A three-dimensional vessel-on-chip model to study Puumala orthohantavirus pathogenesis

Area of Science:

• Virology
• Cell Biology
• Biotechnology

Background:

• Puumala orthohantavirus (PUUV) causes hemorrhagic fever with renal syndrome, primarily infecting endothelial cells (ECs).
• Traditional 2D cell culture models lack physiological relevance due to static conditions and inherent inflammation.
• Understanding ECs' response to PUUV is crucial for disease pathogenesis and therapeutic development.

Purpose of the Study:

• To develop and validate a high-throughput 3D vessels-on-chip model for studying PUUV infection in primary human umbilical vein ECs.
• To compare the transcriptional host response of ECs in 3D vessels-on-chip versus static 2D cultures during PUUV infection.
• To investigate the impact of PUUV infection on vascular permeability and endothelial-leukocyte interactions in a more physiologically relevant model.

Main Methods:

• Primary human umbilical vein ECs were cultured in a 3D vessels-on-chip system and compared to static 2D cultures.
• Transcriptional analysis was performed to compare host responses in both models.
• PUUV infection was assessed for its effects on vascular permeability and monocyte adhesion.

Main Results:

• ECs in the 3D vessels-on-chip model exhibited a phenotype more closely resembling the in vivo situation.
• Gene expression profiles in the 3D model showed higher similarity for markers of disease severity and coagulopathy (e.g., IDO1, LGALS3BP, IL6, PLAT).
• PUUV infection in the 3D model increased monocyte adhesion but did not directly increase vascular permeability.

Conclusions:

• The 3D vessels-on-chip platform provides a more accurate model for studying PUUV pathogenesis and endothelial cell responses.
• This model highlights increased monocyte adhesion as a key interaction during PUUV infection, rather than direct vascular permeability increase.
• The platform is suitable for high-throughput screening of therapeutics for endotheliotropic viral infections, even under high biocontainment conditions.