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Viruses Apr 2024Coxsackievirus B3 (CVB3) is a positive single-strand RNA genome virus which belongs to the enterovirus genus in the picornavirus family, like poliovirus. It is one of...
Coxsackievirus B3 (CVB3) is a positive single-strand RNA genome virus which belongs to the enterovirus genus in the picornavirus family, like poliovirus. It is one of the most prevalent pathogens that cause myocarditis and pancreatitis in humans. However, a suitable therapeutic medication and vaccination have yet to be discovered. Caboxamycin, a benzoxazole antibiotic isolated from the culture broth of the marine strain sp., SC0774, showed an antiviral effect in CVB3-infected HeLa cells and a CVB3-induced myocarditis mouse model. Caboxamycin substantially decreased CVB3 VP1 production and cleavage of translation factor eIF4G1 from CVB3 infection. Virus-positive and -negative strand RNA was dramatically reduced by caboxamycin treatment. In addition, the cleavage of the pro-apoptotic molecules BAD, BAX, and caspase3 was significantly inhibited by caboxamycin treatment. In animal experiments, the survival rate of mice was improved following caboxamycin treatment. Moreover, caboxamycin treatment significantly decreased myocardial damage and inflammatory cell infiltration. Our study showed that caboxamycin dramatically suppressed cardiac inflammation and mouse death. This result suggests that caboxamycin may be suitable as a potential antiviral drug for CVB3.
Topics: Animals; Myocarditis; Mice; Disease Models, Animal; Coxsackievirus Infections; Humans; Enterovirus B, Human; HeLa Cells; Antiviral Agents; Male; Mice, Inbred BALB C; Inflammation; Virus Replication
PubMed: 38793559
DOI: 10.3390/v16050677 -
Journal of Zhejiang University.... May 2024Viral myocarditis (VMC) is one of the most common acquired heart diseases in children and teenagers. However, its pathogenesis is still unclear, and effective treatments...
Viral myocarditis (VMC) is one of the most common acquired heart diseases in children and teenagers. However, its pathogenesis is still unclear, and effective treatments are lacking. This study aimed to investigate the regulatory pathway by which exosomes alleviate ferroptosis in cardiomyocytes (CMCs) induced by coxsackievirus B3 (CVB3). CVB3 was utilized for inducing the VMC mouse model and cellular model. Cardiac echocardiography, left ventricular ejection fraction (LVEF), and left ventricular fractional shortening (LVFS) were implemented to assess the cardiac function. In CVB3-induced VMC mice, cardiac insufficiency was observed, as well as the altered levels of ferroptosis-related indicators (glutathione peroxidase 4 (GPX4), glutathione (GSH), and malondialdehyde (MDA)). However, exosomes derived from human umbilical cord mesenchymal stem cells (hucMSCs-exo) could restore the changes caused by CVB3 stimulation. was enriched in hucMSCs-exo, and the inhibitory effect of hucMSCs-exo on CVB3-induced ferroptosis was higher than that of hucMSCs-exo (NC: negative control). Mothers against decapentaplegic homolog 2 (SMAD2) increased in the VMC group, while the expression of zinc-finger protein 36 (ZFP36) decreased. was confirmed to interact with messenger RNA (mRNA), and the SMAD2 protein interacted directly with the ZFP36 protein. Silencing and overexpressing inhibited the expression of ferroptosis-related indicators. Meanwhile, the levels of GPX4, solute carrier family 7, member 11 (SLC7A11), and GSH were lower in the overexpression plasmid (oe-)+ mimic group than in the oe-NC+ mimic group, while those of MDA, reactive oxygen species (ROS), and Fe increased. In conclusion, these data showed that ferroptosis could be regulated by mediating expression. Exo- derived from hucMSCs could mediate to promote the expression of ZFP36, which further inhibited the ferroptosis of CMCs to alleviate CVB3-induced VMC.
Topics: Ferroptosis; Mesenchymal Stem Cells; Exosomes; Animals; Humans; Mice; Smad2 Protein; MicroRNAs; Enterovirus B, Human; Myocytes, Cardiac; Umbilical Cord; Signal Transduction; Coxsackievirus Infections; Male; Myocarditis; Phospholipid Hydroperoxide Glutathione Peroxidase
PubMed: 38725341
DOI: 10.1631/jzus.B2300077 -
PLoS Pathogens May 2024Major 5'-terminally deleted (5'TD) RNA forms of group-B coxsackievirus (CVB-5'TD) has been associated with myocarditis in both mice and humans. Although it is known that...
Major Group-B Enterovirus populations deleted in the noncoding 5' region of genomic RNA modulate activation of the type I interferon pathway in cardiomyocytes and induce myocarditis.
