Coxsackievirus B3 and the Neonatal CNS: The Roles of Stem Cells, Developing Neurons, and Apoptosis in Infection, Viral Dissemination, and Disease

• Published in: The American journal of pathology Vol. 163; no. 4; pp. 1379 - 1393
• Main Authors: Feuer, Ralph, Mena, Ignacio, Pagarigan, Robb R, Harkins, Stephanie, Hassett, Daniel E, Whitton, J. Lindsay
• Format: Journal Article
• Language: English
• Published: Bethesda, MD ASIP 01.10.2003; American Society for Investigative Pathology
• Subjects: Aging; Animals; Animals, Newborn; Apoptosis; Biological and medical sciences; Brain - virology; Cellular Senescence; Central Nervous System Diseases - mortality; Central Nervous System Diseases - physiopathology; Central Nervous System Diseases - virology; Coxsackievirus Infections - complications; Coxsackievirus Infections - mortality; Coxsackievirus Infections - virology; Disease Progression; Disease Susceptibility; Enterovirus - isolation & purification; Experimental viral diseases and models; Green Fluorescent Proteins; In Situ Hybridization; Indicators and Reagents; Infectious diseases; Luminescent Proteins; Medical sciences; Mice; Mice, Inbred BALB C; Neurons - metabolism; Regular; Stem Cells - virology; Time Factors; Viral diseases; Viral Proteins - metabolism; Immunohistochemistry; Nervous system diseases; Picornaviridae; Stem cell; Rodentia; Central nervous system; Enterovirus; Infection; Virus; Anatomic pathology; Vertebrata; Experimental disease; Mammalia; Neuron; Mouse; Newborn animal; Coxsackievirus B3; Dissemination; Viral disease; Central nervous system disease; Molecular biology; Immunofluorescence; Apoptosis
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/S0002-9440(10)63496-7

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.