Coxsackievirus Infection Research Articles

Serology supportive of recent coxsackievirus B infection is correlated with multisystem inflammatory syndrome in children (MIS-C).

Rarely, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will lead to myocarditis associated with multisystem inflammatory syndrome in children (MIS-C). It remains unclear why MIS-C only targets specific children. To explore an association between coxsackievirus infections with MIS-C, we investigated the sero-epidemiology of CV in admitted pediatric patients in relation to the pandemic. This retrospective case-control study was performed by chart review of children (age ≤21 years) admitted to a tertiary care hospital with CV serological testing from January 2017 to August 2023. Clinical, laboratory, and imaging findings were used to classify patients as MIS-C and CV-unlikely or CV-possible for non-MIS-C patients. Out of 182 admissions (179 patients, median age, 6), CVB complement fixation (CF) assay on serotypes B1-B6 and CVA immunofluorescence assay IgG on serotypes A7, A9, A16, and A24 were positive in at least one serotype in 59.2% and 80.7% of cases, respectively. We observed a significant drop in CVB CF seropositivity during the peak of social distancing in 2020. The likelihood of elevated CVB CF titers was significantly higher in MIS-C than the CV-unlikely group (OR: 1.92, 95% CI: 1.02-3.63, P: 0.04) and showed a trend toward higher values in African Americans than Whites (OR: 1.57, 95% CI: 0.98-2.50, P: 0.057). The frequency of MIS-C was considerably higher in African Americans than Whites (18.1% versus 9%, P: 0.1). A higher likelihood of elevated CVB CF titers in patients with MIS-C compared with those unlikely to have acute CV infection along with a relatively higher frequency of MIS-C in African Americans warrants further investigation into the role of CVB infection in MIS-C development.IMPORTANCEThe emergence of multisystem inflammatory syndrome in children (MIS-C) during the SARS-CoV-2 pandemic raised major concerns in providers caring for children. This condition presents a hyper-inflammation state that can lead to severe complications, including myocarditis and cardiogenic shock. The pathogenesis of MIS-C has not been fully understood. Understanding the pathogenesis of this condition is not only important for developing effective treatments but also for applying preventive strategies. A two-hit hypothesis leading to MIS-C has been proposed. Coxsackievirus infections are prevalent during childhood and can also cause myocarditis, and coxsackievirus B specifically has been shown to cause persistent RNA presence in host cells, leading to continued inflammation. Herein, we show that elevated coxsackievirus B titers are associated with MIS-C cases, implying a role of successive infections with these viruses contributing to such a hyperinflammatory state. This study supports the need for larger investigations into this association.

Choroidal neovascularization in unilateral acute idiopathic maculopathy associated with coxsackievirus B2

Abstract The purpose of the study was to present a case of choroidal neovascularization (CNV) in unilateral acute idiopathic maculopathy (UAIM) associated with coxsackievirus B2. We present a case of UAIM with coxsackie B2 positive serology, presenting CNV as a complication. Follow-up multimodal retinal imaging was performed to characterize the macular abnormalities further. A 27-year-old woman complained of a sudden central visual field scotoma in her left eye (LE) 2 days before her presentation. The patient reported flu-like symptoms 2 weeks before her initial ophthalmic symptoms. Ophthalmologic examination and multimodal imaging were performed at the initial presentation and 2 months follow-up when CNV was detected. The patient underwent an intravitreous ranibizumab injection in the LE. After the injection, the optical coherence tomography was repeated and there was a partial decrement of the subretinal hyperreflective area, and visual acuity improved to 20/30. To the best of our knowledge, no previous reports were found linking coxsackie B2 infection with UAIM and CNV. The present case report demonstrates the importance of serial multimodal imaging to guarantee accurate diagnosis and effective therapy for patients with UAIM secondary to coxsackievirus infection, regardless of the virus variant involved.

