Enterovirus D68 infection in cotton rats results in systemic inflammation with detectable viremia associated with extracellular vesicle and neurologic disease.

Summary

In immunocompetent cotton rats, EV-D68 respiratory infection led to viremia and extra-respiratory organ involvement with inflammation, and EV-D68 was physically associated with extracellular vesicles purified from plasma. Intraperitoneal infection and direct EV-associated virus delivery enabled CNS detection and neurologic signs, providing the first in vivo evidence that EVs facilitate EV-D68 dissemination beyond the respiratory tract.

Key Findings

• EV-D68 was detected in blood and extra-respiratory organs following respiratory infection, indicating systemic dissemination with accompanying inflammation.
• Virus was physically associated with extracellular vesicles purified from plasma.
• Intraperitoneal infection and EV-associated virus delivery led to CNS detection and neurologic signs in young cotton rats.
• Provides first in vivo experimental support that EVs mediate EV-D68 dissemination beyond the respiratory tract.

Clinical Implications

While preclinical, these findings suggest therapeutic avenues targeting extracellular vesicle biogenesis or uptake to limit EV-D68 dissemination and AFM risk; they also refine pathogenesis models for testing antivirals or vaccines.

Limitations

• Preclinical animal model limits direct generalizability to humans
• Strain- and species-specific effects not fully explored; lack of interventional blockade experiments

Future Directions

Test pharmacologic or genetic inhibition of EV biogenesis/uptake to curb dissemination; validate across EV-D68 clades and in human biospecimens; integrate with AFM clinical cohorts.