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New approaches to prevent and treat influenza: The only certainty is change
The Veterinary Journal 199 (2014) 7–8
Contents lists available at ScienceDirect
The Veterinary Journal journal homepage: www.elsevier.com/locate/tvjl
Guest Editorial
New approaches to prevent and treat influenza: The only certainty is change
In 1510, the first recognized pandemics of influenza in humans took place in Africa, Asia and Europe, causing the now familiar symptoms of the disease including coughing, respiratory distress and fever (Morens et al., 2010). It might not be one of the most famously remembered facts of the Renaissance, but at that time the occurrences of these pandemics stimulated an expanding interest, not only in the cause of the disease, but also in attempts to treat it. Although treatments based on the miasmatic theory might have worsened the condition of patients, this theory is the basis of the name of the disease (influenza, which is the Italian word for ‘influence’) stemming from the idea that a misbalance in humors caused by some mystical influence was the cause of this disease. The use of an intrabody to block influenza A virus replication, published in this issue of The Veterinary Journal by Dr. Yoshikazu Fujimoto of Kyushu University Graduate School of Medical Sciences and his colleagues brings several new perspectives on future ways to fight influenza (Fujiomoto et al., 2013). Influenza is a disease that occurs in a seasonal fashion and one that mainly affects the upper respiratory tract of humans, other mammals and birds. Pandemics of highly pathogenic and pantropic forms of the virus have occurred and are expected to occur again. Most of the individual cases and all of the pandemics are related to the influenza A virus (Orthomyxoviridae: Influenzavirus A), an enveloped and pleomorphic virus, with an eight-segmented negativesense single-stranded RNA genome. The influenza A virus genome has a high mutation rate that gives rise to a wide range of serotypes and subtypes of low-to-no antibody cross-protection; this is the main barrier not only for developing a generic vaccine but also for developing antivirals. Intrabodies are intracellularly expressed antibodies able to knockout or knockdown the function of a protein by directly blocking its function or interfering with its normal cellular localization pattern. Intrabody-coding genes can be expressed in target cells via transfection of viral vectors, such as lentiviruses, adenoviruses and retroviruses, or with plasmids into cells using liposomes (Kontermann, 2004). Intrabody transfection not only has been used in vitro against viruses (such as human immunodeficiency virus (HIV), tick-borne flavivirus, hepatitis C virus), bacteriotoxins and nematode secretions (Kontermann, 2004), but also in oncology, neurodegenerative diseases and transplant rejection (Stocks, 2005). The use of intrabodies against the rabies virus, which causes fatal encephalitis and for which only one highly unsuccessful antiviral treatment is available, also shows the therapeutic potential of this approach (Kaku et al., 2011). Finding effective ways to fight influenza is a difficult but absolutely essential task. The emergence of the H1N1 influenza A virus in 2009 in North America and the avian H5N1 in 1997 and H7N7 1090-0233/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tvjl.2013.10.016
influenza A virus in 2013 in China (To et al., 2013) reminds the public and animal health authorities worldwide of the need for vaccines and antivirals as a way to avoid a highly devastating human influenza pandemic, such as the one of 1918, as well as outbreaks of avian influenza that could devastate the poultry industry. Neuraminidase inhibitors such as oseltamivir, which blocks virus release from infected cells, and M2 proton channel blockers such as adamantanes, which inhibit virus uncoating in endosomes, are the only licensed antivirals for human treatment against influenza (Vanderlinden and Naesens, 2013). Yet virus strains resistant to both antiviral classes harboring neuraminidase and M2 amino acid substitutions are known to emerge (Yen et al., 2013), which demonstrates the efficacy of the viral mutation rate, allowing viruses to circumvent these antivirals. However, antiviral strategies also mutate. RNA interference (RNAi), a part of the natural protein expression regulatory system of eukaryotic cells, is increasingly being used as an antiviral platform via transient (with liposomes) or permanent (with viral vectors) transfection of cells with short-hairpin or short-interfering RNAs that trigger mRNA degradation in the cytoplasm. At first glance, RNAi was an excellent choice as a new strategy to defeat influenza: in vivo models showed that the virus can indeed be inhibited with short-interfering RNAs targeted to the viral polymerases and NP, M and NS mRNAs (Baric, 2010). If it is truly that effective, why is RNAi not being extensively used to treat or prevent influenza? The answer is very much the same as the reason why vaccine formulations are continually changed: the influenza virus rapidly evolves, leading to such great genetic diversity that the sequence-dependent RNAi mechanism cannot be sufficiently triggered with only a few short-hairpin or short-interfering RNA types. The work of Fujiomoto et al. (2013) is an exceptional attempt to improve the set of anti-influenza antivirals. The authors successfully transfected MDCK cells with plasmids containing genes for the heavy and light chains of anti-PB2 (one of the influenza A virus basic polymerases) monoclonal antibodies targeting a highly conserved epitope of this protein. They demonstrated that these partial antibodies were effectively produced in the cytoplasm and were able to block PB2 nuclear transportation, thus inhibiting viral RNA synthesis and making cells resistant to the virus. The probability of a generic, single antiviral-based treatment for influenza seems quite improbable at the present time. A combination of approaches that target different steps of the infection, including constantly changing vaccine formulations and effective ways to deliver these to large populations of humans and livestock need to be taken into account, as well as the fact that influenza viruses mutate very rapidly. But antivirals will mutate along.
