Congenital cytomegalovirus infection – a common cause of hearing loss of unknown aetiology

Karltorp, Eva; Hellström, Sten; Lewensohn-Fuchs, Ilona; Carlsson-Hansén, Eva; Carlsson, Peder; Engman, Mona-Lisa

doi:10.1111/j.1651-2227.2012.02711.x

Cited by 35 publications

(28 citation statements)

References 31 publications

(30 reference statements)

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“…There are about 400,000 babies with cCMV infection among the annual 20 million newborns in China and an estimated 40,000 new cases suffering from the sequelae caused by cCMV infection every year. Of the long-lasting sequelae in infants with cCMV, SNHL can be expected to occur most frequently (20,21). Severe brain damage is most commonly observed when cCMV infection occurs at early gestation.…”

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confidence: 99%

Later Passages of Neural Progenitor Cells from Neonatal Brain Are More Permissive for Human Cytomegalovirus Infection

Pan

Liu

et al. 2013

J Virol

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f Congenital human cytomegalovirus (HCMV) infection is the most frequent infectious cause of birth defects, primarily neurological disorders. Neural progenitor/stem cells (NPCs) are the major cell type in the subventricular zone and are susceptible to HCMV infection. In culture, the differentiation status of NPCs may change with passage, which in turn may alter susceptibility to virus infection. Previously, only early-passage (i.e., prior to passage 9) NPCs were studied and shown to be permissive to HCMV infection. In this study, NPC cultures derived at different gestational ages were evaluated after short (passages 3 to 6) and extended (passages 11 to 20) in vitro passages for biological and virological parameters (i.e., cell morphology, expression of NPC markers and HCMV receptors, viral entry efficiency, viral gene expression, virus-induced cytopathic effect, and release of infectious progeny). These parameters were not significantly influenced by the gestational age of the source tissues. However, extended-passage cultures showed evidence of initiation of differentiation, increased viral entry, and more efficient production of infectious progeny. These results confirm that NPCs are fully permissive for HCMV infection and that extended-passage NPCs initiate differentiation and are more permissive for HCMV infection. Later-passage NPCs being differentiated and more permissive for HCMV infection suggest that HCMV infection in fetal brain may cause more neural cell loss and give rise to severe neurological disabilities with advancing brain development.

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confidence: 99%

Later Passages of Neural Progenitor Cells from Neonatal Brain Are More Permissive for Human Cytomegalovirus Infection

Pan

Liu

et al. 2013

J Virol

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“…Peripheral blood count abnormalities, such as lymphocytosis, neutropenia, thrombocytopenia, anemia, petechiae (Figure, Box 1), hepatitis with elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and/or direct hyperbilirubinemia, diffuse pneumonic infiltrates, fundus changes (retinitis), and hearing loss (18) are indicative of congenital infection. Typically, potentially progressive sensorineural hearing loss is present-the most common non-genetic cause of hearing loss (19). The progressive nature of the hearing loss is credited to a chronic productive HCMV infection of the labyrinth (e17, e18).…”

Section: Clinical Presentation Of Congenital Human Cytomegalovirus Inmentioning

confidence: 99%

Primary Human Cytomegalovirus (HCMV) Infection in Pregnancy

Buxmann

Hamprecht

Meyer‐Wittkopf

et al. 2017

Deutsches Ärzteblatt International

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“…The fetal brain and auditory system are the main sites of the clinical manifestations of congenital HCMV (cCMV) infection (1)(2)(3)(4), and sensorineural hearing loss is the most common long-term sequela in congenitally infected infants (4)(5)(6). In the fetal brain, the bilateral subventricular zone (SVZ), where neural progenitor/stem cells (NPCs) are a predominant cell type, is a site of virus-induced damage that has been well described in infants with severe congenital HCMV infection (7)(8)(9)(10)(11).…”

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confidence: 99%

Human Cytomegalovirus Infection Dysregulates the Localization and Stability of NICD1 and Jag1 in Neural Progenitor Cells

Liu

Yang

et al. 2015

J Virol

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Human cytomegalovirus (HCMV) infection of the developing fetus frequently results in major neural developmental damage. In previous studies, HCMV was shown to downregulate neural progenitor/stem cell (NPC) markers and induce abnormal differentiation. As Notch signaling plays a vital role in the maintenance of stem cell status and is a switch that governs NPC differentiation, the effect of HCMV infection on the Notch signaling pathway in NPCs was investigated. HCMV downregulated mRNA levels of Notch1 and its ligand, Jag1, and reduced protein levels and altered the intracellular localization of Jag1 and the intracellular effector form of Notch1, NICD1. These effects required HCMV gene expression and appeared to be mediated through enhanced proteasomal degradation. Transient expression of the viral tegument proteins of pp71 and UL26 reduced NICD1 and Jag1 protein levels endogenously and exogenously. Given the critical role of Notch signaling in NPC growth and differentiation, these findings reveal important mechanisms by which HCMV disturbs neural cell development in vitro. Similar events in vivo may be associated with HCMV-mediated neuropathogenesis during congenital infection in the fetal brain. IMPORTANCE Congenital human cytomegalovirus (HCMV) infection is the leading cause of birth defects that primarily manifest as neurological disabilities. Neural progenitor cells (NPCs), key players in fetal brain development, are the most susceptible cell type for HCMV infection in the fetal brain. Studies have shown that NPCs are fully permissive for HCMV infection, which causes neural cell loss and premature differentiation, thereby perturbing NPC fate. Elucidation of virus-host interactions that govern NPC proliferation and differentiation is critical to understanding neuropathogenesis. The Notch signaling pathway is critical for maintaining stem cell status and functions as a switch for differentiation of NPCs. Our investigation into the impact of HCMV infection on this pathway revealed that HCMV dysregulates Notch signaling by altering expression of the Notch ligand Jag1, Notch1, and its active effector in NPCs. These results suggest a mechanism for the neuropathogenesis induced by HCMV infection that includes altered NPC differentiation and proliferation.

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Congenital cytomegalovirus infection – a common cause of hearing loss of unknown aetiology

Abstract: Congenital CMV infection is a high risk factor in hearing impairment among children.

Cited by 35 publications

References 31 publications

Later Passages of Neural Progenitor Cells from Neonatal Brain Are More Permissive for Human Cytomegalovirus Infection

Later Passages of Neural Progenitor Cells from Neonatal Brain Are More Permissive for Human Cytomegalovirus Infection

Primary Human Cytomegalovirus (HCMV) Infection in Pregnancy

Human Cytomegalovirus Infection Dysregulates the Localization and Stability of NICD1 and Jag1 in Neural Progenitor Cells

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