Prerequisites for the acquisition of mammalian pathogenicity by influenza A virus with a prototypic avian PB2 gene
Chung-Young Lee1, Se-Hee An1, Ilhwan Kim2
1Laboratory of Avian Diseases, College of Veterinary Medicine, Seoul National University, 08826, Seoul, Republic of Korea.
Abstract:
The polymerase of avian influenza A virus (AIV) is a heterotrimer composed of PB2, PB1, and PA. PB2 plays a role in overcoming the host barrier; however, the genetic prerequisites for avian PB2 to acquire mammalian pathogenic mutations have not been well elucidated. Previously, we identified a prototypic avian PB2 that conferred non-replicative and non-pathogenic traits to a PR8-derived recombinant virus when it was used to infect mice. Here, we demonstrated that key amino acid mutations (I66M, I109V, and I133V, collectively referred to as MVV) of this prototypic avian PB2 increase the replication efficiency of recombinant PR8 virus carrying the mutated PB2 in both avian and mammalian hosts. The MVV mutations caused no weight loss in mice, but they did allow replication in infected lungs, and the viruses acquired fatal mammalian pathogenic mutations such as Q591R/K, E627K, or D701N in the infected lungs. The MVV mutations are located at the interfaces of the trimer and are predicted to increase the strength of this structure. Thus, gaining MVV mutations might be the first step for AIV to acquire mammalian pathogenicity. These results provide new insights into the evolution of AIV in birds and mammals.
Insights
Key mutations in avian influenza A virus (AIV) PB2, termed MVV, enhance viral replication in mammals. These mutations may represent an initial step for AIV to gain mammalian pathogenicity.
Area of Science:
- Virology
- Evolutionary Biology
- Molecular Biology
Background:
- The avian influenza A virus (AIV) polymerase complex, particularly the PB2 protein, is crucial for host adaptation.
- Understanding genetic factors enabling avian PB2 to acquire mammalian pathogenic traits is essential for pandemic preparedness.
Purpose of the Study:
- To investigate the role of specific mutations in a prototypic avian PB2 protein in enhancing viral replication and pathogenicity in mammalian hosts.
- To elucidate the evolutionary pathway of AIV towards mammalian adaptation.
Main Methods:
- Generation of recombinant AIV (PR8-derived) carrying mutated avian PB2 (MVV mutations: I66M, I109V, I133V).
- Infection of mammalian models (mice) to assess viral replication, pathogenicity, and acquisition of mutations.
- Analysis of PB2 protein structure and trimer interface interactions.
Main Results:
- The MVV mutations significantly increased the replication efficiency of the recombinant virus in both avian and mammalian hosts.
- While MVV mutations alone did not cause weight loss in mice, they enabled viral replication in lungs and facilitated the acquisition of known fatal mammalian pathogenic mutations (Q591R/K, E627K, D701N).
- MVV mutations are located at the PB2 trimer interface, potentially stabilizing the structure.
Conclusions:
- The MVV mutations in avian PB2 may represent a critical early step in the evolution of AIV towards mammalian pathogenicity.
- These findings offer insights into the adaptation mechanisms of AIV and potential risks for interspecies transmission.
More Related Videos
Related Concept Videos
02:28Leaky Scanning
00:57Viral Recombination