Differentiated human airway organoids to assess infectivity of emerging influenza virus

Abstract

SignificanceInfluenza virus infection represents a major threat to public health worldwide. There is no biologically relevant, reproducible, and readily available in vitro model for predicting the infectivity of influenza viruses in humans. Based on the long-term expanding 3D human airway organoids, we developed proximal differentiation and further established a 2D monolayer culture of airway organoids. The resultant 3D and 2D proximal differentiated airway organoids can morphologically and functionally simulate human airway epithelium and as a proof of concept can discriminate human-infective influenza viruses from poorly human-infective viruses. Thus, the proximal differentiated airway organoids can be utilized to predict the infectivity of influenza viruses and, more broadly, provide a universal platform for studying the biology and pathology of the human airway.

Long‐term expanding human airway organoids for disease modeling

“…For example, 46T (mutant TP53) is resistant to Nutlin-3a treatment, 65T (mutant ALK1) is resistant to treatment with crizotinib, and 52MET (mutant ERBB2) is sensitive to treatment with erlotinib and gefitinib. See Appendix Fig (Hui et al, 2018;Zhou et al, 2018), and cryptosporidium (Heo et al, 2018). Taken together, we anticipate that human AOs will continue to find broad applications in the study of adult human airway epithelium in health and disease.…”

“…Tumors show features of adenocarcinomas (HE stainings) and are integrated within murine stroma (human keratin immunolabeling). Validating the robustness of AOs as model for human pulmonary infections are recent studies with enterovirus (van der Sanden et al, 2018), influenza virus (Hui et al, 2018;Zhou et al, 2018), and cryptosporidium (Heo et al, 2018). C WGS reveals largely conserved mutation status of lung cancer genes between matched tumor-organoid pairs (left plot, Appendix Table S1).…”

Identification and characterization of GLDC as host susceptibility gene to severe influenza

“…The qPCR primers are listed in Appendix Table S1. Viral titers in the culture media and supernatants of homogenized mouse tissues were detected with plaque assay in MDCK cells (Zhou et al , ).…”

Organoids – New Models for Host–Helminth Interactions

“…Currently, organoids are used as models of different pathologies, including infectious diseases caused by viruses, bacteria, and protozoans [3][4][5]. Viral infection studies with organoid systems have included: norovirus, rotavirus, enteric adenovirus, and coronavirus invasion of intestinal organoids [3][4][5][6]; herpes simplex virus 1 [23] and cytomegalovirus [24] infection of cerebral organoids; Zika virus infection of cerebral [4,5] and human testicular organoids [25]; human airway organoids to model pathology and assess infectivity of emerging influenza [26], parainfluenza [27] and respiratory syncytial viruses [28]; BK virus infection in human kidney tubuloids [29]; and human liver organoids to study infection with hepatitis B and its related tumorigenesis [30].…”