Coxsackievirus B3 and the Neonatal CNS

Abstract

Neonates are particularly susceptible to coxsackievirus infections of the central nervous system (CNS), which can cause meningitis, encephalitis, and long-term neurological deficits. However, viral tropism and mechanism of spread in the CNS have not been examined. Here we investigate coxsackievirus B3 (CVB3) tropism and pathology in the CNS of neonatal mice, using a recombinant virus expressing the enhanced green fluorescent protein (eGFP). Newborn pups were extremely vulnerable to coxsackievirus CNS infection, and this susceptibility decreased dramatically by 7 days of age. Twenty-four hours after intracranial infection of newborn mice, viral genomic RNA and viral protein expression were detected in the choroid plexus, the olfactory bulb, and in cells bordering the cerebral ventricles. Many of the infected cells bore the anatomical characteristics of type B stem cells, which can give rise to neurons and astrocytes, and expressed the intermediate filament protein nestin, a marker for progenitor cells. As the infection progressed, viral protein was identified in the brain parenchyma, first in cells expressing neuron-specific class III beta-tubulin, an early marker of neuronal differentiation, and subsequently in cells expressing NeuN, a marker of mature neurons. At later time points, viral protein expression was restricted to neurons in specific regions of the brain, including the hippocampus, the entorhinal and temporal cortex, and the olfactory bulb. Extensive neuronal death was visible, and appeared to result from virus-induced apoptosis. We propose that the increased susceptibility of the neonatal CNS to CVB infection may be explained by the virus' targeting neonatal stem cells; and that CVB is carried into the brain parenchyma by developing neurons, which continue to migrate and differentiate despite the infection. On full maturation, some or all of the infected neurons undergo apoptosis, and the resulting neuronal loss can explain the longer-term clinical picture.

Differential expression of coxsackievirus and adenovirus receptor on alveolar epithelial cells between fetal and adult mice determines their different susceptibility to coxsackievirus B infection

“…Moreover, primary neurons become less susceptible to CVB following maturation due to the decreased surface expression of CAR [17]. Agespecific expression of CAR in the brains of newborn mice has been associated with their unique susceptibility to CVB encephalitis [43,44], suggesting that CAR is an important determinant of viral tropism for the murine brain [45]. It is also likely that the host range of CVBs depends on speciesspecific interactions with CAR molecules (i.e., mouse or human).…”

Coxsackievirus Protein 2BC Blocks Host Cell Apoptosis by Inhibiting Caspase-3

“…Both forms of cell death, i.e. necrotic-like CPE and apoptosis, have been documented in cardiomyocyte, neuron, and pancreatic ␤ cell death (17,24,25). However, how much either form of cell death individually contributes in vivo to viral replication and spreading and also subsequent viral-induced autoimmunity and chronic disease such as seen in dilated cardiomyopathy (61) remains to be investigated.…”

“…The cytopathic effects (CPE) induced share characteristics with necrosis (16,17). However, in some cell types or environments or when virus replication is inhibited, the virus-triggered cell destruction adopts the apoptotic path, as extensively documented for poliovirus (18 -22) and Coxsackievirus B (23)(24)(25)(26)(27). The molecular mechanism responsible for the switch between the two forms of cell death is still poorly understood, but poliovirus has been shown to induce an antiapoptotic activity under conditions of permissive replication and infection that would favor necrosis-like CPE over cell death by apoptosis.…”

Homology modeling, docking, molecular dynamics simulation, and structural analyses of coxsakievirus B3 2A protease: An enzyme involved in the pathogenesis of inflammatory myocarditis

“…Persisting CVB3 may produce dilated cardiomyopathy without obligate previous myocardial inflammation [3,4]. CVB3 has also been involved in the pathogenesis of diseases such as hepatitis [5], pancreatitis [6], and aseptic meningitis [7]. Studies in animal models and cultured cells have shown that both acute and persisting CVB3 infection may directly cause cytopathology in cardiac cells [4,5,[8][9][10].…”