Neuropathogenesis in cytomegalovirus infection: indication of the mechanisms using mouse models

Abstract

Cytomegalovirus (CMV) is the most frequent infectious cause of developmental brain disorders and also causes brain damage in immunocompromised individuals. Although the brain is one of the main targets of CMV infection, little is known about the neuropathogenesis of the brain disorders caused by CMV in humans because of the limitations in studying human subjects. Murine CMV (MCMV) is similar to human CMV (HCMV) in terms of genome structure, pattern of gene expressions, cell tropism and infectious dynamics. In mouse models, it has been shown that neural stem/progenitor cells are the most susceptible to CMV infection in developing brains. During brain development, lytic infection tends to occur in immature glial cells, presumably causing structural disorders of the brain. In the prolonged phase of infection, CMV preferentially infects neuronal cells. Infection of neurons may tend to become persistent by evasion of immune reactions, anti-apoptotic effects and neuron-specific activation of the e1-promoter, presumably causing functional neuronal disorders. It has also been shown that CMV infection in developing brains may become latent in neural immature cells. Brain disorders may occur long after infection by reactivation of the latent infection.

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

“…We have developed mouse models for investigation of the brain abnormalities due to congenital CMV infection. 19,20 In the present study, we demonstrated the enhanced susceptibility of the inner ear to intraperitoneal (i.p.) infection with MCMV in newborn mice in combination with intracerebral (i.c.)…”

Modulación de la apoptosis por cytomegalovirus en la perspectiva del sistema nervioso central

“…Esta posibilidad fue sustentada mediante un estudio in vitro empleando cultivos primarios de neuronas, en el cual se encontró que tras la infección con CMV murino las neuronas eran más resistentes a la ausencia de nutrientes o el tratamiento con glutamato que normalmente induciría apoptosis, además de que no se encontraron células infectadas TUNEL-positivas 54 . Por lo anterior, la inhibición de apoptosis en neuronas propone que es en estas células donde CMV humano establece latencia dentro del SNC 5 . Estos resultados sugieren que la apoptosis es inducida en las células que no se encuentran infectadas, a través de mecanismos indirectos como la liberación de un factor soluble como ocurre en las células de retina.…”

“…La incidencia de la infección congénita por CMV se encuentra entre 0,8 y 2,6% del total de recién nacidos a nivel global, porcentaje del cual entre 5 y 10% presenta una enfermedad de inclusión citomegálica al nacimiento con síntomas que incluyen microcefalia, hidrocefalia y calcificaciones cerebrales. De la misma manera, el grupo de infantes asintomáticos puede desarrollar trastornos cerebrales como pérdida de la audición y retraso mental 5 .…”

Animal models of human cytomegalovirus congenital infection

“…Despite poor transplacental transmission of MCMV in the laboratory setting, direct injection into the foetus or the newborn pup has been shown to mimic HCMV-induced congenital disease 12,13 . Similar to RhCMV, the susceptibility of neuronal stem cells to MCMV infection is maturation stage-dependent, with a rapid resistance to infection of the brain developing after birth 16 .…”

“…Several GPCMV vaccines (live attenuated, subunit and DNA) administered before conception, have been evaluated 5,11 . Whilst sterilising immunity to any vaccination program has not been demonstrated, Cost is high for vaccine and drug studies Similar SNHL sequelae 7 Proven model for drug efficacy 6,8,9 Proven model for vaccine immunogenicity and efficacy 5,10,11 Highly refined model with respect to virus dose, timing of infection, end organ disease 9 Mouse MCMV 230 kb Good newborn infection model 12,13 Poor transplacental transmission 6 Excellent knowledge of virus-host interactions 14 Not suited for vaccine/drug efficacy studies targeted at preventing congenital infection…”