What is the clinical evidence from this study?

Study design: Other. Population: Enterovirus D68 infection. Intervention: Enterovirus D68 infection (strains US/IL/14-18952 and US/MA/18-23089) vs. Mock infection. Primary outcome: Cellular tropism and transcriptional responses.

What does this research mean for the field?

Enterovirus D68 strains exhibit distinct cellular tropisms in the human spinal cord, with strain US/IL/14-18952 preferentially infecting neurons and strain US/MA/18-23089 preferentially infecting cycling astrocytes and oligodendrocyte progenitor cells. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

November 19, 2025Frontiers in Microbiology3 citationsOpen Access

Strain-specific tropism and transcriptional responses of enterovirus D68 infection in human spinal cord organoids

NDNathânia DábillaNational Institutes of Health SMSarah MayaUniversity of Pittsburgh CMColton McNinchNational Institutes of Health

Key Result

EV-D68 strain US/IL/14-18952 preferentially infected neurons, while strain US/MA/18-23089 exhibited higher rates of infection in cycling astrocytes and oligodendrocyte progenitor cells.

Structured PICO

Population

In vitro study utilizing human spinal cord organoids derived from induced pluripotent stem cells to investigate the cellular tropism and transcriptional responses of two Enterovirus D68 strains.

Intervention

Infection with Enterovirus D68 (EV-D68) strains US/IL/14-18952 (B2) or US/MA/18-23089 (B3) at 10^5 PFU for 48 hours.

Comparator

Mock-infected human spinal cord organoids.

Outcome

Cellular tropism and host transcriptional responses assessed by single-cell RNA sequencing (scRNA-seq).

Different strains of EV-D68 exhibit distinct cellular tropism and transcriptional responses in human spinal cord organoids, highlighting potential strain-specific mechanisms of acute flaccid myelitis pathogenesis.

Limitations

hSCO cells are relatively immature and represent a developing human spinal cord, which may differ from infection dynamics in a child.
Relatively low number of infected cells identified (~1.3-1.6% of total population), constraining the resolution of cell type-specific comparisons.
Analysis focused on a single early time point (48 hours post-infection), potentially missing delayed responses.
Lack of in vivo validation for the observed transcriptional shifts.

Abstract

The mechanisms by which Enterovirus D68 (EV-D68) infection leads to acute flaccid myelitis (AFM), a severe neurological condition characterized by sudden muscle weakness and paralysis, remain poorly understood. To investigate the cellular tropism and infection dynamics of EV-D68, we profiled naive and EV-D68-infected human spinal cord organoids (hSCOs) derived from induced pluripotent stem cells (iPSCs) using single-cell RNA sequencing (scRNA-seq). Examining the cellular composition of healthy hSCOs, we found that hSCOs include diverse cell types, including neurons, astrocytes, oligodendrocyte progenitor cells (OPCs), and multipotent glial progenitor cells (mGPCs). Upon infection with 2 EV-D68 strains, US/IL/14-18952 (a B2 strain) and US/MA/18-23089 (a B3 strain), we observed distinct viral tropism and host transcriptional responses. Notably, US/IL/14-18952 showed a significant preference for neurons, while US/MA/18-23089 exhibited higher rates of infection in cycling astrocytes and OPCs. These findings provide novel insights into the host cell tropism of EV-D68 in the spinal cord, offering insight into the potential mechanisms underlying AFM pathogenesis. Understanding the dynamics of infection at single-cell resolution will inform future therapeutic strategies aimed at mitigating the neurological impact of enterovirus infections.

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