Characterization and optimization of exopolysaccharide extracted from a newly isolated halotolerant cyanobacterium, Acaryochloris Al-Azhar MNE ON864448.1 with antiviral activity

Several antiviral agents lost their efficacy due to their severe side effects and virus mutations. This study aimed to identify and optimize the conditions for exopolysaccharide (EPS) production from a newly isolated cyanobacterium, Acaryochloris Al-Azhar MNE ON864448.1, besides exploring its antiviral activity. The cyanobacterial EPS was purified through DEAE-52 cellulose column with a final yield of 83.75%. Different analysis instruments were applied for EPS identification, including Fourier-transform infrared (FT-IR) spectroscopy, thermogravimetric analysis (TGA), and gas chromatographic-mass spectrometry (GC–MS). Plackett–Burman’s design demonstrated that working volume (X1), EDTA (X2), inoculum size (X3), CaCl2 (X4), and NaCl (X5) are the most important variables influencing EPS production. Central composite design (CCD) exhibited maximum EPS yield (9.27 mg/mL) at a working volume of 300 mL in a 1 L volumetric flask, EDTA 0.002 g/L, inoculum size 7%, CaCl2 0.046 g/L, and NaCl 20 g/L were applied. EPS showed potent antiviral activities at different stages of herpes simplex virus type-1 and 2 (HSV-1, HSV-2), adenovirus (ADV) and coxsackievirus (A16) infections. The highest half-maximal inhibitory concentration (IC50) (6.477 µg/mL) was recorded during HSV-1 internalization mechanism, while the lowest IC50 (0.005669 µg/mL) was recorded during coxsackievirus neutralization mechanism.

Post-infectious N-methyl-D-aspartate Receptor Encephalitis Antibody Associated with Coxsackie Virus Infection (P7-14.012)

Post-infectious N-methyl-D-aspartate Receptor Encephalitis Antibody Associated with Coxsackie Virus Infection (P7-14.012)

Coxsackievirus infection induces direct pancreatic β cell killing but poor antiviral CD8+ T cell responses.

Coxsackievirus B (CVB) infection of pancreatic β cells is associated with β cell autoimmunity and type 1 diabetes. We investigated how CVB affects human β cells and anti-CVB T cell responses. β cells were efficiently infected by CVB in vitro, down-regulated human leukocyte antigen (HLA) class I, and presented few, selected HLA-bound viral peptides. Circulating CD8+ T cells from CVB-seropositive individuals recognized a fraction of these peptides; only another subfraction was targeted by effector/memory T cells that expressed exhaustion marker PD-1. T cells recognizing a CVB epitope cross-reacted with β cell antigen GAD. Infected β cells, which formed filopodia to propagate infection, were more efficiently killed by CVB than by CVB-reactive T cells. Our in vitro and ex vivo data highlight limited CD8+ T cell responses to CVB, supporting the rationale for CVB vaccination trials for type 1 diabetes prevention. CD8+ T cells recognizing structural and nonstructural CVB epitopes provide biomarkers to differentially follow response to infection and vaccination.

Antiviral activity of some benzo[g]quinazolines against coxsackievirus B4: biological screening and docking study.

Serotype coxsackievirus B (CVB) infection has been linked to viral myocarditis, dilated cardiomyopathy, meningitis, and pancreatitis in children and young adults. As of yet, no antiviral drug has been authorized for the treatment of coxsackievirus infection. Therefore, there is perpetual demand for new therapeutic agents and the improvement of existing ones. Benzo[g]quinazolines, the subject of several well-known heterocyclic systems, have risen to prominence and played a significant role in the development of antiviral agents, particularly those for anti-coxsackievirus B4 infection. This study investigated the cytotoxicity of the target benzo[g]quinazolines (1-16) in the BGM cells line as well as their anti-coxsackievirus B4 activity. Determination of CVB4 titers using a plaque assay. Most of the target benzoquinazolines exhibited antiviral activity, however, compounds 1-3 appeared to be the most effective (reduction percentages of 66.7, 70, and 83.3%, respectively). The binding mechanisms and interactions of the three most active 1-3 with the constitutive amino acids in the active site of the multi-target of coxsackievirus B4 (3Clpro and RdRp) targets were also investigated using molecular docking. The anti coxsackievirus B4 activity has resulted, and the top three active benzoquinazolines (1-3) have bonded to and interacted with the constitutive amino acids in the active region of the multi-target coxsackievirus B4 (RdRp and 3Clpro). Further research is required in the lab. to determine the exact benzoquinazolines mechanism of action.