Major 5'-terminally deleted (5'TD) RNA forms of group-B coxsackievirus (CVB-5'TD) has been associated with myocarditis in both mice and humans. Although it is known that interferon-β (IFN-β) signaling is critical for an efficient innate immune response against CVB-induced myocarditis, the link between CVB-5'TD RNA forms and type I IFN signaling in cardiomyocytes remains to be explored. In a mouse model of CVB3/28-induced myocarditis, major early-emerging forms of CVB-5'TD RNA have been characterized as replicative viral populations that impair IFN-β production in the heart. Synthetic CVB3/28 RNA forms mimicking each of these major 5'TD virus populations were transfected in mice and have been shown to modulate innate immune responses in the heart and to induce myocarditis in mice. Remarkably, transfection of synthetic viral RNA with deletions in the secondary structures of the 5'-terminal CVB3 RNA domain I, modifying stem-loops "b", "c" or "d", were found to impair IFN-β production in human cardiomyocytes. In addition, the activation of innate immune response by Poly(I:C), was found to restore IFN-β production and to reduce the burden of CVB-5'TD RNA-forms in cardiac tissues, thereby reducing the mortality rate of infected mice. Overall, our results indicate that major early-emerging CVB3 populations deleted in the domain I of genomic RNA, in the 5' noncoding region, modulate the activation of the type I IFN pathway in cardiomyocytes and induce myocarditis in mice. These findings shed new light on the role of replicative CVB-5'TD RNA forms as key pathophysiological factors in CVB-induced human myocarditis.
Topics: Myocarditis; Animals; Myocytes, Cardiac; Mice; Enterovirus B, Human; Coxsackievirus Infections; Interferon Type I; RNA, Viral; Humans; Immunity, Innate; Signal Transduction; Interferon-beta; Male; 5' Untranslated Regions
PubMed: 38696536
DOI: 10.1371/journal.ppat.1012125 -
Virulence Dec 2024Enteroviruses (EV) are common and can cause severe diseases, particularly in young children. However, the information of EV infection in infants in China is limited due...
BACKGROUND
Enteroviruses (EV) are common and can cause severe diseases, particularly in young children. However, the information of EV infection in infants in China is limited due to the vast population size and extensive geographical area of the country. Here, we conducted a retrospective multicenter analysis of available EV data to assess the current epidemiological situation in the infant population in southern China.
METHODS
The study enrolled infants with suspected EV infection from 34 hospitals across 12 cities in southern China between 2019 to 2022, and the confirmation of EV was done using RT-PCR and VP1 gene sequencing.
RESULTS
Out of 1221 infants enrolled, 330 (27.03%) were confirmed as EV-infected. Of these, 260 (78.79%) were newborns aged 0-28 days. The EV belonged to three species: EV-B (80.61%), EV-A (11.82%), and human rhinovirus (7.58%). Newborns were more susceptible to EV-B than older infants ( < 0.001). Within EV-B, we identified 15 types, with coxsackievirus (CV) B3 (20.91%), echovirus (E) 11 (19.70%), and E18 (16.97%) being the most common. The predominant EV types changed across different years. EV infection in infants followed a seasonal pattern, with a higher incidence from May to August. Furthermore, perinatal mother-to-child EV transmission in 12 mother-newborn pairs were observed.
CONCLUSION
Our study is the first to demonstrate the emergence and widespread circulation of EV-B species, mainly CVB3, E11, and E18, in southern China, primarily affecting young infants. This research provides valuable insights for future epidemic assessment, prediction, as well as the elimination of mother-to-child transmission.
Topics: Female; Humans; Infant; Infant, Newborn; China; Enterovirus; Enterovirus B, Human; Enterovirus Infections; Genotype; Infectious Disease Transmission, Vertical; Phylogeny
PubMed: 38555521
DOI: 10.1080/21505594.2024.2329569 -
Frontiers in Immunology 2024For many decades viral infections have been suspected as 'triggers' of autoimmune disease, but mechanisms for how this could occur have been difficult to establish.... (Review)
Review
For many decades viral infections have been suspected as 'triggers' of autoimmune disease, but mechanisms for how this could occur have been difficult to establish. Recent studies have shown that viral infections that are commonly associated with viral myocarditis and other autoimmune diseases such as coxsackievirus B3 (CVB3) and SARS-CoV-2 target mitochondria and are released from cells in mitochondrial vesicles that are able to activate the innate immune response. Studies have shown that Toll-like receptor (TLR)4 and the inflammasome pathway are activated by mitochondrial components. Autoreactivity against cardiac myosin and heart-specific immune responses that occur after infection with viruses where the heart is not the primary site of infection (e.g., CVB3, SARS-CoV-2) may occur because the heart has the highest density of mitochondria in the body. Evidence exists for autoantibodies against mitochondrial antigens in patients with myocarditis and dilated cardiomyopathy. Defects in tolerance mechanisms like autoimmune regulator gene (AIRE) may further increase the likelihood of autoreactivity against mitochondrial antigens leading to autoimmune disease. The focus of this review is to summarize current literature regarding the role of viral infection in the production of extracellular vesicles containing mitochondria and virus and the development of myocarditis.
