Roles of neural stem progenitor cells in cytomegalovirus infection of the brain in mouse models

Abstract

Cytomegalovirus (CMV) is the most significant infectious cause of brain disorders in humans. Although the brain is the principal target organ for CMV infection in infants with congenital infection and in immunocompromised patients, little has been known about cellular events in pathogenesis of the brain disorders. Mouse models have been developed by the authors for studying the cell tropism, infectious dynamics of CMV infection and the effects of CMV infection on proliferation, regeneration and differentiation of neural cells. It has been shown, using brain slice cultures and neurospheres, that neural stem progenitor (NSP) cells are the most susceptible to CMV infection in developing brains. The NSP cells are also susceptible to CMV infection in adult and aged brains. The susceptibility can be enhanced by stimulation of neurogenesis. It was shown that latent murine CMV infection occurs in NSP cells by demonstrating the reactivation in brain slice culture or neurospheres. It is hypothesized that CMV brain disorder such as microcephaly is caused by disturbance of cellular events in the ventricular regions, including proliferation and differentiation of the neural stem cells, whereas neurons are also targets in persistent CMV infection, presumably resulting in functional disorders such as mental retardation.

Effects of cytomegalovirus infection in human neural precursor cells depend on their differentiation state

“…Nevertheless, these animal models have provided evidence that the highest CMV susceptibility in CNS is presented by neural precursor cells (NPCs) (Tsutsui et al 2002). Infection of these cells might be the cause of microcephaly and mental retardation since it has been observed that murine CMV inhibits NPC proliferation and migration (Shinmura et al 1997;Tsutsui et al 2008). Furthermore, studies of functional neural cells after CMV infection, though scarce, reveal that infected cells have altered intercellular communication and deficient response to neurotransmitters (Ho and van den Pol 2007).…”

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

“…Recientemente se le ha atribuido parte del daño causado por el virus a efectos sobre las CPN, al localizarse las células infectadas, principalmente en las regiones ventricular y subventricular donde residen este tipo de células. Se han relacionado algunas de las manifestaciones clínicas más frecuentes con la infección de las CPN, como la microcefalia que podría tener su origen en la disminución de su proliferación y posterior migración, así como interfiriendo con procesos de diferenciación en estas células 58,66,67 . No obstante, son necesarios más estudios que logren esclarecer los mecanismos que subyacen al daño en SNC inducido por el virus, así como las consecuencias clínicas que estos efectos tengan.…”

Peroxisome proliferator-activated receptor γ (PPARγ) activation: A key determinant of neuropathogeny during congenital infection by cytomegalovirus

“…Founder studies in the mouse revealed that HCMV murine counterpart, namely murine cytomegalovirus (MCMV), infected the developing brain the cerebral ventricular walls, a region known to contain neural progenitors. 6 Strikingly, infected cells seemed to migrate from the (sub-) ventricular zones to the cortical plate or the hippocampus. 6 Mouse neurons were also found to be sensitive to infection.…”

“…6 Strikingly, infected cells seemed to migrate from the (sub-) ventricular zones to the cortical plate or the hippocampus. 6 Mouse neurons were also found to be sensitive to infection. Studies in human were limited for obvious reasons, and in vitro studies were performed with primary cultures of human brain cells prepared from deceased, uninfected fetus.…”