Latent Mastoiditis And Facial Paralysis In A Child As Complications After A Coxsackie Virus Infection. Clinical Case

Latent Mastoiditis And Facial Paralysis In A Child As Complications After A Coxsackie Virus Infection. Clinical Case

Why does the immune system destroy pancreatic β-cells but not α-cells in type 1 diabetes?

A perplexing feature of type 1 diabetes (T1D) is that the immune system destroys pancreatic β-cells but not neighbouring α-cells, even though both β-cells and α-cells are dysfunctional. Dysfunction, however, progresses to death only for β-cells. Recent findings indicate important differences between these two cell types. First, expression of BCL2L1, a key antiapoptotic gene, is higher in α-cells than in β-cells. Second, endoplasmic reticulum (ER) stress-related genes are differentially expressed, with higher expression levels of pro-apoptotic CHOP in β-cells than in α-cells and higher expression levels of HSPA5 (which encodes the protective chaperoneBiP)in α-cells than in β-cells. Third, expression of viral recognition and innate immune response genes is higher in α-cells than in β-cells, contributing to the enhanced resistance of α-cells to coxsackievirus infection. Fourth, expression of the immune-inhibitory HLA-E molecule is higher in α-cells than in β-cells. Of note, α-cells are less immunogenic than β-cells, and the CD8+ T cells invading the islets in T1D are reactive to pre-proinsulin but not to glucagon. We suggest that this finding is a result of the enhanced capacity of the α-cell to endure viral infections and ER stress, which enables them to better survive early stressors that can cause cell death and consequently amplify antigen presentation to the immune system. Moreover, the processing of the pre-proglucagon precursor in enteroendocrine cells might favour immune tolerance towards this potential self-antigen compared to pre-proinsulin.

Potential Antiviral Herbal Therapeutics for Viral Infections

Background Ayurved, an ancient system of medicine with rich heritage and antiquity, is well known since Vedic period. Viral infections are responsible for many illnesses, and recent outbreaks have raised public health concerns. Viral infections are being managed therapeutically through available antiviral regimens with unsatisfactory clinical outcomes. The refractory viral infections immune to available antiviral drugs are alarming threats and a significant health concern. For hepatitis, the interferon and vaccine therapies solely aren't ultimate solutions thanks to recurrence of hepatitis C virus. Owing to the growing incidences of viral infections and particularly of resistant viral strains, the available therapeutic modalities got to be improved, complemented with the invention of novel antiviral agents to combat refractory viral infections. It is widely accepted that medicinal plant heritage is nature gifted, precious, and fueled with the valuable resources for treatment of metabolic and infectious disorders. The aims of this review are to assemble the facts and to conclude the therapeutic potential of medicinal plants within the eradication and management of various viral diseases such as influenza, human immunodeficiency virus (HIV), herpes simplex virus (HSV), hepatitis, and coxsackievirus infections, which have been proven in diverse clinical studies. The scientific literature mainly focusing on plant extracts and herbal products with therapeutic efficacies against experimental models of influenza, HIV, HSV, hepatitis, and coxsackievirus were included in the study. Pure compounds possessing antiviral activity were excluded, and plants possessing activity against viruses other than viruses in inclusion criteria were excluded. Hundreds of plant extracts with antiviral effect were recognized. On the basis of the work of several independent research groups, the therapeutic potential of medicinal plants against listed common viral diseases in the region has been proclaimed. In this context, the herbal formulations as alternative medicine may contribute to the eradication of complicated viral infection significantly. The current review consolidates the data of the various medicinal plants, holding promising specific antiviral activities scientifically proven through studies on experimental animal models. Consequently, the original research addressing the development of novel nutraceuticals based on listed medicinal plants is highly recommended for the management of viral disorders

