Understanding the pandemic potential of the avian influenza Virus- key insights into pathogenesis, transmission, and host immunity.

Avian influenza virus (AIV) can infect domestic and wild birds, and recent trends have shown an alarming transmission to non-avian hosts, including humans. The AIV infection is associated with fowl deaths and huge economic losses, besides having high pandemic potential, as per the reports of the WHO. The emergence of new virus subtypes, especially H5N1, driven by rapid mutation rates and genomic reassortments, has been linked to frequent transmission and adaptation to mammalian hosts, posing a significant global threat. The same is reflected by the global increase in AIV infection among humans, with 954 cases reported from January 2001 to December 2024 and a 49% case fatality rate. Likewise, the spillover of the virus into farm cattle and subsequent transmission to other animals from them could potentially lead to wider ecological and public health risks. Therefore, a clear understanding of disease transmission and multi-species invasion is crucial for predicting potential outbreaks, identifying susceptible hosts, and developing targeted interventions. The current review provides a detailed insight into AIV invasion, its infectious cycle, and transmission, with a prime focus on host immune responses as well as immune evasion. The review also highlights the adaptability of AIVs to humans, attributed to shifts in receptor specificity and mutations in viral proteins, which could contribute to the potential for a pandemic. Thus, the review aims to improve our understanding of AIV transmission and immune evasion by examining the complex mechanisms through which the virus spreads and how it circumvents the host defense system. The review underscores the development of a robust surveillance system, mainly in high-risk interfaces, owing to its cross-species transmission potential. Additionally, unraveling host-pathogen interactions and identifying genetic and immunological factors, strengthening global data-sharing platforms, and developing multivalent or universal vaccines will be important in designing future AIV control and preparedness strategies.