Induction of cytomegalovirus-infected labyrinthitis in newborn mice by lipopolysaccharide: a model for hearing loss in congenital CMV infection

Li, Li; Kosugi, Isao; Han, Guiping; Kawasaki, Hideya; Arai, Yoshifumi; Takeshita, Tamotsu; Tsutsui, Yoshihiro

doi:10.1038/labinvest.2008.39

Cited by 33 publications

(25 citation statements)

References 44 publications

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“…Indeed, the ventricular reservoirs of the brain are contiguous with the cochlear perilymphatic compartments and have been reported as a route of CMV viral entry into the inner ear (Li et al , 2008; Otis and Brent, 1954). .Infectious agents can also enter the cochlea via typanogenic (through the round window) and hematogenic (through the blood).…”

Section: Discussionmentioning

confidence: 99%

“…Mouse models using murine (M)CMV infection (Staczek, 1990) are useful because peripheral and intracranial MCMV infection produces end organ disease that mimics that associated with vertically transmitted CMV-infection in humans (Bantug et al , 2008; Li et al , 2008). Furthermore, employment of transgenic mice enables the identification of genes critical to CMV infection and the immune response associated with viral infection.…”

Section: Introductionmentioning

confidence: 99%

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Cytomegalovirus-induced sensorineural hearing loss with persistent cochlear inflammation in neonatal mice

et al. 2011

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Congenital cytomegalovirus (CMV) infection is the leading cause of sensorineural hearing loss (SNHL) in children. During murine (M)CMV-induced encephalitis, the immune response is important for both the control of viral dissemination and the clearance of virus from the brain. While the importance of CMV-induced SNHL has been described, the mechanisms surrounding its pathogenesis and the role of inflammatory responses remain unclear. This study presents a neonatal mouse model of profound SNHL in which MCMV preferentially infected both cochlear perilymphatic epithelial cells and spiral ganglion neurons. Interestingly, MCMV infection induced cochlear hair cell death by 21 days post-infection, despite a clear lack of direct infection of hair cells and the complete clearance of the virus from the cochlea by 14 dpi. Flow cytometric, immunohistochemical, and quantitative PCR analysis of MCMV-infected cochlea revealed a robust and chronic inflammatory response, including a prolonged increase in reactive oxygen species production by infiltrating macrophages. These data support a pivotal role for inflammation during MCMV-induced SNHL.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cytomegalovirus-induced sensorineural hearing loss with persistent cochlear inflammation in neonatal mice

et al. 2011

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“…Interestingly, the organ of Corti was completely void of MCMV-infected cells. 138 Infection induces the infiltration of immune cells largely composed of macrophages and T lymphocytes that populate MCMV-positive regions and persist after viral clearance from the cochlea. Lymphocytic infiltration is concomitant with the production of pro-inflammatory cytokines and chemokines, including TNF-a and IL-6, whose levels in the scala tympani are increased; 139 however, the inner ear injury possibly being mediated by the host inflammatory response was suggested by a study using intracranial MCMV inoculation.…”

Section: Sensorineural Hearing Loss Due To Congenital CMV Infectionmentioning

confidence: 99%

Immunobiology of congenital cytomegalovirus infection of the central nervous system—the murine cytomegalovirus model

et al. 2014

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Congenital human cytomegalovirus infection is a leading infectious cause of long-term neurodevelopmental sequelae, including mental retardation and hearing defects. Strict species specificity of cytomegaloviruses has restricted the scope of studies of cytomegalovirus infection in animal models. To investigate the pathogenesis of congenital human cytomegalovirus infection, we developed a mouse cytomegalovirus model that recapitulates the major characteristics of central nervous system infection in human infants, including the route of neuroinvasion and neuropathological findings. Following intraperitoneal inoculation of newborn animals with mouse cytomegalovirus, the virus disseminates to the central nervous system during high-level viremia and replicates in the brain parenchyma, resulting in a focal but widespread, non-necrotizing encephalitis. Central nervous system infection is coupled with the recruitment of resident and peripheral immune cells as well as the expression of a large number of pro-inflammatory cytokines. Although infiltration of cellular constituents of the innate immune response characterizes the early immune response in the central nervous system, resolution of productive infection requires virus-specific CD8 1 T cells. Perinatal mouse cytomegalovirus infection results in profoundly altered postnatal development of the mouse central nervous system and long-term motor and sensory disabilities. Based on an enhanced understanding of the pathogenesis of this infection, prospects for novel intervention strategies aimed to improve the outcome of congenital human cytomegalovirus infection are proposed.

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“…Moreover, species specificity of HCMV precludes the direct study of the virus in an animal model limits our understanding of HCMV associated deafness. Research conducted on animal models display that cochlear vascular, neural, and epithelial cells are likely targets of CMV infection [16]. In neonatal mouse model of profound SNHL, MCMV preferentially infected both cochlear perilymphatic epithelial cells and spiral ganglion neurons [17].…”

Section: Discussionmentioning

confidence: 99%

Immune Modulatory Function of Human Cytomegalovirus-Encoded UL128 in the Pathogenesis of Infection Related Hearing Loss

Qi¹,

Tao²,

H³

et al. 2017

J Infect Dis Ther

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Inflammatory cytokines such as tumor necrosis factor (TNF)-a, interleukin (IL)-6 were supposed to participate in the tissue damage of human cytomegalovirus (HCMV) infection related diseases. The pathogenesis of HCMV associated hearing loss is poorly understood mainly due to the lack of applicable virus infected model. We subjected cochlear epithelial cell line derived from human auditory progenitors to HCMV infection and examined the levels of cytokines released in the co-cultural supernatant of peripheral blood monocytes and HCMV pre-infected cochlear epithelial cells. Human cochlear epithelial cell line cultured in vitro is replicable and permissive for HCMV productive infection. Detection of the co-culture system revealed up-regulation of cytokines including IL-6 and TNF-α. Since HCMV UL128 protein interferes with virus entry into epithelial cells as well as eliciting primary antibody in vivo, transcription of HCMV UL128 gene was suppressed by short interference RNA in this experiment. Cytokine analysis revealed that UL128 deficient HCMV got impairment of inducing IL-6 and TNF-α production when interacted with host immune cells. We deduce that UL128 may serve as a viral immune modulator participating in the pathology of HCMV related hearing loss and UL128 gene can be a potential target for treatment of infection induced immune pathological damage.

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Induction of cytomegalovirus-infected labyrinthitis in newborn mice by lipopolysaccharide: a model for hearing loss in congenital CMV infection

Cited by 33 publications

References 44 publications

Cytomegalovirus-induced sensorineural hearing loss with persistent cochlear inflammation in neonatal mice

Cytomegalovirus-induced sensorineural hearing loss with persistent cochlear inflammation in neonatal mice

Immunobiology of congenital cytomegalovirus infection of the central nervous system—the murine cytomegalovirus model

Immune Modulatory Function of Human Cytomegalovirus-Encoded UL128 in the Pathogenesis of Infection Related Hearing Loss

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