The Human Nose Organoid Respiratory Virus Model: an Ex Vivo Human Challenge Model To Study Respiratory Syncytial Virus (RSV) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Pathogenesis and Evaluate Therapeutics

mBio

Fabio Stossi¹  Hannah L. Johnson¹  Michael A. Mancini¹  Felipe-Andrés Piedra²  Letisha Aideyan²  Xi-Lei Zeng²  Joseph Jelinski²  Trevor McBride²  Sarah Blutt²  Pedro A. Piedra²  Gina Marie Aloisio²  Vasanthi Avadhanula²  Malli Rama Kanthi Yerramilli²  Anthony W. Maresso²  Anubama Rajan²  Ashley Morgan Weaver²  Mary K. Estes²  Xunyan Ye²  Susan F. Venable³  Ernestina Melicoff-Portillo⁴  Shalaka A. Kotkar⁵ 

[1] Advanced Technology Cores, Baylor College of Medicine, Houston, Texas, USA;Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA;Department of Pathology, Baylor College of Medicine, Houston, Texas, USA;Department of Pediatrics, Pulmonary Medicine Service, Baylor College of Medicine, Houston, Texas, USA;Environmental Safety Department, Baylor College of Medicine, Houston, Texas, USA;

关键词: nose organoids;    respiratory syncytial virus (RSV);    severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2);    cilia;    palivizumab;    air-liquid interface (ALI) culture;   

DOI  :  10.1128/mbio.03511-21

来源: DOAJ

【 摘 要 】

ABSTRACT There is an unmet need for preclinical 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 noninvasive technique to generate human nose organoids (HNOs) as an alternative 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 hypersecretion. 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 alternative to lung organoids to study respiratory viruses and test therapeutics. IMPORTANCE Preclinical models that recapitulate aspects of human airway disease are essential for the advancement of novel therapeutics and vaccines. Here, we report a versatile airway organoid model, the human nose organoid (HNO), that recapitulates the complex interactions between the host and virus. HNOs are obtained using noninvasive procedures and show divergent responses to SARS-CoV-2 and RSV infection. SARS-CoV-2 induces severe damage to cilia and the epithelium, no interferon-λ response, and minimal mucus secretion. In striking contrast, RSV induces hypersecretion of mucus and a profound interferon-λ response with ciliary damage. We also demonstrated the usefulness of our ex vivo HNO model of RSV infection to test the efficacy of palivizumab, an FDA-approved monoclonal antibody to prevent severe RSV disease in high-risk infants. Our study reports a breakthrough in both the development of a novel nose organoid model and in our understanding of the host cellular response to RSV and SARS-CoV-2 infection.

【 授权许可】

Unknown