Faculty Collaboration Database

HCMV infection of terminally differentiated neurons disrupts microtubule organization, resulting in neurite retraction. Microbiol Spectr 2025 Nov 04;13(11):e0119825

Date

10/08/2025

Pubmed ID

41059695

Pubmed Central ID

PMC12584624

DOI

10.1128/spectrum.01198-25

Scopus ID

2-s2.0-105020947428 (requires institutional sign-in at Scopus site)

Abstract

Human cytomegalovirus (HCMV) is a prolific human herpesvirus that infects most individuals by adulthood. While typically asymptomatic in adults, congenital infection can induce serious neurological symptoms, including hearing loss, visual deficits, cognitive impairment, and microcephaly in 10%-15% of cases. HCMV has been shown to infect most neural cells, with our group recently demonstrating this capacity in stem cell-derived forebrain neurons. Infection of neurons induces deleterious effects on calcium dynamics and electrophysiological function paired with gross restructuring of neuronal morphology. Here, we utilize an induced pluripotent stem cell-derived model of the human forebrain to demonstrate how HCMV infection induces syncytia, drives neurite retraction, and remodels microtubule networks to promote viral production and release. We establish that HCMV downregulates microtubule-associated proteins while largely sparing other cytoskeletal elements. Furthermore, we pharmacologically modulate microtubule dynamics using paclitaxel (stabilize) and colchicine (destabilize) to examine the effects on neurite structure, syncytial morphology, and viral release. With paclitaxel, we found improvement of neurite outgrowth, but neither paclitaxel nor colchicine impacted viral titers. Together, these data suggest that HCMV infection-induced disruption of microtubules in human cortical neurons can be partially mitigated with microtubule stabilization, suggesting a potential avenue for future neuroprotective strategies.IMPORTANCEInfection by human cytomegalovirus (HCMV) continues to cause significant damage to human health. In the absence of a vaccine, vertical transmission from mother to fetus can result in profound neurological damage impacting quality of life. These studies focus on understanding the impact of HCMV infection on forebrain cortical neurons derived from induced pluripotent stem cells (iPSCs). We show that infection results in loss of neurite extension accompanied by cell-to-cell fusion. These pathogenic changes involve HCMV infection-mediated disruption of the microtubule network in iPSCs from different patient backgrounds. The microtubule stabilization agent paclitaxel partially protected neurite length and altered syncytia morphology without impacting viral replication. This work is part of our continued efforts to define putative strategies to limit HCMV-induced neurological damage.

Author List

Adelman JW, Sukowaty AT, Partridge KJ, Gawrys JE, Akins A, Terhune SS, Ebert AD

Authors

Allison D. Ebert PhD Center Director, Professor in the Cell Biology Neurobiology and Anatomy department at Medical College of Wisconsin
Scott Terhune PhD Professor in the Microbiology and Immunology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Cell Differentiation
Cells, Cultured
Cytomegalovirus
Cytomegalovirus Infections
Humans
Induced Pluripotent Stem Cells
Microtubule-Associated Proteins
Microtubules
Neurites
Neurons
Paclitaxel
Prosencephalon