TY - JOUR

T1 - Bioprinted multi-cell type lung model for the study of viral inhibitors

AU - Berg, Johanna

AU - Weber, Zia

AU - Fechler-Bitteti, Mona

AU - Hocke, Andreas C.

AU - Hippenstiel, Stefan

AU - Elomaa, Laura

AU - Weinhart, Marie

AU - Kurreck, Jens

N1 - Funding Information: Funding: This work was funded by the Prize for the Development of Alternatives to Animal Experimentation of the City of Berlin and by the Einstein Foundation Berlin (Einstein Center 3R, EZ-2020-597-2). We acknowledge support by the German Research Foundation and the Open Access Publication Funds of TU Berlin.

PY - 2021/8/11

Y1 - 2021/8/11

N2 - Influenza A virus (IAV) continuously causes epidemics and claims numerous lives every year. The available treatment options are insufficient and the limited pertinence of animal models for human IAV infections is hampering the development of new therapeutics. Bioprinted tissue models support studying pathogenic mechanisms and pathogen-host interactions in a human micro tissue environment. Here, we describe a human lung model, which consisted of a bioprinted base of primary human lung fibroblasts together with monocytic THP-1 cells, on top of which alveolar epithelial A549 cells were printed. Cells were embedded in a hydrogel consisting of alginate, gelatin and collagen. These constructs were kept in long-term culture for 35 days and their viability, expression of specific cell markers and general rheological parameters were analyzed. When the models were challenged with a combination of the bacterial toxins LPS and ATP, a release of the proinflammatory cytokines IL-1β and IL-8 was observed, confirming that the model can generate an immune response. In virus inhibition assays with the bioprinted lung model, the replication of a seasonal IAV strain was restricted by treatment with an antiviral agent in a dose-dependent manner. The printed lung construct provides an alveolar model to investigate pulmonary pathogenic biology and to support development of new therapeutics not only for IAV, but also for other viruses.

AB - Influenza A virus (IAV) continuously causes epidemics and claims numerous lives every year. The available treatment options are insufficient and the limited pertinence of animal models for human IAV infections is hampering the development of new therapeutics. Bioprinted tissue models support studying pathogenic mechanisms and pathogen-host interactions in a human micro tissue environment. Here, we describe a human lung model, which consisted of a bioprinted base of primary human lung fibroblasts together with monocytic THP-1 cells, on top of which alveolar epithelial A549 cells were printed. Cells were embedded in a hydrogel consisting of alginate, gelatin and collagen. These constructs were kept in long-term culture for 35 days and their viability, expression of specific cell markers and general rheological parameters were analyzed. When the models were challenged with a combination of the bacterial toxins LPS and ATP, a release of the proinflammatory cytokines IL-1β and IL-8 was observed, confirming that the model can generate an immune response. In virus inhibition assays with the bioprinted lung model, the replication of a seasonal IAV strain was restricted by treatment with an antiviral agent in a dose-dependent manner. The printed lung construct provides an alveolar model to investigate pulmonary pathogenic biology and to support development of new therapeutics not only for IAV, but also for other viruses.

KW - Bioprinting

KW - Human lung model

KW - Influenza A virus

KW - LPS stimulation

UR - http://www.scopus.com/inward/record.url?scp=85113164370&partnerID=8YFLogxK

U2 - 10.3390/v13081590

DO - 10.3390/v13081590

M3 - Article

C2 - 34452455

AN - SCOPUS:85113164370

VL - 13

JO - Viruses

JF - Viruses

SN - 1999-4915

IS - 8

M1 - 1590

ER -