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Modeling the Human Immune Response to Severe Influenza Infection in an Immunocompetent Lung-on-Chip

ABSTRACT: Severe influenza affects 3-5 million people worldwide each year, resulting in more than 300,000 deaths annually. However, standard-of-care antiviral therapeutics have limited effectiveness in these patients. Current preclinical models of severe influenza fail to recapitulate the human immune response to severe viral infection accurately. Here, we develop an immune-competent, microvascularized, human lung-on-chip device to model the small airways, successfully demonstrating the cytokine storm, immune cell activation, epithelial cell damage, and other cellular- and tissue-level human immune responses to severe H1N1 infection. We find that IL-1β and TNF-α play opposing roles in the initiation and regulation of the cytokine storm associated with severe influenza. Furthermore, we discover the critical stromal-immune CXCL12-CXCR4 interaction and its role in immune response to infection. Our results underscore the importance of stromal cells and immune cells in microphysiological models of severe lung disease, describing a scalable model for severe influenza research. We expect the human lung-on-chip device to enable critical discoveries in respiratory host-pathogen interactions, therapeutic side effects, vaccine potency evaluation, and crosstalk between systemic and mucosal immunity in human lung.

ORGANISM(S): Homo sapiens

PROVIDER: GSE294626 | GEO | 2025/07/13

REPOSITORIES: GEO

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Project description:Background: Pandemic H1N1 influenza A is a newly emerging strain of human influenza that is easily transmitted between people and has spread globally to over 116 countries. Human infection leads to symptoms ranging from mild to severe with lower respiratory complications observed in a small but significant number of infected individuals. Little is currently known about host immunity and Pandemic H1N1 influenza infections. Methods: We examined the pathogenic potential of the pandemic influenza A vaccine strain, A/California/07/2009 (H1N1), in ferrets, and characterized the host immune responses using microarray analysis. Gene expression profiles in lung tissue were compared with those from ferrets infected with A/Brisbane/59/2007. Results: Chemokines CCL2, CCL8, CXCL7 and CXCL10 along with the majority of ISGs were expressed early, correlated to lung pathology, and abruptly decreased expression in 5 days. Interestingly, the drop in innate immune gene expression was replaced by a significant increase in the expression of the adaptive immune genes for granzymes and immunoglobulins. Serum anti-pandemic influenza H1N1 antibodies were also observed on day 7, commensurate with the elimination of viral load. Conclusions: We propose that the innate phase of host immunity causes lung pathology and a delay or failure to effectively switch to the adaptive phase contributes to morbidity and mortality during severe human pandemic H1N1 influenza A infections. Keywords: influenza, immune response, cytokines, chemokines, lung infection, time course In the experiment with influenza A/California/07/2009 (H1N1),15 ferrets were randomly allocated to 5 groups: Day 0 (before infection), and Day 3, 5, 7 and 14 (post infection) with 3 biological replicates for each group. Likewise, a second experiment with A/Brisbane/59/2007 (H1N1) was carried out using the same experimental groups, except for a group in Day 2, instead Day 3. Ferrets were euthanized and lung tissue was excised for RNA purification on the scheduled date. The subsequent gene expression analysis was performed with Affymetrix GeneChip Canine Genome 2.0 Array. Day 0 groups were used as control.

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Modeling the Human Immune Response to Severe Influenza Infection in an Immunocompetent Lung-on-Chip

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