Highly pathogenic avian influenza (HPAI) H5N1 continues to cause disease outbreaks in domestic poultry with high morbidity and mortality, and no approved treatments or vaccines are currently available

The Department of Agriculture Animal and Plant Health Inspection Service awarded Montana State University a $1.902 million cooperative agreement on February 2, 2026, under the Plant and Animal Disease, Pest Control, and Animal Care program (CFDA 10.025) to develop in vitro organotypic models of the chicken digestive tract for evaluating antiviral strategies against Highly Pathogenic Avian Influenza H5N1.

The recipient will develop and characterize organoid lines from four sections of the domestic chicken digestive tract, model HPAI infection dynamics in chicken gut organoids, assess transcriptional and metabolic changes induced by infection, suppress HPAI infection with known molecules that interfere with viral entry, modulate metabolism to enhance antiviral signaling, and evaluate the effectiveness of identified candidate treatments in challenge experiments with live chickens. The project addresses the current lack of physiological experimental models that limits rapid evaluation of antiviral strategies and the ineffectiveness of stamping-out approaches in controlling HPAI transmission. Deliverables include a biobank of intestinal organoids from domestic chickens and a list of candidate treatments to reduce viral shedding and limit HPAI spread to neighboring poultry operations.

The cooperative agreement runs through February 1, 2029, with work performed in Montana.

The strategy of 'stamping-out' affected flocks remains ineffective at limiting HPAI transmission while incurring significant economic losses. Therefore, there is a need for the development of alternative management methods that can be implemented in the event of an outbreak. HPAI replication in the digestive tract of poultry is one of the predominant means of virus shedding and transmission. Currently, the lack of physiological experimental models limits the capacity to rapidly evaluate antiviral strategies. We propose using novel organotypic in vitro models of the chicken digestive tract in mechanistic experiments to evaluate compounds to reduce viral shedding, thereby limiting the further spread of HPAI to neighboring operations. Our team of infectious disease and organoid experts is uniquely suited to leverage intestinal organoids to model infection dynamics and cellular responses and to test preventive strategies that can limit HPAI entry, replication and pathogenesis. We will pursue five objectives: (1) develop and characterize organoid lines from four sections of the digestive tract in domestic chickens; (2) model HPAI infection dynamics in chicken GUT organoids and assess the transcriptional and metabolic changes induced by the infection; (3) suppress HPAI infection with known molecules that interfere with HPAI entry; (4) modulate metabolism to enhance antiviral signaling and to suppress metabolic changes that promote viral replication; (5) evaluate effectiveness of identified candidate treatments in reducing HPAI infection in challenge experiments with live chickens. The deliverables from this project include: first, a biobank of intestinal organoids from domestic chickens that we will use to understand HPAI infection dynamics in the GUT; and second, a list of orally deliverable antiviral feed supplements that decrease HPAI infection in the GUT and that could be deployed to limit transmission of HPAI during outbreaks. The intended beneficiaries of our work are poultry farmers and the domestic poultry industry, as our proposed approach seeks to limit HPAI shedding and transmission by reducing viral titers in affected animals.