Predicting Influenza Virus Host Tropism and Zoonotic Spillover Risk from Protein Sequences

Novel infectious diseases, predominately originating from non-human animals, pose a significant threat to global public health and economic stability. Avian influenza virus presents an especially significant challenge due to its high mortality rates and spillover capability into new host species. Recent H5N1 spillover events into poultry and cattle resulted in massive economic burden and increased human health risk. Traditional methods of disease surveillance rely on reactive case detection and pathogen characterization, providing insufficient lead time for effective intervention. Computational tools that allow efficient and proactive prediction of zoonotic potential are critical in mitigation of influenza outbreaks and identification of strains with human spillover risk. Existing models predicting influenza virus subtypes or host have been developed; however, the complexity of spillover events, including the non-binary nature of zoonotic potential, limits the capabilities of these models. In the approach reported here, rich protein language model embeddings were generated from ESM-2 for each protein in influenza virus strains and used to predict the protein host tropism probabilities across nine animal families. The protein host tropism model achieved weighted precision and recall scores of 0.95 and 0.95, respectively. We then constructed a zoonotic risk prediction model using the outputs from the protein host tropism prediction model to classify the strains into six classifications: avian, mammal, human, avian-to-human zoonotic, avian-to-mammal zoonotic, or mammal-to-human zoonotic. The average weighted precision and recall scores for this model were 0.90 and 0.90, respectively. This framework advances the prediction of influenza zoonotic risk by being agnostic to influenza subtype, incorporating non-human mammals and mammal zoonotic spillover classifications, and using the full influenza proteome to capture the complexity of spillover dynamics.