The NS1 influenza protein (NS1) is a viral nonstructural protein encoded by the NS gene segments of type A, B and C influenza viruses. Also encoded by this segment is the nuclear export protein (NEP), formally referred to as NS2 protein, which mediates the export of influenza virus ribonucleoprotein (RNP) complexes from the nucleus, where they are assembled.[1][2]

Characteristics

The NS1 of influenza A virus is a 26,000 Dalton protein. It prevents polyadenylation of cellular mRNAs to circumvent antiviral responses of the host, e.g., maturation and translation of interferon mRNAs. NS1 might also inhibit splicing of pre-mRNA by binding to a stem-bulge region in U6 small nuclear RNA (snRNA).[3] In addition, NS1 is probably able to suppress the interferon response in the virus-infected cell leading to unimpaired virus production.[4]

NS1 also binds dsRNA. Binding assays with NS1 protein mutants established that the RNA-binding domain of the NS1 protein is required for binding to dsRNA as well as for binding to polyA and U6 snRNA. In addition, dsRNA competed with U6 snRNA for binding to the NS1 protein, a result consistent with both RNAs sharing the same binding site on the protein. As a consequence of its binding to dsRNA, the NS1 protein blocks the activation of the dsRNA-activated protein kinase (PKR) in vitro. This kinase phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (elF-2 alpha), leading to a decrease in the rate of initiation of translation.[3] In the absence of NS1, this pathway is inhibited during anti-viral response to halt all protein translation – thus stopping the synthesis of viral proteins; however, the influenza virus' NS1 protein is an agent that circumvents host defenses to allows viral gene transcription to occur.

The NS1 protein can be divided into an N terminal (RNA binding) domain and C terminal (effector domain). The RNA binding domain is able to target RIG-I, and therefore prevent the activation of induction of interferon responses. At the effector domain, it interacts and inhibits cleavage and polyadenylation specificity factor (CPSF30). CPSF30 is part of processing pathway for cellular mRNAs, and its inhibition leads to inability of the cellular mRNA to be exported outside the nucleus for translation, thereby hindering the ability of host cell to produce Interferon-stimulated genes.[5]

Avian

The NS1 protein of the highly pathogenic avian H5N1 viruses circulating in poultry and waterfowl in Southeast Asia is currently believed to be responsible for the enhanced virulence of the strain. H5N1 NS1 is characterized by a single amino acid change at position 92. By changing the amino acid from glutamic acid to aspartic acid, researchers were able to annul the effect of the H5N1 NS1. This single amino acid change in the NS1 gene greatly increased the pathogenicity of the H5N1 influenza virus.[6] However, the effect of residue 92 on the function of H5N1 NS1 appears to be questionable as noted by Nature Medicine editors:

The above paper originally reported that H5N1 viruses are resistant to interferon in the SJPL cell line.[6] The editors wish to alert our readers about three facts that may affect this conclusion. First, Ngunjiri et al. [7] have recently found that aliquots of the SJPL cell line obtained from the American Type Culture Collection were heavily contaminated with mycoplasma. Although the mycoplasma status of the cells used in the original paper is unknown, it is not possible to rule out that they were contaminated. Second, SJPL cells were originally reported to be of porcine origin, but a recent analysis[8] has indicated that they are of simian origin. Third, Ngunjiri et al.[7] have found H5N1 viruses to be sensitive to interferons in all cell lines tested from multiple species.[9]

Pathogenicity

The fact that NS1 is involved in the pathogenicity of influenza A viruses makes it a good target to attenuate these viruses. Several studies demonstrated that influenza viruses with partial deletions in NS1 proteins are attenuated and do not cause disease, but induce a protective immune response in different species including mice,[10][11] pigs,[12][13] horses,[14] birds[15] and macaques.[16] Although it had been known for more than a decade that influenza viruses with partial deletions in NS1 proteins were attenuated, all but one[17] NS1 truncation variants of influenza A viruses were generated by in vitro mutagenesis. Wang et al. later demonstrated that the naturally truncated variant [17] had propensity to generate new variants when passaged in ovo.[18] Remarkably, the new variants were excellent live-attenuated influenza vaccine candidates.[18] The ability to attenuate influenza viruses by truncation of the NS1 protein presents a novel approach in design and development of the next generation live-attenuated influenza vaccines for both poultry and humans.