Topics: Humans; Myocarditis; Autoimmunity; Coxsackievirus Infections; Enterovirus B, Human; Autoimmune Diseases; Mitochondria; Extracellular Vesicles
PubMed: 38550582
DOI: 10.3389/fimmu.2024.1374796 -
Cureus Feb 2024Human enterovirus (EV) and Parechovirus (PeV) infections are major causes of sepsis-like illness in infants < 90 days of age. Enterovirus species B (EV-B) was found to...
Human enterovirus (EV) and Parechovirus (PeV) infections are major causes of sepsis-like illness in infants < 90 days of age. Enterovirus species B (EV-B) was found to be the leading cause of aseptic meningitis in young infants. In Thailand, EV and PeV are not part of the routine screening of blood or cerebrospinal fluid (CSF) of children with suspected aseptic meningitis and sepsis-like illness. Consequently, data on EV and PeV epidemiology are limited. This study tested clinical samples from hospitalized young infants with suspected aseptic meningitis or sepsis-like illness between 2013 and 2022 for EV, PeV, and Herpes simplex virus (HSV). Of 95 specimens, 10 were positive for EV, representing 10.5%. These positive samples included eight CSF and two stool samples. No samples were positive for PeV and HSV. Of these positive cases, EV-B was detected in eight, and EV-A was detected in two cases. The species of EV-B detected include echovirus-18 (E18) (n=2), E21 (n=2), E4(n=1), E5 (n=1), E9 (n=1), and E11 (n=1). Our report demonstrates the significant role of EV-B, and less frequently EV-A, in Thai infants with aseptic meningitis and sepsis-like illness.
PubMed: 38550451
DOI: 10.7759/cureus.54997 -
Nature Communications Mar 2024Picornaviruses are a leading cause of central nervous system (CNS) infections. While genotypes such as parechovirus A3 (PeV-A3) and echovirus 11 (E11) can elicit severe...
Picornaviruses are a leading cause of central nervous system (CNS) infections. While genotypes such as parechovirus A3 (PeV-A3) and echovirus 11 (E11) can elicit severe neurological disease, the highly prevalent PeV-A1 is not associated with CNS disease. Here, we expand our current understanding of these differences in PeV-A CNS disease using human brain organoids and clinical isolates of the two PeV-A genotypes. Our data indicate that PeV-A1 and A3 specific differences in neurological disease are not due to infectivity of CNS cells as both viruses productively infect brain organoids with a similar cell tropism. Proteomic analysis shows that PeV-A infection significantly alters the host cell metabolism. The inflammatory response following PeV-A3 (and E11 infection) is significantly more potent than that upon PeV-A1 infection. Collectively, our findings align with clinical observations and suggest a role for neuroinflammation, rather than viral replication, in PeV-A3 (and E11) infection.
Topics: Humans; Parechovirus; Proteomics; Picornaviridae Infections; Inflammation; Brain; Enterovirus B, Human; Central Nervous System Diseases
PubMed: 38514653
DOI: 10.1038/s41467-024-46634-9 -
Environmental Science & Technology Mar 2024The sensitivity of enteroviruses to disinfectants varies among genetically similar variants and coincides with amino acid changes in capsid proteins, although the effect...
The sensitivity of enteroviruses to disinfectants varies among genetically similar variants and coincides with amino acid changes in capsid proteins, although the effect of individual substitutions remains unknown. Here, we employed reverse genetics to investigate how amino acid substitutions in coxsackievirus B5 (CVB5) capsid proteins affect the virus' sensitivity to free chlorine and heat treatment. Of ten amino acid changes observed in CVB5 variants with free chlorine resistance, none significantly reduced the chlorine sensitivity, indicating a minor role of the capsid composition in chlorine sensitivity of CVB5. Conversely, a subset of these amino acid changes located at the C-terminal region of viral protein 1 led to reduced heat sensitivity. Cryo-electron microscopy revealed that these changes affect the assembly of intermediate viral states (altered and empty particles), suggesting that the mechanism for reduced heat sensitivity could be related to improved molecular packing of CVB5, resulting in greater stability or altered dynamics of virus uncoating during infection.