Coxsackie B – Pantropic Viruses

Abstract Coxsackieviruses (CV), as all enteroviruses, are small, non-enveloped, icosahedral-shaped capsid viruses. They belong to the family Picornaviridae. This group was named after the town of Coxsackie in New York State (USA) where was recognized the first human case of coxsackievirus infection in the 40s of the XX century. Coxsackie B (CVB) are distinguished from other enteroviruses by ability to infect many types of tissues and organs. This wide tropism reason that these viruses are etiologic agents of large number of different diseases. CVB cause infection of the heart, pleura, pancreas, lungs and liver, causing myocarditis, pleurodynia, pericarditis, pneumonia and hepatitis. They can invade the central nervous system and induce meningitis, encephalitis, or acute flaccid paralysis. They also cause systemic neonatal disease and chronic infections such as type 1 diabetes and chronic myocarditis. This pantropic character of CVB can be determinate by specific virus – receptor interaction, which initiate the infection and viral spread. CVB attach at least two receptor proteins: the coxsackievirus – adenovirus receptor (CAR) and the decay – accelerating factor (DAF). Moreover, other anonymous determinant may play a role in tissue permissiveness and disease severity. This article summarizes the main aspects of Coxsackieviruses B infection: replication, virus-receptor interaction, genetic variability, pathogenesis, epidemiology and diagnostics.

COXSACKIE VIRUS-ASSOCIATED ONYCHOMADESIS IN CHILDREN: A CLINICAL-DERMOSCOPIC PRESENTATION

A case report describes infection-related onychomadesis in a 4-year-old patient. The Coxsackie virus infection, which causes hand, foot, and mouth disease, developed with specific symptoms. One month after the end of the illness, the patient began significant changes in their fingernails and toenails. Pathological changes were observed on all fingernails and the first and second toenails. The nail plates were detached from the matrix, and in the middle and distal areas, they adhered to the nail bed. The patient had no history of local trauma to the nails and fingers, no detrimental nail-related habits, and no underlying systemic diseases. Finally, the diagnosis was established based on the patient's medical history, a physical examination of the skin and its appendages, and the dermoscopic findings. The patient's progress was monitored continuously. After two months, the patient's clinical recovery became evident, and the nail plates were completely restored without any structural abnormalities. Although data on onychomadesis associated with coxsackie virus are not so scarce, it remains a topical issue in pediatric dermatology due to its importance and developmental features.&nbsp

A cysteine protease inhibitor GC376 displays potent antiviral activity against coxsackievirus infection

Infection with coxsackievirus A10 (CV-A10) can cause hand-foot-mouth disease and is also associated with severe complications, including viral pneumonia, aseptic and viral meningitis. Coxsackievirus infection may also play a role in the pathogenesis of acute myocardial infarction and in the increased risk of type 1 diabetes mellitus in adults. However, there are no approved vaccines or direct antiviral agents available to prevention or treatment of coxsackievirus infection. Here, we reported that GC376 potently inhibited CV-A10 infection in different cell lines without cytotoxicity, significantly suppressed production of viral proteins, and strongly reduced the yields of infectious progeny virions. Further study indicated that GC376, as viral 3C protease inhibitor, had the potential to restrain the cleavage of the viral polyprotein into individually functional proteins, thus suppressed the replication of CV-A10. Furthermore, the drug exhibited antiviral activity against coxsackieviruses of various serotypes including CV-A6, CV-A7 and CV-A16, suggesting that GC376 is a broad-spectrum anti-coxsackievirus inhibitor and the 3C protease is a promising target for developing anti-coxsackievirus agents.

