Defining molecular interactions between commensal respiratory viruses and the human host

The National Institutes of Health Office of the Director awarded J. David Gladstone Institutes $377,999 on September 1, 2026, under the Trans-NIH Research Support program (CFDA 93.310) to define molecular interactions between commensal respiratory viruses and the human host.

The research team will generate molecular clones of abundant commensal viruses in the respiratory tract and characterize viral infection and host responses in primary human airway organoids using single-cell RNA sequencing. The work will also map virus-host protein-protein interaction networks through affinity-purification mass spectrometry and test identified functional interactions by generating knockouts in organoids. The central hypothesis is that commensal viruses establish unique molecular interactions with the respiratory epithelium that enable persistence and modulate immune homeostasis; understanding these dynamics will inform factors influencing host immunity, disease susceptibility, and therapeutic response.

Performance runs from September 1, 2026, through August 31, 2028, with work conducted in San Francisco, California. This is a Project Grant assistance type.

Abstract

While respiratory pathogens have received significant attention from the research community, we have a limited understanding of the most abundant commensal viruses in the human respiratory tract and their interaction with the host to maintain homeostasis in healthy individuals. The project's research team has significantly contributed to understanding the interaction between pathogenic respiratory viruses and the human host. The long-term goal is to leverage cutting-edge techniques we have developed in sequencing, proteomics, viral genetics and primary cell models to study interactions between commensal viruses in the human respiratory tract and the host. Our central hypothesis is that commensal viruses establish unique molecular interactions with the respiratory epithelium that enable persistence and modulate immune homeostasis. The rationale for this project is that understanding how commensal respiratory viruses replicate and persist in the host, without causing disease, will offer insights into the factors that influence host immunity, disease susceptibility, and therapeutic response. This will be tested via two specific aims: 1) generate molecular clones of the top abundant commensal viruses of the respiratory tract and characterize viral infection and host responses in primary human airway organoids (haos) and 2) map virus-host protein-protein interaction (PPI) networks. Under the first aim, we will develop molecular clones and characterize their infection in haos with single-cell RNA-sequencing. For the second aim, PPI network maps for commensal respiratory viruses will be mapped with affinity-purification mass spectrometry and the identified functional interactions will be tested by generating knockouts in organoids. The proposed research is innovative as IT goes beyond the status QUO of identification of commensal viruses to molecularly characterizing their replication and interaction with the host. The proposed work is significant because IT addresses an important and yet underexplored aspect of respiratory health, namely the benefit of homeostatic colonization with eukaryotic commensal viruses. Ultimately, such knowledge can offer new insight into respiratory tract homeostasis and contributions of the commensal virome to disease trajectories. To support the NIH's mission, the team will work collaboratively with all the HVP consortium investigators to ensure the integration and sharing of data, tools and resources across the program and the broader scientific community.