Human Lung Nipah Virus Microfluidic Lung Chip – Disease Modeling and Antiviral Treatments in Maximum Containment

Featured session at Bethesda MPS Day, which took place on November 9, 2023.

Dr. Sushma Bhosle from the Integrated Research Facility (IRF) at NIAID/NIH presents her work on using Lung-Chip models in maximum biosafety containment (BSL-4) settings for studying high-risk viruses such as Nipah virus (NiV). Traditional preclinical models (e.g., simple 2D cell cultures or animal models) often fail to accurately predict human clinical outcomes, and there’s a need for more physiologically relevant, human-based systems. Microphysiological systems (MPS), like the Emulate Small Airway Lung-Chip, provide a complex, human-relevant platform that incorporates airway epithelium and microvascular endothelium under air-liquid interface and flow conditions.

Dr. Bhosle’s team validated a Small Airway Lung-Chip using human primary cells, confirming proper differentiation and expression of markers indicative of mature airway tissue. They infected these chips with Nipah virus under BSL-4 conditions and monitored viral replication, barrier integrity, and immune responses. Compared to traditional transwell assays, the Airway Lung-Chip supported robust viral replication across both apical and basal compartments, displayed increased barrier permeability changes, and allowed detailed observation of cytokine profiles and endothelial inflammation. Treatment with antiviral drugs, such as zotatifin (an mRNA translation inhibitor) and remdesivir, reduced viral burden and restored barrier function. The chips also enabled the study of donor-to-donor variability in immune and inflammatory responses, reflecting the personalized aspects of human disease.

Furthermore, incorporation of immune cells (neutrophils) into the chip environment showed that immune cell recruitment and cytokine release patterns differed markedly upon viral infection, emphasizing the importance of including immune components for a more comprehensive disease model. This approach sets the stage for using Lung-Chip systems in maximum containment labs to test therapeutics, explore patient-specific responses, and understand high-risk virus biology with greater predictive value for clinical outcomes.

Key learnings from this presentation include:

  • High containment feasibility: The Airway Lung-Chip is successfully operated in BSL-4 conditions, enabling the study of severe pathogens like Nipah virus.
  • Physiological complexity: Compared to transwells, MPS offer dynamic air-liquid interface, fluid flow, and mechanical stretch, better replicating human lung physiology and yielding more meaningful data on viral infection and tissue responses.
  • Antiviral interventions: Testing antivirals directly on the chip shows how candidate drugs (zotatifin, remdesivir) impact viral replication, barrier integrity, and cytokine profiles in a human-relevant context.
  • Donor variability and immune involvement: The system captures variations in immune and inflammatory markers between donors and highlights the critical role of immune cell infiltration in shaping virus-induced pathology.
  • Broad potential applications: Beyond Nipah virus, these methods can extend to studying various high-risk pathogens, informing therapeutic development, and advancing precision medicine approaches in infectious diseases.