SARS-COV-2-INDUCED COAGULOPATHY DEMONSTRATING HEMORRHAGIC CARDIAC TAMPONADE: A TIGHT SQUEEZE

SARS-COV-2-INDUCED COAGULOPATHY DEMONSTRATING HEMORRHAGIC CARDIAC TAMPONADE: A TIGHT SQUEEZE

Detection of coxsackie virus B and measurement level of Tumor necrosis factor alpha in patients suffered in T1DM with coxsackie virus infection

Objective. Infection with Coxsackie virus. This virus that damages pancreatic cells, has long been linked to the onset of insulin-dependent diabetic mellitus (IDDM). Pro-inflammatory cytokines can be produced as a result of this illness. Tumor necrosis factor-a is one of these pro-inflammatory cytokines. Materials and Methods. Blood sample were collected from 180 Iraqi participants. Ninety of them is type 1 diabetic patients and other 90 is healthy control .both groups were tested for the incidence of Coxsackie virus B IgG. So the patients groups is divided to two groups according to sero positivity of CVB-IgG .all 180 patients tested to measure of level of TNF-α. Results. The Results showed increasing in levels of TNF-α in CBV positive Type 1 Diabetes mellitus was (34.85 ± 11.00 pg/ml). The level of this interleukin in Type 1 Diabetes mellitus negative to that virus was (26.16 ± 7.79 pg/ml). While the results of this interleukin in control group was (13.82 ± 3.93 pg/ml) with p-value 0. Conclusion. The concentration of TNF-α, according to results, has been shown to be associated with type 1 diabetes mellitus patients infected with CVB-IgG and diabetic patients without CVB.

TRIM7 Restricts Coxsackievirus and Norovirus Infection by Detecting the C-Terminal Glutamine Generated by 3C Protease Processing.

TRIM7 catalyzes the ubiquitination of multiple substrates with unrelated biological functions. This cross-reactivity is at odds with the specificity usually displayed by enzymes, including ubiquitin ligases. Here we show that TRIM7′s extreme substrate promiscuity is due to a highly unusual binding mechanism, in which the PRYSPRY domain captures any ligand with a C-terminal helix that terminates in a hydrophobic residue followed by a glutamine. Many of the non-structural proteins found in RNA viruses contain C-terminal glutamines as a result of polyprotein cleavage by 3C protease. This viral processing strategy generates novel substrates for TRIM7 and explains its ability to inhibit Coxsackie virus and norovirus replication. In addition to viral proteins, cellular proteins such as glycogenin have evolved C-termini that make them a TRIM7 substrate. The ‘helix-ΦQ’ degron motif recognized by TRIM7 is reminiscent of the N-end degron system and is found in ~1% of cellular proteins. These features, together with TRIM7′s restricted tissue expression and lack of immune regulation, suggest that viral restriction may not be its physiological function.

Dynamic alterations of the mice gut virome after Coxsackievirus B3 infection.

The gut microbiome plays an essential role in the human health and dysbiosis has been implicated in numerous diseases. Coxsackievirus B3 infects millions of humans yearly and yet limited research has explored dynamic alterations of the gut virome after infection. Here, we established the mouse model of Coxsackievirus B3 infection and collected fecal samples at several time points to investigate alterations of the gut virome using viral metagenomic analysis. We found that the mice virome was dominated by Caudovirales and Microviridae, and phylogenetic analyses showed that both Caudovirales and Microviridae had high diversity. The gut virome had significant variations with the increase of Caudovirales and the decrease of Microviridae after infection. We proposed that Caudovirales and Microviridae may be biomarkers for the Coxsackievirus infection process. This study provides a reference for the dynamic changes of the gut virome after human Enterovirus infection, which may help guide the rational drug use in clinical treatment and provide new ideas for preventing Enterovirus infection.

Novel Antiviral Activity of Ethyl 3-Hydroxyhexanoate Against Coxsackievirus B Infection.

