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

Abstract

Cytomegalovirus (CMV) is the most common cause of congenital infection in developed countries and a major cause of neurological disability in children. Although CMV can affect multiple organs, the most important sequelae of intrauterine infection are related to lesions of the central nervous system. However, little is known about the pathogenesis and the cellular events responsible for neuronal damage in infants with congenital infection. Some studies have demonstrated that neural precursor cells (NPCs) show the greatest susceptibility to CMV infection in the developing brain. We sought to establish an in vitro model of CMV infection of the developing brain in order to analyze the cellular events associated with invasion by this virus. To this end, we employed two cell lines as a permanent source of NPC, avoiding the continuous use of human fetal tissue, the human SK-N-MC neuroblastoma cell line, and an immortalized cell line of human fetal neural origin, hNS-1. We also investigated the effect of the differentiation stage in relation to the susceptibility of these cell lines by comparing the neuroblastoma cell line with the multipotent cell line hNS-1. We found that the effects of the virus were more severe in the neuroblastoma cell line. Additionally, we induced hNS-1 to differentiate and evaluated the effect of CMV in these differentiated cells. Like SK-N-MC cells, hNS-1-differentiated cells were also susceptible to infection. Viability of differentiated hNS-1 cells decreased after CMV infection in contrast to undifferentiated cells. In addition, differentiated hNS-1 cells showed an extensive cytopathic effect whereas the effect was scarce in undifferentiated cells. We describe some of the effects of CMV in neural stem cells, and our observations suggest that the degree of differentiation is important in the acquisition of susceptibility.

Toxoplasma gondii inhibits differentiation of C17.2 neural stem cells through Wnt/β-catenin signaling pathway

“…Neural cell number and maturely differentiated neural cells are the foundation for fetal brain development. Researchers have found that human cytomegalovirus (HCMV), the leading cause of central nervous system disorders following congenital infection, can infect and replicate in neural progenitor cells (NPC), thereby causing neural cell loss and premature differentiation, perturbing NPC fate, and leading to brain malformations [16,17]. T. gondii is known to be capable of invading almost any nucleated cells, and is a critical factor relevantly causing brain pathological damage.…”

The antiviral cytokine interferon‐gamma restricts neural stem/progenitor cell proliferation through activation of STAT1 and modulation of retinoblastoma protein phosphorylation

“…Neural stem/progenitor cells (NSPCs) are capable of self‐renewal and differentiation into neurons, astrocytes, or oligodendrocytes. During CNS insults (viral infection, stroke, protein misfolding stress), the NSPC pool can expand or contract (Chucair‐Elliott et al, ; Das and Basu, ; Das et al, ; Deierborg et al, ; Gonzalez‐Sanchez et al, ; Hoglinger et al, ; Lee et al, ; Sun et al, ). During many neurotropic infections, NSPC proliferation and neurogenesis declines (Mutnal et al, ; Ruller et al, ; Sharma et al, ).…”

Human Cytomegalovirus Disruption of Calcium Signaling in Neural Progenitor Cells and Organoids

“…NPCs derived from induced pluripotent stem cells (iPSCs) and fetal stem cells are fully permissive for HCMV infection (8)(9)(10)(11), with susceptibility influenced by the degree of differentiation (12,13). Expression of viral genes has been shown to alter signaling pathways and expression of key development factors, including Notch and Sox2 (14)(15)(16), and infection results in abnormal proliferation and differentiation (13,17,18). For the pluripotency factor Sox2, expression of HCMV IE1 causes downregulation of Sox2, involving IE1 sequestration of unphosphorylated STAT3 to the nucleus (15,19).…”