Role of Coxsackievirus B3-Induced Immune Responses in the Transition from Myocarditis to Dilated Cardiomyopathy and Heart Failure.

Dilated cardiomyopathy (DCM) is a cardiac disease marked by the stretching and thinning of the heart muscle and impaired left ventricular contractile function. While most patients do not develop significant cardiac diseases from myocarditis, disparate immune responses can affect pathological outcomes, including DCM progression. These altered immune responses, which may be caused by genetic variance, can prolong cytotoxicity, induce direct cleavage of host protein, or encourage atypical wound healing responses that result in tissue scarring and impaired mechanical and electrical heart function. However, it is unclear which alterations within host immune profiles are crucial to dictating the outcomes of myocarditis. Coxsackievirus B3 (CVB3) is a well-studied virus that has been identified as a causal agent of myocarditis in various models, along with other viruses such as adenovirus, parvovirus B19, and SARS-CoV-2. This paper takes CVB3 as a pathogenic example to review the recent advances in understanding virus-induced immune responses and differential gene expression that regulates iron, lipid, and glucose metabolic remodeling, the severity of cardiac tissue damage, and the development of DCM and heart failure.

Increased detection of Echovirus 6-associated meningitis in patients hospitalized during the COVID-19 pandemic, Israel 2021-2022.

BACKGROUND: Outbreaks of enteroviral meningitis occur periodically and may lead to hospitalization and severe disease. OBJECTIVE: To analyze and describe the meningitis outbreak in patients hospitalized in Israel in 2021-2022, during the COVID-19 pandemic. RESULTS: In December 2021, before the emergence of the SARS-CoV-2 omicron variant, an off-season increase in enterovirus (EV) infections was observed among patients hospitalized with meningitis. In January 2022, enterovirus cases decreased by 66% in parallel with the peak of the Omicron wave, and then increased rapidly by 78% in March (compared with February) after a decline in Omicron cases. Sequencing of the enterovirus-positive samples showed a dominance of echovirus 6 (E-6) (29%) before and after the Omicron wave. Phylogenetic analysis found that all 29 samples were very similar and all clustered in the E-6 C1 subtype. The main E-6 symptoms observed were fever and headache, along with vomiting and neck stiffness. The median patient age was 25 years, with a broad range (0-60 years). CONCLUSION: An upsurge in enterovirus cases was observed after the decline of the SARS-CoV-2 omicron wave. The dominant subtype was E-6, which was present prior to the emergence of the omicron variant, but increased rapidly only after the omicron wave decline. We hypothesize that the omicron wave delayed the rise in E-6-associated meningitis.

Pathophysiological Mechanisms of Cardiac Dysfunction in Transgenic Mice with Viral Myocarditis.

Viral myocarditis is pathologically associated with RNA viruses such as coxsackievirus B3 (CVB3), or more recently, with SARS-CoV-2, but despite intensive research, clinically proven treatment is limited. Here, by use of a transgenic mouse strain (TG) containing a CVB3ΔVP0 genome we unravel virus-mediated cardiac pathophysiological processes in vivo and in vitro. Cardiac function, pathologic ECG alterations, calcium homeostasis, intracellular organization and gene expression were significantly altered in transgenic mice. A marked alteration of mitochondrial structure and gene expression indicates mitochondrial impairment potentially contributing to cardiac contractile dysfunction. An extended picture on viral myocarditis emerges that may help to develop new treatment strategies and to counter cardiac failure.

Fulminant Myocardial Involvement in Neonatal Echovirus-induced Sepsis. Two Autopsy Cases.

Group-B Enteroviruses, such as Echoviruses, are a common cause of infections in neonates but fatal myocarditis during Echovirus-induced sepsis have been rarely reported. We report on 2 cases of neonatal Echovirus-related sepsis with myocarditis. Fatal cardiorespiratory failure occurred in both cases. Autopsies and thorough histologic and microbiologic investigations evidenced Echoviruses 5- and 11-induced myocarditis as the cause of death.

Sex-Specific Effects of Plastic Caging in Murine Viral Myocarditis.

BACKGROUND: Myocarditis is an inflammatory heart disease caused by viral infections that can lead to heart failure, and occurs more often in men than women. Since animal studies have shown that myocarditis is influenced by sex hormones, we hypothesized that endocrine disruptors, which interfere with natural hormones, may play a role in the progression of the disease. The human population is exposed to the endocrine disruptor bisphenol A (BPA) from plastics, such as water bottles and plastic food containers. METHODS: Male and female adult BALB/c mice were housed in plastic versus glass caging, or exposed to BPA in drinking water versus control water. Myocarditis was induced with coxsackievirus B3 on day 0, and the endpoints were assessed on day 10 post infection. RESULTS: We found that male BALB/c mice that were exposed to plastic caging had increased myocarditis due to complement activation and elevated numbers of macrophages and neutrophils, whereas females had elevated mast cell activation and fibrosis. CONCLUSIONS: These findings show that housing mice in traditional plastic caging increases viral myocarditis in males and females, but using sex-specific immune mechanisms.

In vitro virucidal efficacy of a dry steam disinfection system against Human Coronavirus, Human Influenza Virus, and Echovirus.

