The human nose organoid respiratory virus model: an ex-vivo human challenge model to study RSV and SARS-CoV-2 pathogenesis and evaluate therapeutics

Abstract

There is an unmet need for pre-clinical models to understand the pathogenesis of human respiratory viruses; and predict responsiveness to immunotherapies. Airway organoids can serve as an ex-vivo human airway model to study respiratory viral pathogenesis; however, they rely on invasive techniques to obtain patient samples. Here, we report a non-invasive technique to generate human nose organoids (HNOs) as an alternate to biopsy derived organoids. We made air liquid interface (ALI) cultures from HNOs and assessed infection with two major human respiratory viruses, respiratory syncytial virus (RSV) and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Infected HNO-ALI cultures recapitulate aspects of RSV and SARS-CoV-2 infection, including viral shedding, ciliary damage, innate immune responses, and mucus hyper-secretion. Next, we evaluated the feasibility of the HNO-ALI respiratory virus model system to test the efficacy of palivizumab to prevent RSV infection. Palivizumab was administered in the basolateral compartment (circulation) while viral infection occurred in the apical ciliated cells (airways), simulating the events in infants. In our model, palivizumab effectively prevented RSV infection in a concentration dependent manner. Thus, the HNO-ALI model can serve as an alternate to lung organoids to study respiratory viruses and testing therapeutics.

Alveolar Organoids in Lung Disease Modeling

“…In addition, the success rate of growth and purity of tumor organoids vary [91]. Also, ethical issues associated with human challenge models restrict their use and access [92]. Taken together, lung organoids can be considered an excellent potential platform for studying virus pathobiology, lung disease development, and robust screening tools for drug candidates in vitro.…”

Human Organoids and Organs‐on‐Chips for Addressing COVID‐19 Challenges

“…• Strong induction of a generic viral response program [95] • Active viral replication, induction of type III IFNs and inflammatory mediators in human enteroids [96] • Inhibiting SARS-CoV-2 infection in colonic organoids with FDA-approved drugs treatment [81] • Pretreatment with type I and III IFNs controlled viral infection [98] Brain [ 104,105,107,109] hiPSC • Human neural progenitor cells, neurospheres, and brain organoids [ 107] • Brain choroid plexus organoids, choroid plexus epithelial cells [ 104,105] • Neurons in human brain organoids [ 109] • Caused cytotoxicity in the infected hNPCs [ 107] • Increased cell death and transcriptional upregulation of inflammatory genes in infected choroid plexus organoids [ 104] • Aberrant Tau localization and neuronal cell death [ 109] • Disrupted the blood-cerebrospinal fluid barrier [ 105] Eye [118] hESC • hESC-derived eye organoids • Eye organoids express ACE2 and TMPRSS2, and can be infected by SARS-CoV-2 [118] Nose [ 117] hASC • Human nose organoids • Viral shedding, ciliary damage, and innate immune responses in infected nose organoids [ 117] may help for understanding potential disease mechanism and speeding up drug development. However, organoid models remain limitations, such as the lack of immune systems.…”

“…[ 111 , 112 , 113 , 114 ] Other types of stem cell organoids, such as the kidney, liver, pancreas, vasculature, eye, and nose organoids, have been established to study the SARS‐CoV‐2 tropism, replication, and immune responses in distinct targeted organs. [ 106 , 115 , 116 , 117 , 118 ] For example, liver ductal organoids containing ACE2 + /TMPRSS2 + cholangiocytes showed a high susceptibility of SARS‐CoV‐2 infection that induced direct cholangiocyte injury and bile acid accumulation (Figure 2D ). [ 116 ] These observations may be associated with COVID‐19 patient liver damage.…”

“…In addition, human nose organoid established from nasal wash and turbinate swab samples recapitulated host responses to SARS‐CoV‐2 infection, including ciliary damage, immune responses, and mucus hypersecretion, which could be used as a non‐invasive alternate model to lung organoids. [ 117 ] Recently, researchers found the expression of SARS‐CoV‐2 antigens in COVID‐19 patient ocular surface tissue. [ 118 ] They further established the hESC‐derived eye organoid model and identified limbus cells as a target for viral replication in accompany with chemokine production and diminished interferon signaling (Figure 2E ).…”