A human nose organoid (HNO) has been developed to study how the first events of a viral infection take place and the complex interactions between the host and virus. The versatile model is a laboratory representation of the cells layering the inside of the nose. Human airway disease models are essential for the advancement of novel therapeutics and vaccines for respiratory infections.

Air-liquid interface (ALI) cultures were made from HNOs and infection with two major human respiratory viruses, respiratory syncytial virus (RSV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was assessed. Infected HNO-ALI cultures, the authors noted, “recapitulated aspects of RSV and SARS-CoV-2 infection, including viral shedding, ciliary damage, innate immune responses, and mucus hypersecretion.”

Using the HNO model, the team of researchers showed key differences between the infection caused by SARS-CoV-2 and that of RSV, a major pediatric respiratory virus. The study provides an advance in both the development of a novel nose organoid model and in the understanding of the host cellular response to RSV and SARS-CoV-2 infection.

The paper is published in mBio in the paper, “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.”

“In the case of respiratory viruses, such as SARS-CoV-2 and RSV, the infection begins in the nose when one breathes in the virus,” said corresponding author Pedro Piedra, MD, professor of molecular virology and microbiology at Baylor College of Medicine. “The human nose organoids we have developed provide access to the inside of the human nose, enabling us to study the early events of the infection in the lab, something we had not had before. We have successfully developed human nose organoids from both adults and infants.”

The cells lining the inside of the nose, the epithelium, are exposed to air on one side and to the blood circulatory system on their opposite side.

“Our three-dimensional organoid system replicates this natural situation in the lab using nose epithelium harvested with a nasal swab,” explained first author Anubama Rajan, PhD, postdoctoral associate in the Piedra lab. “We grow the harvested epithelium in tissue culture plates that provide an air-liquid interphase, where the top side of the epithelium is exposed to air and the bottom side is bathed in liquid with nutrients and other factors.”

To study the interaction between SARS-CoV-2 or RSV and the nose epithelium, the researchers simulated a natural infection by placing each virus separately on the air side of the culture plates and studying the changes that occurred on the nose organoid.

The model also proved to be a useful tool to test the efficacy of therapeutics such as palivizumab, an FDA-approved monoclonal antibody to prevent severe RSV disease in high-risk infants. The human nose organoid system is part of preclinical evaluation of therapies that would help accelerate the transfer of lab-developed therapeutics to the bedside.

“We observed divergent responses to SARS-CoV-2 and RSV infection,” said Vasanthi Avadhanula, PhD, assistant professor of molecular virology and microbiology at Baylor. “SARS-CoV-2 induces severe damage to the epithelium, no interferon response (an antiviral first defense response), and minimal mucus secretion. In striking contrast, RSV induces abundant mucus secretion and a profound interferon response.”

The team also used the human nose organoid model of RSV infection to test the efficacy of palivizumab. In this case, they placed the therapeutic monoclonal antibody in the liquid-filled chamber to more closely resemble the human experience where therapeutic antibodies enter the blood circulation and provide protection of the airways against RSV infection.

More specifically, “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,” said Avadhanula.

In this study, for the first time, the team described a noninvasive, reproducible and reliable approach to establish human nose organoids that allow for long-term studies. Previous models were produced using invasive lung or nose biopsy or broncho alveolar lavage. “The ease in obtaining the nasal swab samples facilitates our noninvasive approach in the general adult population as well as the vulnerable pediatric population,” Piedra said.

Another advantage of using this novel human nose organoid system is that it can reveal how a person’s initial control of the infection occurs and provide insights into what would make a person more susceptible to a virus than another. This system also can be used to study other respiratory viruses and potentially other disease-causing microbes.

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