Coxsackievirus group B (CVB) is a member of the genus Enterovirus in the family Picornaviridae. CVB infection has been implicated as a major etiologic agent of viral myocarditis, dilated cardiomyopathy, meningitis, and pancreatitis among children and young adults. Until date, no antiviral agent has been licensed for the treatment of Coxsackievirus infection. In an effort to identify antiviral agents against diseases caused by the CVB, we found that ethyl 3-hydroxyhexanoate (EHX), a volatile compound present in fruits and food additives, is a potent antiviral compound. In this study, we demonstrated that EHX treatment significantly inhibits CVB replication both in vivo and in vitro. Furthermore, EHX possesses antiviral activity at 50% effective concentration (EC50) of 1.2 μM and 50% cytotoxicity (CC50) of 25.6 μM, yielding a selective index (SI) value as high as 20.8. Insights into the mechanism of antiviral activity of EHX showed that it acts at the step of viral RNA replication. Since EHX has received approval as food additives, treatment of CVB-related infections with EHX might be a safe therapeutic option and may be a promising strategy for the development of semi-synthetic antiviral drugs for viral diseases.

Analysis of miRNAs Involved in Mouse Heart Injury Upon Coxsackievirus A2 Infection.

Coxsackievirus A2 (CVA2) has recently been constantly detected, and is associated with viral myocarditis in children. Our previous study demonstrated that CVA2 led to heart damage in a neonatal murine model. However, the molecular mechanism of heart injury caused by CVA2 remains largely unknown. Emerging evidence suggests the significant functions of miRNAs in Coxsackievirus infection. To investigate potential miRNAs involved in heart injury caused by CVA2, our study, for the first time, conducted a RNA-seq in vivo employing infected mice hearts. In total, 87, 101 and 76 differentially expressed miRNAs were identified at 3 days post infection (dpi), 7 dpi and 7 dpi vs 3 dpi. Importantly, above 3 comparison strategies shared 34 differentially expressed miRNAs. These results were confirmed by quantitative PCR (qPCR). Next, we did GO, KEGG, and miRNA-mRNA integrated analysis of differential miRNAs. The dual-luciferase reporter assay confirmed the miRNA-mRNA pairs. To further confirm the above enriched pathways and processes, we did Western blotting and immunofluorescence staining. Our results suggest that inflammatory responses, T cell activation, apoptosis, autophagy, antiviral immunity, NK cell infiltration, and the disruption of tight junctions are involved in the pathogenesis of heart injury caused by CVA2. The dysregulated miRNAs and pathways recognized in the current study can improve the understanding of the intricate interactions between CVA2 and the heart injury, opening a novel avenue for the future study of CVA2 pathogenesis.

VP32.08: Case report of fetal bowel dilation and echogenic bowel in the third trimester of pregnancy: a coxsackie virus infection manifestation

VP32.08: Case report of fetal bowel dilation and echogenic bowel in the third trimester of pregnancy: a coxsackie virus infection manifestation

Virus Infection Variability by Single-Cell Profiling.

Cell-to-cell variability of infection has long been known, yet it has remained one of the least understood phenomena in infection research. It impacts on disease onset and development, yet only recently underlying mechanisms have been studied in clonal cell cultures by single-virion immunofluorescence microscopy and flow cytometry. In this review, we showcase how single-cell RNA sequencing (scRNA-seq), single-molecule RNA-fluorescence in situ hybridization (FISH), and copper(I)-catalyzed azide-alkyne cycloaddition (click) with alkynyl-tagged viral genomes dissect infection variability in human and mouse cells. We show how the combined use of scRNA-FISH and click-chemistry reveals highly variable onsets of adenoviral gene expression, and how single live cell plaques reveal lytic and nonlytic adenovirus transmissions. The review highlights how scRNA-seq profiling and scRNA-FISH of coxsackie, influenza, dengue, zika, and herpes simplex virus infections uncover transcriptional variability, and how the host interferon response tunes influenza and sendai virus infections. We introduce the concept of “cell state” in infection variability, and conclude with advances by single-cell simultaneous measurements of chromatin accessibility and mRNA counts at high-throughput. Such technology will further dissect the sequence of events in virus infection and pathology, and better characterize the genetic and genomic stability of viruses, cell autonomous innate immune responses, and mechanisms of tissue injury.