Zika virus differentially infects human neural progenitor cells according to their state of differentiation and dysregulates neurogenesis through the Notch pathway

Abstract

Zika virus (ZIKV) is a mosquito-borne Flavivirus that causes Zika disease with particular neurological complications, including Guillain-Barré Syndrome and congenital microcephaly. Although ZIKV has been shown to directly infect human neural progenitor cells (hNPCs), thereby decreasing their viability and growth, it is as yet unknown which of the cellular pathways involved in the disruption of neurogenesis are affected following ZIKV infection. By comparing the effect of two ZIKV strains in vitro on hNPCs, the differentiation process of the latter cells was found to lead to a decreased susceptibility to infection and cell death induced by each of the ZIKV strains, which was associated with an earlier and stronger antiviral innate immune response in infected, differentiated hNPCs, as compared to undifferentiated cells. Moreover, ZIKV modulated, both in hNPCs and in vivo in fetal brain in an experimental mouse model, the expression of the Notch pathway which is involved in cellular proliferation, apoptosis and differentiation during neurogenesis. These results show that the differentiation state of hNPCs is a significant factor contributing to the outcome of ZIKV infection and furthermore suggest that ZIKV infection might initiate early activation of the Notch pathway resulting in an abnormal differentiation process, implicated in ZIKV-induced brain injury.

mRNA and miRNA profiling of Zika virus-infected human umbilical cord mesenchymal stem cells identifies miR-142-5p as an antiviral factor

“…Several groups have noted phenotypic differences between Asian and African lineage ZIKV strains depending on the cell type. In particular, infection with African lineage strains of human neuronal stem cells resulted in a higher rate of infection and virus production, as well as elevated degree of cell death and antiviral response [38][39][40][41][42]. Similar findings were observed in African-lineage ZIKV-infected trophoblasts [43].…”

Pathological modeling of TBEV infection reveals differential innate immune responses in human neurons and astrocytes that correlate with their susceptibility to infection

“…Understanding viral tropism is critical for understanding virus-induced neuropathogenesis. Some viruses, like Zika virus, preferentially infect neural progenitors [41,42], whereas human immunodeficiency virus has a strong affinity for microglial cells [43], JC virus for astrocytes [44] and the JHM strain of mouse hepatitis virus (JHMV) for oligodendrocytes [45]. Flaviviruses such as TBEV, WNV, and JEV have a preferential tropism for neurons, a feature that has been observed in human patients [12,46,47], as well as in rodent models [48,49].…”

Pathological modeling of TBEV infection reveals differential innate immune responses in human neurons and astrocytes that correlate with their susceptibility to infection

“…Understanding viral tropism is critical for understanding virus-induced neuropathogenesis. Some viruses, like Zika virus, preferentially infect neural progenitors (36, 37) whereas human immunodeficiency virus has a strong affinity for microglial cells (38), JC virus for astrocytes (39) and the JHM strain of mouse hepatitis virus (JHMV) for oligodendrocytes (40). Flaviviruses such as TBEV, WNV and JEV have a preferential tropism for neurons, a feature that has been observed in human patients (12,41,42), as well as in rodent models (43, 44).…”