An in vitro/ex vivo human lung infection model for studying the macrophage innate immune response to Ebola virus Kikwit

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Abstract Ebola virus causes a severe and often fatal hemorrhagic fever in people, for which no approved vaccines or therapeutics are available. Disease pathogenesis and countermeasure studies are typically performed using animal models; however, ex vivo models recapitulating human immune responses may provide valuable information. We optimized engineered lung tissue constructs comprised of human lung epithelial cells and human endothelial cells that mimic the vascularized lower airway alveolar tissue micro-environment to study the human innate immune response to Ebola virus Kikwit (EBOV/Kik). Human lung tissue macrophages are difficult to obtain due to practical and ethical considerations, so macrophages were chemically derived from human monocytes. We inoculated the constructs, in the presence and absence of monocyte derived macrophages (MDM), and quantified cytokines/chemokines secreted on days 0, 3, 6, 9, and 15 post-infection using 29-plex and 1-plex human cytokine/chemokine kits. Prior to infection, MDM were secreting IL-13, MCP-1, MIP-1a, MIP-1b; however, these levels rapidly declined by day 3 post-infection (pi). The MDM secreted peak levels of IL-4, IFN-a2, Eotaxin, IL-12P40, and IFNg at day 6pi, and IL-1ra peaked at day 9 pi. In response to EBOV/Kik, the human lung epithelial cells in the engineered lung tissue construct secreted G-CSF, IL-1ra, IL-8, IP-10, and PDGF-AA/BB. G-CSF and IL-8, cytokines known to mobilize hematopoietic progenitors from bone marrow to blood and recruit neutrophils to sites of infection, were abundantly secreted by both endothelial cells and macrophages in response to infection. This model system may be a valuable resource to the field to study human immune responses during acute infections.

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