# A Review of Cross-Species Transmission Mechanisms of Influenza Viruses

## TL;DR

This paper reviews how influenza viruses spread between species, highlighting genetic changes and host factors that enable transmission and suggesting ways to prevent future pandemics.

## Contribution

The paper provides a comprehensive review of mechanisms and challenges in influenza cross-species transmission, emphasizing the need for integrated strategies for pandemic preparedness.

## Key findings

- Mutations in hemagglutinin and neuraminidase enable influenza viruses to cross host barriers.
- Intermediate hosts like pigs facilitate viral diversification through reassortment.
- Multidisciplinary approaches are needed to build effective pandemic defense systems.

## Abstract

The cross-species transmission of influenza viruses is pivotal in zoonotic pandemics, driven by viral genetic adaptability, host–receptor compatibility, and ecological factors. Key mutations in hemagglutinin and neuraminidase enable host barrier breaches, while intermediate hosts (e.g., pigs) act as viral “mixers” for strain diversification. Advances in sequencing and structural biology have identified critical molecular markers, yet challenges persist in deciphering dynamic virus–host evolution, establishing real-time surveillance, and designing broad-spectrum interventions. Integrating multidisciplinary strategies—including One Health networks and artificial intelligence-driven prediction models—is crucial for building a multi-layered defense system. This review synthesizes current progress and challenges, offering a framework to optimize pandemic preparedness against influenza spillover risks.

The cross-species transmission of influenza viruses represents a critical link in the pandemic of zoonotic diseases. This mechanism involves multi-level interactions, including viral genetic adaptability, host–receptor compatibility, and ecological drivers. Recent studies have highlighted the essential role of mutations in hemagglutinin and neuraminidase in overcoming host barriers, while elucidating the differences in the distribution of host sialic acid receptors. Furthermore, the “mixer” function of intermediate hosts, such as pigs, plays a significant role in viral redistribution. Advances in high-throughput sequencing and structural biology technologies have gradually resolved key molecular markers and host restriction factors associated with these viruses. However, challenges remain in understanding the dynamic evolutionary patterns of virus–host interaction networks, developing real-time early warning capabilities for cross-species transmission, and formulating broad-spectrum prevention and control strategies. Moving forward, it is essential to integrate multidisciplinary approaches to establish a multi-level defense system, leveraging the ‘One Health’ monitoring network, artificial intelligence prediction models, and new vaccine research and development to address the ongoing threat of cross-species transmission of influenza viruses. This paper systematically reviews the research progress and discusses bottlenecks in this field, providing a theoretical foundation for optimizing future prevention and control strategies.