This in vitro study was aimed to assess the efficacy of dry steam in inactivating Human Coronavirus OC43 (HCoV-OC43) as surrogate of SARS-CoV-2, Human Influenza Virus A/H1N1/WSN/33 and Echovirus 7 on stainless steel, polypropylene, and cotton. The virus models were chosen on the basis of their transmission route and environmental resistance. Tests were carried out under a laminar flow cabinet, where two panels of each material were contaminated with a viral suspension. The inocula were left to dry and then the virus on untreated panel (control) was collected by swabbing in order to determine the initial titer. The other panel was treated using a professional vacuum cleaner equipped with a dry steam generator. Dry steam is generated in a boiler where tap water is heated up to 155 °C at 5.5 bar pressure and then during the passage along the flexible hose the temperature decreases to a value between 100 °C and 110 °C at the output. The dry steam was applied for four sec with a window wiper on metal and plastic panels or a brush covered by a microfiber cap on cotton, simulating the steam application during routine cleaning. After the treatment, infectious virus possibly remained on the surface was collected following the same swabbing procedure applied for controls. HCoV-OC43 and Echovirus 7 were titrated by end-point method on HCT-8 line cells and Vero cells, respectively, while Human Influenza Virus was quantified by plaque reduction assay on MDCK cells. Dry steam resulted effective against the three viruses on all tested materials, achieving a mean Log10 reduction factor ≥4 in viral titer of treated samples compared with controls according to UNI EN 14476:2019. Thus, dry steam may be proposed as an ease to use, effective, fast, and nontoxic alternative to chemicals for surface disinfection without damaging materials. Therefore, this device could be employed not only in healthcare facilities but also in occupational, domestic, and community settings, with advantages for environment and human health.

Polarity-Dominated Stable N97 Respirators for Airborne Virus Capture Based on Nanofibrous Membranes.

The longevity and reusability of N95-grade filtering facepiece respirators (N95 FFRs) are limited by consecutive donning and disinfection treatments. Herein, we developed stable N97 nanofibrous respirators based on chemically modified surface to enable remarkable filtration characteristics via polarity driven interaction. This was achieved by a thin-film coated polyacrylonitrile nanofibrous membrane (TFPNM), giving an overall long-lasting filtration performance with high quality factor at 0.42 Pa-1 (filtration efficiency: over 97 %; pressure drop: around 10 Pa), which is higher than that of the commercial N95 FFRs (0.10-0.41 Pa-1 ) tested with a flow rate of 5 L min-1 and the 0.26 µm NaCl aerosol. A coxsackie B4 virus filtration test demonstrated that TFPNM also had strong virus capture capacity of 97.67 %. As compared with N95 FFRs, the TFPNM was more resistant to a wider variety of disinfection protocols, and the overall filtration characteristics remained N97 standard.

Modulation of the acute defence reaction by eplerenone prevents cardiac disease progression in viral myocarditis.

AIMS: Left ventricular (LV) dysfunction in viral myocarditis is attributed to myocardial inflammation and fibrosis, inducing acute and long-time cardiac damage. Interventions are not established. On the basis of the link between inflammation, fibrosis, aldosterone, and extracellular matrix regulation, we aimed to investigate the effect of an early intervention with the mineralocorticoid receptor antagonist (MRA) eplerenone on cardiac remodelling in a murine model of persistent coxsackievirus B3 (CVB3)-induced myocarditis. METHODS AND RESULTS: SWR/J mice were infected with 5 × 104 plaque-forming units of CVB3 (Nancy strain) and daily treated either with eplerenone (200 mg/kg body weight) or with placebo starting from Day 1. At Day 8 or 28 post infection, mice were haemodynamically characterized and subsequently sacrificed for immunohistological and molecular biology analyses. Eplerenone did not influence CVB3 load. Already at Day 8, 1.8-fold (P < 0.05), 1.4-fold (P < 0.05), 3.2-fold (P < 0.01), and 2.1-fold (P < 0.001) reduction in LV intercellular adhesion molecule 1 expression, presence of monocytes/macrophages, oxidative stress, and apoptosis, respectively, was observed in eplerenone-treated vs. untreated CVB3-infected mice. In vitro, eplerenone led to 1.4-fold (P < 0.01) and 1.2-fold (P < 0.01) less CVB3-induced cardiomyocyte oxidative stress and apoptosis. Furthermore, collagen production was 1.1-fold (P < 0.05) decreased in cardiac fibroblasts cultured with medium of eplerenone-treated vs. untreated CVB3-infected HL-1 cardiomyocytes. These ameliorations were in vivo translated into prevention of cardiac fibrosis, as shown by 1.4-fold (P < 0.01) and 2.1-fold (P < 0.001) lower collagen content in the LV of eplerenone-treated vs. untreated CVB3-infected mice at Days 8 and 28, respectively. This resulted in an early and long-lasting improvement of LV dimension and function, as indicated by reduced LV end-systolic volume and end-diastolic volume, and an increase in LV contractility (dP/dtmax ) and LV relaxation (dP/dtmin ), respectively (P < 0.05). CONCLUSIONS: Early intervention with the MRA eplerenone modulates the acute host and defence reaction and prevents cardiac disease progression in experimental CVB3-induced myocarditis without aggravation of viral load. The findings advocate for an initiation of therapy of viral myocarditis as early as possible, even before the onset of inflammation-induced myocardial dysfunction. This may also have implications for coronavirus disease-19 therapy.