Abstract Title
Genetic Determinants of Avian Influenza A Virus Adaptation in Seals and Their Implications for Human Infection
Abstract
Avian influenza viruses cause significant mortality in marine mammals, particularly seals, which are frequently infected with both AIVs and human influenza viruses. However, there are still knowledge gaps regarding AIV virulence factors in seals and their potential role as generators of zoonotic influenza strains. Here, we studied the effects of mutations in the non-structural protein 1 derived from seal H3-, H4-, H5-, and H10-type viruses compared to their avian ancestors. We assessed these mutations' impact on NS1 expression, stability, and function—especially for H10N7 viruses—in avian, seal, and human cells, as well as their interaction with cellular and viral factors.
Our results indicate that seal-adapted NS1 is more effective at blocking interferon induction in human cells than its avian counterpart. Seal-specific substitutions in NS1 exhibited a synergistic effect, optimizing NS1 expression and replication across different cell types while enhancing IFN inhibition efficiency. Notably, we observed that NS1 mutations influenced the polymerase activity of AIVs in human cells, although we found no evidence of interaction between NS1 of H10N7 viruses and CPSF30. On the other hand, three specific amino acids in the H10N7 seal polymerase basic 2 (PB2) were critical for increased polymerase activity in mammalian cells, even in the absence of known mammalian adaptation markers like PB2-627K.
These findings are important to understand the genetic determinants for adaptation of AIVs in seals and underscore the potential role of seals in the emergence of AIVs with enhanced human adaptation. The newly identified mutations may serve as predictive markers for assessing the zoonotic potential of AIV strains in seals.
Our results indicate that seal-adapted NS1 is more effective at blocking interferon induction in human cells than its avian counterpart. Seal-specific substitutions in NS1 exhibited a synergistic effect, optimizing NS1 expression and replication across different cell types while enhancing IFN inhibition efficiency. Notably, we observed that NS1 mutations influenced the polymerase activity of AIVs in human cells, although we found no evidence of interaction between NS1 of H10N7 viruses and CPSF30. On the other hand, three specific amino acids in the H10N7 seal polymerase basic 2 (PB2) were critical for increased polymerase activity in mammalian cells, even in the absence of known mammalian adaptation markers like PB2-627K.
These findings are important to understand the genetic determinants for adaptation of AIVs in seals and underscore the potential role of seals in the emergence of AIVs with enhanced human adaptation. The newly identified mutations may serve as predictive markers for assessing the zoonotic potential of AIV strains in seals.
Co-Author(s)
Maryna Kuryshko1, Christine Luttermann2, Mahmoud Bayoumi3, Ahmed Mostafa3,4, Diana I. Palme1, Thomas C. Mettenleiter5, Luis Martinez-Sobrido3, Elsayed M. Abdelwhab1
1Institute of Molecular Virology and Cell Biology, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems, Germany
2Institute of Immunology, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems, Germany
3Texas Biomedical Research Institute, San Antonio, TX 78227, USA.
4Center of Scientific Excellence for Influenza Viruses, National Research Centre, Giza 12611, Egypt
5Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems, Germany
Abstract Category
Avian influenza in mammals, pandemic preparedness, and one health