Encephalitic alphavirus infection reduces neurite outgrowth and downregulates Rho GTPase pathways in human iPSC-derived neurospheres
- 1Institute for Food Quality and Food Safety, Research Group Food Toxicology and Alternative/Complementary Methods to Animal Experiments, University of Veterinary
Abstract
Venezuelan equine encephalitis virus (VEEV) is a re-emerging neurotropic arbovirus, which affects the developing human brain, potentially leading to miscarriage, stillbirth, or long-term neurological sequelae. Currently, the mechanisms underlying these sequelae remain largely elusive. Using human induced pluripotent stem cell (iPSC)-derived neurospheres as a model for brain development, we show that both human neurons and glial cells are susceptible to VEEV infection. Microscopy-based quantification reveals that VEEV impairs neurite outgrowth in the human neurospheres. To mechanistically assess these observations, we performed multi-omics analyses of VEEV-infected neurospheres and demonstrate translational shutoff including downregulation of Rho GTPase pathways. The transcriptional and proteome profile is indicative of reduced actin cytoskeleton dynamics and consequently migratory defects of cells in the neurospheres. Shotgun secretomics moreover revealed downmodulation of neurite outgrowth associated proteins including midkine (MDK), amyloid-beta precursor protein (APP) and microtubule-associated protein 1B (MAP1B). Our findings reveal mechanistic insights into how VEEV infection impairs neuronal development and demonstrate that neurospheres are a powerful platform for assessing teratogenic effects of viruses on brain development.
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BibTeX
@misc{cirksena2026encephalitic,
title = {{Encephalitic alphavirus infection reduces neurite outgrowth and downregulates Rho GTPase pathways in human iPSC-derived neurospheres}},
author = {K. Cirksena and L. M. Haiber and B. A. Kuehne and J. Hupfeld and M. Duven and A. Fischer and M. Schenke and F. Richter and S. Weiss and M. C. Altenbuchinger and N. Seifert and H. U. Zacharias and S. Konzok and B. Seeger and G. Gerold},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.08.755254},
url = {https://www.biorxiv.org/content/10.64898/2026.10.08.755254v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Encephalitic alphavirus infection reduces neurite outgrowth and downregulates Rho GTPase pathways in human iPSC-derived neurospheres
AU - K. Cirksena
AU - L. M. Haiber
AU - B. A. Kuehne
AU - J. Hupfeld
AU - M. Duven
AU - A. Fischer
AU - M. Schenke
AU - F. Richter
AU - S. Weiss
AU - M. C. Altenbuchinger
AU - N. Seifert
AU - H. U. Zacharias
AU - S. Konzok
AU - B. Seeger
AU - G. Gerold
PY - 2026
DA - 2026/10/08
PB - bioRxiv
DO - 10.64898/2026.10.08.755254
UR - https://www.biorxiv.org/content/10.64898/2026.10.08.755254v1
AB - Venezuelan equine encephalitis virus (VEEV) is a re-emerging neurotropic arbovirus, which affects the developing human brain, potentially leading to miscarriage, stillbirth, or long-term neurological sequelae. Currently, the mechanisms underlying these sequelae remain largely elusive. Using human induced pluripotent stem cell (iPSC)-derived neurospheres as a model for brain development, we show that both human neurons and glial cells are susceptible to VEEV infection. Microscopy-based quantification reveals that VEEV impairs neurite outgrowth in the human neurospheres. To mechanistically assess these observations, we performed multi-omics analyses of VEEV-infected neurospheres and demonstrate translational shutoff including downregulation of Rho GTPase pathways. The transcriptional and proteome profile is indicative of reduced actin cytoskeleton dynamics and consequently migratory defects of cells in the neurospheres. Shotgun secretomics moreover revealed downmodulation of neurite outgrowth associated proteins including midkine (MDK), amyloid-beta precursor protein (APP) and microtubule-associated protein 1B (MAP1B). Our findings reveal mechanistic insights into how VEEV infection impairs neuronal development and demonstrate that neurospheres are a powerful platform for assessing teratogenic effects of viruses on brain development.
ER -