Differences in Type I interferon response in human lung epithelial cells infected by highly pathogenic H5N1 and low pathogenic H11N1 avian influenza viruses
Influenza A virus infection induces type I interferons (IFNs α/β) which activate host antiviral responses through a cascade of IFN signaling events. Herein, we compared highly pathogenic H5N1 and low pathogenic H11N1 avian influenza viruses isolated from India, for their replication kinetics and ability to induce IFN-β and interferon-stimulating genes (ISGs). The H5N1 virus showed a higher replication rate and induced less IFN-β and ISGs compared to the H11N1 virus when grown in the human lung epithelial A549 cells, reflecting the generation of differential innate immune responses during infection by these viruses. The non-structural 1 (NS1) protein, a major IFN-antagonist, known to help the virus in evading host innate immune response was compared from both the strains using bioinformatics tools. Analyses revealed differences in the composition of the NS1 proteins from the two strains that may have an impact on the modulation of the innate immune response. Intriguingly, H5N1 virus attenuated IFN-β response in a non-NS1 manner, suggesting the possible involvement of other viral proteins (PB2, PA, PB1/PB1-F2) of H5N1 in synergy with NS1. Preliminary analyses of the above proteins of the two strains by sequence comparison show differences in charged residues. The insight gained will be useful in designing experimental studies to elucidate a probable role of the polymerase protein(s) in association with NS1 in inhibiting the IFN signaling and understanding the molecular mechanism governing the difference.
KeywordsInfluenza Avian influenza H5N1 H11N1 Interferon NS1 Innate immune response CPSF30
We thank Ajit Rattan, Sachin Keng, Dinesh Singh, JPN Babu, SK Waghmare, AB Khare, and BSL3 staff for laboratory assistance, and P Aher, Drs. K Lole, P Yadav, and P Devhare for their help. We acknowledge the constant support of Dr. AC Mishra (Ex-Director) and Dr. DT Mourya, Director, NIV. We are grateful to Dr. Cecilia Dayaraj and Dr. Sarah Cherian for their critical comments. The work was supported by intramural funds from the Indian Council of Medical Research, New Delhi, India, and financial assistance to M. Thube from the Council of Scientific and Industrial Research, New Delhi, India and R. Kasbe from the University Grants Commission, New Delhi, India is gratefully acknowledged.
Conceived the idea and initiated the work: MMT & JM. Contributed to design of experiments: MMT, SDP, PS, & JM. Performed the experiments: MMT, RK, & PS (Bioinformatics). Contributed reagents/materials/analysis tools: JM, SDP, & PS. Analysis of experiments and results: MMT, PS, & JM. Contribution in generating graphics: MMT, RK, & AAP. Writing of the manuscript: MMT, PS, & JM. All the authors read and approved the manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Research involving human participants and/or animals
This research work does not involve human participants and/or animals.
Not applicable as no human participants are involved.
- 1.P. Palese, M.L. Shaw, in Fields of Virology, ed. by D.M. Knipe, P.M. Howley (Lippincott Williams and Wilkins, Philadelphia, 2007), p. 1647Google Scholar
- 3.D.L. Suarez, in Avian Influenza, 1st edn., ed. by D.E. Swayne (Blackwell, Iowa, 2008), p. 3Google Scholar
- 14.G.A. Versteeg, A. Garcia, in Viruses and Interferon Current Research, ed. by K. Mossman (Caister Academic Press, Norfolk, 2011), p. 181Google Scholar
- 37.CDC protocol of realtime RTPCR for influenza A viruses, http://www.who.int/csr/resources/publications/swineflu/realtimeptpcr/en/