See also

References

  1. ↑ Influenza B and C Virus NEP (NS2) Proteins Possess Nuclear Export Activities Journal of Virology, August 2001, p. 7375-7383, Vol. 75, No. 16
  2. ↑ O'Neill RE, Talon J, Palese P (1998). "The influenza virus NEP (NS2 protein) mediates the nuclear export of viral ribonucleoproteins". EMBO J. 17 (1): 288–296. doi:10.1093/emboj/17.1.288. PMC 1170379. PMID 9427762.
  3. 1 2 Lu, Y et al., 1995. Binding of the influenza virus NS1 protein to double-stranded RNA inhibits the activation of the protein kinase that phosphorylates the elF-2 translation initiation factor. Virology. 1995 Dec 1;214(1):222-8.
  4. ↑ Kumar KU, Srivastava SP, Kaufman RJ (February 1999). "Double-stranded RNA-activated protein kinase (PKR) is negatively regulated by 60S ribosomal subunit protein L18". Mol Cell Biol. 19 (2): 1116–25. doi:10.1128/mcb.19.2.1116. PMC 116041. PMID 9891046.
  5. ↑ Hale BG1, Randall RE, Ortín J, Jackson D (2008). "The multifunctional NS1 protein of influenza A viruses". J Gen Virol. 89 (10): 2359–76. doi:10.1099/vir.0.2008/004606-0. hdl:10023/3001. PMID 18796704.
  6. 1 2 Seo SH, Hoffmann E, Webster RG (2002). "Lethal H5N1 influenza viruses escape host anti-viral cytokine responses". Nat. Med. 8 (9): 950–4. doi:10.1038/nm757. PMID 12195436. S2CID 8293109.
  7. 1 2 Ngunjiri JM, Mohni KN, Sekellick MJ, Schultz-Cherry S, Webster RG, Marcus PI (2012). "Lethal H5N1 influenza viruses are not resistant to interferon action in human, simian, porcine or chicken cells". Nature Medicine. 18 (10): 1456–1457. doi:10.1038/nm.2879. PMID 23042343. S2CID 205389804.
  8. ↑ Silversides DW, Music N, Jacques M, Gagnon CA, Webby R (2010). "Investigation of the species origin of the St. Jude Porcine Lung epithelial cell line (SJPL) made available to researchers". J. Virol. 84 (10): 5454–5. doi:10.1128/jvi.00042-10. PMC 2863845. PMID 20200241.
  9. ↑ (2012) Nature Medicine 18: 1592
  10. ↑ Hai R, Martinez-Sobrido L, Fraser KA, Ayllon J, Garcia-Sastre A, Palese P (2008). "Influenza B virus NS1-truncated mutants: live-attenuated vaccine approach". J Virol. 82 (21): 10580–10590. doi:10.1128/jvi.01213-08. PMC 2573209. PMID 18768976.
  11. ↑ Talon J, Salvatore M, O'Neill RE, Nakaya Y, Zheng H, Muster T, Garcia-Sastre A, Palese P (2000). "Influenza A and B viruses expressing altered NS1 proteins: A vaccine approach". Proc Natl Acad Sci U S A. 97 (8): 4309–4314. Bibcode:2000PNAS...97.4309T. doi:10.1073/pnas.070525997. PMC 18238. PMID 10725408.
  12. ↑ Solorzano A, Webby RJ, Lager KM, Janke BH, Garcia-Sastre A, Richt JA (2005). "Mutations in the NS1 protein of swine influenza virus impair anti-interferon activity and confer attenuation in pigs". J Virol. 79 (12): 7535–7543. doi:10.1128/jvi.79.12.7535-7543.2005. PMC 1143661. PMID 15919908.
  13. ↑ Vincent AL, Ma W, Lager KM, Janke BH, Webby RJ, Garcia-Sastre A, Richt JA (2007). "Efficacy of intranasal administration of a truncated NS1 modified live influenza virus vaccine in swine". Vaccine. 25 (47): 7999–8009. doi:10.1016/j.vaccine.2007.09.019. PMC 2099695. PMID 17933442.
  14. ↑ Quinlivan M, Zamarin D, Garcia-Sastre A, Cullinane A, Chambers T, Palese P (2005). "Attenuation of equine influenza viruses through truncations of the NS1 protein". J Virol. 79 (13): 8431–8439. doi:10.1128/jvi.79.13.8431-8439.2005. PMC 1143746. PMID 15956587.
  15. ↑ Steel J, Lowen AC, Pena L, Angel M, Solorzano A, Albrecht R, Perez DR, Garcia-Sastre A, Palese P (2009). "Live attenuated influenza viruses containing NS1 truncations as vaccine candidates against H5N1 highly pathogenic avian influenza". Journal of Virology. 83 (4): 1742–1753. doi:10.1128/jvi.01920-08. PMC 2643794. PMID 19073731.
  16. ↑ Baskin CR, Bielefeldt-Ohmann H, Garcia-Sastre A, Tumpey TM, Hoeven N Van, Carter VS, Thomas MJ, Proll S, Solorzano A, Billharz R, Fornek JL, Thomas S, Chen CH, Clark EA, Murali-Krishna K, Katze MG (2007). "Functional genomic and serological analysis of the protective immune response resulting from vaccination of macaques with an NS1-truncated influenza virus". J Virol. 81 (21): 11817–11827. doi:10.1128/jvi.00590-07. PMC 2168783. PMID 17715226.
  17. 1 2 García-Sastre A, Egorov A, Matassov D, Brandt S, Levy DE, Durbin JE, Palese P, Muster T (1998). "Influenza A virus lacking the NS1 gene replicates in interferon-deficient systems". Virology. 252 (2): 324–30. doi:10.1006/viro.1998.9508. PMID 9878611.
  18. 1 2 Wang L, Suarez DL, Pantin-Jackwood M, Mibayashi M, García-Sastre A, Saif YM, Lee CW (2008). "Characterization of Influenza Virus Variants with Different Sizes of the Non-structural (NS) Genes and Their Potential as a Live Influenza Vaccine in Poultry". Vaccine. 26 (29–30): 3580–3586. doi:10.1016/j.vaccine.2008.05.001. PMC 2785844. PMID 18539366.
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