Topics: Capsid Proteins; Chlorine; Cryoelectron Microscopy; Amino Acid Substitution; Enterovirus B, Human; Amino Acids
PubMed: 38488515
DOI: 10.1021/acs.est.3c10409 -
International Journal of Infectious... May 2024Following the alert of echovirus 11 (E-11) infection in neonates in EU/EEA Member States, we conducted an investigation of E-11 circulation by gathering data from...
Increased circulation of echovirus 11 in the general population and hospital patients as elicited by the non-polio enterovirus laboratory-based sentinel surveillance in northern Italy, 2023.
OBJECTIVES
Following the alert of echovirus 11 (E-11) infection in neonates in EU/EEA Member States, we conducted an investigation of E-11 circulation by gathering data from community and hospital surveillance of enterovirus (EV) in northern Italy from 01 August 2021 to 30 June 2023.
METHODS
Virological results of EVs were obtained from the regional sentinel surveillance database for influenza-like illness (ILI) in outpatients, and from the laboratory database of ten hospitals for inpatients with either respiratory or neurological symptoms. Molecular characterization of EVs was performed by sequence analysis of the VP1 gene.
RESULTS
In our ILI series, the rate of EV-positive specimens showed an upward trend from the end of May 2023, culminating at the end of June, coinciding with an increase in EV-positive hospital cases. The E-11 identified belonged to the D5 genogroup and the majority (83%) were closely associated with the novel E-11 variant, first identified in severe neonatal infections in France since 2022. E-11 was identified sporadically in community cases until February 2023, when it was also found in hospitalized cases with a range of clinical manifestations. All E-11 cases were children, with 14 out of 24 cases identified through hospital surveillance. Of these cases, 60% were neonates, and 71% had severe clinical manifestations.
CONCLUSION
Baseline epidemiological data collected since 2021 through EV laboratory-based surveillance have rapidly tracked the E-11 variant since November 2022, alongside its transmission during the late spring of 2023.
Topics: Child; Infant, Newborn; Humans; Infant; Enterovirus; Sentinel Surveillance; Inpatients; Enterovirus Infections; Enterovirus B, Human; Virus Diseases; Italy; Hospitals; Phylogeny
PubMed: 38458420
DOI: 10.1016/j.ijid.2024.106998 -
Medicine Mar 2024In rare occasions, coxsackievirus infections can cause serious illness, such as encephalitis and myocarditis. The immunotherapies of cancer could increase the risk of... (Review)
Review
INTRODUCTION
In rare occasions, coxsackievirus infections can cause serious illness, such as encephalitis and myocarditis. The immunotherapies of cancer could increase the risk of myocarditis, especially when applying immune checkpoint inhibitors. Herein, we report a rare case of Coxsackie B virus-induced myocarditis in a patient with a history of lymphoma.
CASE PRESENTATION
A 32-year-old woman was admitted to the hospital with recurrent fever for more than 20 days, and she had a history of lymphoma. Before admission, the positron emission tomography/computed tomography result indicated that the patient had no tumor progression, and she was not considered the cancer-related fever upon arriving at our hospital. Patient's red blood cell, platelet count, and blood pressure were decreased. In addition, she had sinus bradycardia and 3 branch blocks, which was consistent with acute high lateral and anterior wall myocardial infarction. During hospitalization, the patient had recurrent arrhythmia, repeated sweating, poor mentation, dyspnea, and Coxsackie B virus were detected in patient's blood samples by pathogen-targeted next-generation sequencing. The creatine kinase, creatine kinase MB, and N-terminal pro-brain natriuretic peptide were persistently elevated. Consequently, the patient was diagnosed with viral myocarditis induced by Coxsackie B virus, and treated with acyclovir, gamma globulin combined with methylprednisolone shock therapy, trimetazidine, levosimendan, sildenan, continuous pump pressors with m-hydroxylamine, entecavir, adefovir, glutathione, pantoprazole, and low-molecular-weight heparin. Her symptoms worsened and died.
CONCLUSION
We reported a case with a history of lymphoma presented with fever, myocardial injury, who was ultimately diagnosed with Coxsackie B virus-induced myocarditis. Moreover, pathogen-targeted next-generation sequencing indeed exhibited higher sensitivity compared to mNGS in detecting Coxsackie B virus.
Topics: Humans; Female; Adult; Myocarditis; Enterovirus B, Human; Coxsackievirus Infections; Virus Diseases; Fever; Lymphoma
PubMed: 38457543
DOI: 10.1097/MD.0000000000037248