-1248, and NOTCH2/METTL3 not only elucidates a complex regulatory network essential for CVB3 replication but also highlights the potential of targeting these molecular interactions in developing treatments for viral myocarditis​​​​​​.

These findings contribute significantly to the growing body of research on CVB3-induced myocarditis, underscoring the critical role of non-coding RNAs in the pathogenesis and progression of viral heart diseases. The potential therapeutic implications of these discoveries are vast, paving the way for novel strategies to combat viral myocarditis through manipulation of circRNA and miRNA interactions.

Comprehensive Overview of Coxsackievirus B3 Infection: Therapies, Spread, Dangers, Symptoms, and Bodily Damage

Coxsackievirus B3 (CVB3) is a significant human pathogen that causes a range of diseases from mild to severe, including myocarditis, dilated cardiomyopathy, and pancreatitis. Despite its impact on public health, therapeutic interventions specifically targeting CVB3 infection have been limited. However, recent research has explored novel therapeutic strategies and provided insights into the virus’s mechanisms of disease.

Novel Therapeutic Targets and Strategies

  • Metabolic Reprogramming: A study has shown that CVB3 infection induces metabolic alterations in host cells, particularly by increasing glycolysis levels. This finding has led to the proposal of using glycolysis inhibitors, such as 2-Deoxy-D-glucose and sodium oxide, as potential antiviral agents. These inhibitors have been demonstrated to significantly reduce CVB3 titers post-infection, offering a novel mechanism by which CVB3 infection can be controlled through the regulation of host cell metabolism​​. (https://pubmed.ncbi.nlm.nih.gov/36605593/)
  • Manassantin B: Another research avenue has focused on Manassantin B (Man B), a compound that exhibits antiviral activity against CVB3 infection by reducing pro-inflammatory cytokines and chemokines in the serum of infected mice. The study suggests that Man B ameliorates CVB3 infection-associated symptoms, functioning similarly to ribavirin, a known antiviral medication. This indicates Man B’s potential as a therapeutic agent in treating CVB3 infections, particularly during the early stages of infection​​. (https://www.nature.com/articles/s41598-019-45868-8)

Spread and Transmission

CVB3 is part of the Enterovirus genus and is transmitted primarily through the fecal-oral route, although respiratory transmission is also possible. The virus can spread through direct contact with an infected person, contaminated surfaces, or ingestion of contaminated water or food. Outbreaks have been associated with communal facilities, including schools and day-care centers, highlighting the importance of hygiene and sanitation measures in preventing the virus’s spread.

Dangers, Symptoms, and Bodily Damage

  • Acute and Chronic Myocarditis: CVB3 is a leading cause of myocarditis, an inflammation of the heart muscle that can lead to chronic heart conditions, including dilated cardiomyopathy. This can result in heart failure and is a significant cause of morbidity and mortality.
  • Pancreatitis and Type 1 Diabetes: The virus has also been linked to acute pancreatitis and is considered a trigger for type 1 diabetes by inducing islet autoimmunity in susceptible individuals.
  • Other Symptoms: Infection can present with a wide range of symptoms, from mild, flu-like symptoms to more severe conditions such as aseptic meningitis, encephalitis, and severe neonatal sepsis-like disease.

The development of effective therapies against CVB3 is crucial in managing and mitigating the health impacts of this virus. Research into metabolic reprogramming and compounds like Manassantin B offers promising avenues for therapeutic intervention. Continued exploration of novel therapeutic targets and strategies, alongside preventive measures to curb the spread of CVB3, is essential in addressing the challenges posed by this virus.

Coxsackievirus B3: Global Incidence, Molecular Profile, and Impact on Human Health

Coxsackievirus B3 (CVB3) is a single-stranded RNA virus belonging to the Enterovirus genus, notorious for its role in a variety of human diseases. The virus is implicated in myocarditis, dilated cardiomyopathy, and pancreatitis, among other conditions. Despite its significant impact on public health, CVB3 remains a challenge with no specific antiviral treatments currently recommended. The management of CVB3 infections primarily revolves around symptomatic and supportive care, with particular attention to complications such as seizures or heart failure that may arise from neurological or myocardial syndromes, respectively​​.

Global Incidence and Evolutionary History

CVB3 has demonstrated a capacity for widespread outbreaks, notably associated with hand, foot, and mouth disease (HFMD), as observed in several instances across China. Phylogenetic analyses have shed light on the evolutionary trajectory of CVB3, highlighting its genetic diversity and the distinct epidemiological patterns it exhibits in various geographic regions. Studies incorporating whole-genome sequencing have been pivotal in understanding CVB3’s genetic landscape, offering insights into its transmission dynamics and aiding in the development of surveillance strategies​​.

Molecular Profile and Pathogenicity

The molecular profile of CVB3 reveals a virus adept at manipulating host cell mechanisms to its advantage, contributing to the diverse clinical manifestations seen in infected individuals. The virus’s ability to induce metabolic alterations in host cells, for instance, has been proposed as a novel target for therapeutic intervention. By increasing glycolysis levels within host cells, CVB3 not only ensures a conducive environment for its replication but also opens potential avenues for treatment via glycolysis inhibition​​.

Therapeutic Approaches and Solutions

In the absence of targeted antiviral therapies, recent research has focused on novel strategies to mitigate the impact of CVB3 infections. Compounds like Manassantin B have shown promise in reducing pro-inflammatory cytokines and chemokines in CVB3-infected mice, offering a potential therapeutic pathway by modulating the host immune response. Additionally, the exploration of metabolic reprogramming as a therapeutic target provides a unique angle for future treatment developments, aiming to disrupt the metabolic alterations induced by CVB3 infection​​​​.

