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Towards threat-agnostic biorisk assessment using nanoproteomics with a lung-on-a-chip platform

EMSL Project ID


The air we breathe is one of the main routes for pathogenic transmission. When discovered, it is essential to determine if poorly studied or engineered micro-organisms present a threat to human health. Most airborne pathogen characterizations have been performed on non-human models or using either submerged cell or air-liquid interface (ALI) monocultures. These in vitro models often fail to recapitulate the physiology of the pulmonary tissues. The Lung-on-a-chip (LOAC) has been described to recapitulate better lung physiology than these existing models. To date, the potential of this model to characterize pathogens has not been established. Here, we propose to verify the usability of this model for the identification and classification of pathogenic agents. We will culture primary human epithelial and endothelial cells from matching donors to establish donor-specific lung-on-a-chip models. Using nano-proteomics approaches, we will profile the proteome of LOAC, ALI, and submerged cell cultures of the same primary cells. We will compare these proteomics profiles to previously generated in vivo profiles for the same donors to establish if the LOAC better recapitulates tissue-level lung physiology at the molecular level. We will then challenge the LOAC and the ALI models with three risk-group-2 pathogenic challenges: with a well-studied virulence factor (Lipopolysaccharide), with a bacterial agent (B. pseudomallei), and with a viral agent (H1N1 influenza virus). The molecular profiling performed during these challenges will enable us to evaluate the host-pathogen molecular processes recapitulated in the tested models. We will perform pathogenic challenges with risk-group 3 agents of the same virus and bacteria to establish if the model generated is capable of distinguishing different threat level agents. The work performed will establish the LOAC as a capability at PNNL. It will also establish if omics measurement performed in the LOAC model should become the method of choice for the characterization of new pathogenic agents.

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Principal Investigator

Geremy CD Clair
Pacific Northwest National Laboratory