Transition from Coxsackievirus B3-Induced Myocarditis to Dilated Cardiomyopathy: Insights and Therapeutic Approaches

Myocarditis, often triggered by viral infections such as Coxsackievirus B3 (CVB3), can lead to dilated cardiomyopathy (DCM), a condition marked by the heart’s diminished capacity to pump blood effectively. This transition involves complex interactions between the virus, host immune responses, and various molecular pathways, including metabolic remodeling and cytokine signaling.

Viral Proteases and Host Immune Response

CVB3 encodes proteases, notably 2A and 3C, that disrupt host cellular functions by cleaving critical proteins involved in maintaining cellular integrity and immune response. The cleavage of proteins like eIF4G halts protein synthesis and induces apoptosis, while the disruption of mitochondrial antiviral-signaling proteins (MAVS) and TIR-domain-containing adapter-inducing interferon-β (TRIF) dampens the antiviral immune response. These actions impair the cell’s ability to counter the viral infection effectively, contributing to the progression of myocarditis to DCM​​.

Iron Metabolism and Mitochondrial Dysfunction

The relationship between CVB3 infection and altered iron metabolism is pivotal to understanding myocarditis’s progression to DCM. Iron is crucial for mitochondrial function and energy metabolism; however, CVB3 infection disrupts iron homeostasis, leading to either iron deficiency or overload. Such disturbances can impair mitochondrial function and contribute to the pathogenesis of DCM through mechanisms like ferroptosis, an iron-dependent form of cell death characterized by lipid peroxidation​​.

Inflammatory Mediators and Metabolic Remodeling

CVB3-induced myocarditis is associated with significant inflammatory responses, including the upregulation of cytokines and chemokines that mediate immune cell recruitment and activation. This inflammatory milieu contributes to metabolic remodeling, with alterations in lipid and glucose metabolism that impair cardiac function. The release of pro-inflammatory cytokines like TNF-α by infiltrating immune cells exacerbates cardiac damage, promoting the development of DCM​​.

Potential Therapeutic Targets

Understanding the molecular mechanisms underpinning the transition from myocarditis to DCM has identified potential therapeutic targets. Strategies aiming to mitigate the effects of CVB3 proteases, restore iron homeostasis, and modulate the immune response may offer new avenues for treatment. Early intervention with agents targeting these pathways could inhibit the development of chronic cardiomyopathy and improve patient outcomes​​.


Transition from Coxsackievirus B3-Induced Myocarditis to Dilated Cardiomyopathy

CategoryDetailsImplicationsPotential Therapeutic Targets
Viral ProteasesCVB3 proteases 2A and 3C disrupt cellular and immune functions by cleaving key proteins like eIF4G, MAVS, and TRIF​​.Impairment of antiviral immune responses and apoptosis induction, facilitating viral replication and spread.Protease inhibitors; modulation of immune protein activity.
Iron Metabolism and Mitochondrial DysfunctionAltered iron homeostasis and mitochondrial damage through ferroptosis, characterized by lipid peroxidation​​.Compromised energy metabolism leading to cardiomyocyte death and contributing to DCM pathogenesis.Iron chelators or supplements; antioxidants to mitigate oxidative stress.
Inflammatory MediatorsElevated cytokines and chemokines contribute to immune cell recruitment and activation, aggravating cardiac inflammation​​.Sustained inflammation results in cardiomyocyte necrosis, fibrosis, and metabolic remodeling, impairing heart function.Anti-inflammatory agents; cytokine inhibitors to reduce immune cell infiltration and activation.
Metabolic RemodelingCVB3 infection leads to shifts in lipid and glucose metabolism, impacting mitochondrial oxidative phosphorylation and energy production​​.Altered metabolic pathways exacerbate cardiac dysfunction, contributing to the progression toward DCM.Metabolic modulators to restore normal energy metabolism; interventions targeting mitochondrial biogenesis and function.

References:

  • [35†source]: PubMed – Role of Coxsackievirus B3-Induced Immune Responses in the Transition from Myocarditis to Dilated Cardiomyopathy and Heart Failure.
  • [37†source]: PubMed – Advancement of Mechanisms of Coxsackie Virus B3-Induced Myocarditis Pathogenesis and the Potential Therapeutic Targets.

This scheme integrates critical insights into how CVB3 induces myocarditis and the subsequent transition to DCM, highlighting the interplay between viral factors, host immune responses, and metabolic changes. Each category identifies potential therapeutic targets aiming to intercept the pathological progression from initial infection to chronic heart disease. This approach underscores the importance of multidisciplinary research in developing effective treatments for viral myocarditis and its severe outcomes.


Conclusion

The transition from CVB3-induced myocarditis to DCM is a multifaceted process involving direct viral effects, immune-mediated damage, metabolic alterations, and mitochondrial dysfunction. Continued research into these mechanisms is essential for developing targeted therapies to prevent the progression of viral myocarditis to DCM, a condition with significant morbidity and mortality.

The challenge posed by CVB3 to global public health is compounded by its genetic diversity and the broad spectrum of diseases it can cause. While current management strategies are limited to symptomatic treatment, ongoing research into the virus’s molecular mechanisms and potential therapeutic targets holds promise for more effective interventions in the future. As our understanding of CVB3’s genomic epidemiology and pathogenesis deepens, so too does the potential for developing novel treatment modalities to combat this pervasive pathogen.


reference link : https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2022.1012124/full

https://www.mdpi.com/1422-0067/24/9/7717

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