8
Guest Editorial / The Veterinary Journal 199 (2014) 7–8
Paulo E. Brandão Department of Preventive Veterinary Medicine and Animal Health, School of Veterinary Medicine, University of São Paulo, CEP 05508-270 São Paulo, SP, Brazil E-mail address: [email protected]
References
Baric, S., 2010. SiRNA for influenza therapy. Viruses 2, 1448–1457. Fujiomoto, Y., Ozaki, K., Maeda, M., Nishijima, K., Takakuwa, H., Ostuki, K., Kida, H., Ono, E., 2013. Resistance to influenza A virus infection in transformed cell lines expressing an anti-PB2 monoclonal antibody. The Veterinary Journal 198, 487– 493.
Kaku, Y., Noguchi, A., Hotta, K., Yamada, A., Inoue, S., 2011. Inhibition of rabies virus propagation in mouse neuroblastoma cells by an intrabody against the viral phosphoprotein. Antiviral Research 91, 64–71. Kontermann, R.E., 2004. Intrabodies as therapeutic agents. Methods 34, 163–170. Morens, D.M., North, M., Taubenberger, J.K., 2010. Eyewitness accounts of the 1510 influenza pandemic in Europe. Lancet 376, 1894–1895. Stocks, M., 2005. Intrabodies as drug discovery tools and therapeutics. Current Opinion in Chemical Biology 9, 359–365. To, K., Chan, J.F., Chen, H., Li, L., Yuen, K.Y., 2013. The emergence of influenza A H7N9 in human beings 16 years after influenza A H5N1: A tale of two cities. Lancet Infectious Diseases 13, 809–821. Vanderlinden, E., Naesens, L., 2013. Emerging antiviral strategies to interfere with influenza virus entry. Medicinal Research Reviews. http://dx.doi.org/10.1002/ med.21289. Yen, H.L., McKimm-Breschkin, J.L., Choy, K.T., Wong, D.D., Cheung, P.P., Zhou, J., Ng, I.H., Zhu, H., Webby, R.J., Guan, Y., et al, 2013. Resistance to neuraminidase inhibitors conferred by an R292K mutation in a human influenza virus H7N9 isolate can be masked by a mixed R/K viral population. MBio 4, http:// dx.doi.org/pii: e00396-13. 10.1128/mBio. 00396-13.
Contents lists available at ScienceDirect
The Veterinary Journal journal homepage: www.elsevier.com/locate/tvjl
Guest Editorial
New approaches to prevent and treat influenza: The only certainty is change
In 1510, the first recognized pandemics of influenza in humans took place in Africa, Asia and Europe, causing the now familiar symptoms of the disease including coughing, respiratory distress and fever (Morens et al., 2010). It might not be one of the most famously remembered facts of the Renaissance, but at that time the occurrences of these pandemics stimulated an expanding interest, not only in the cause of the disease, but also in attempts to treat it. Although treatments based on the miasmatic theory might have worsened the condition of patients, this theory is the basis of the name of the disease (influenza, which is the Italian word for ‘influence’) stemming from the idea that a misbalance in humors caused by some mystical influence was the cause of this disease. The use of an intrabody to block influenza A virus replication, published in this issue of The Veterinary Journal by Dr. Yoshikazu Fujimoto of Kyushu University Graduate School of Medical Sciences and his colleagues brings several new perspectives on future ways to fight influenza (Fujiomoto et al., 2013). Influenza is a disease that occurs in a seasonal fashion and one that mainly affects the upper respiratory tract of humans, other mammals and birds. Pandemics of highly pathogenic and pantropic forms of the virus have occurred and are expected to occur again. Most of the individual cases and all of the pandemics are related to the influenza A virus (Orthomyxoviridae: Influenzavirus A), an enveloped and pleomorphic virus, with an eight-segmented negativesense single-stranded RNA genome. The influenza A virus genome has a high mutation rate that gives rise to a wide range of serotypes and subtypes of low-to-no antibody cross-protection; this is the main barrier not only for developing a generic vaccine but also for developing antivirals. Intrabodies are intracellularly expressed antibodies able to knockout or knockdown the function of a protein by directly blocking its function or interfering with its normal cellular localization pattern. Intrabody-coding genes can be expressed in target cells via transfection of viral vectors, such as lentiviruses, adenoviruses and retroviruses, or with plasmids into cells using liposomes (Kontermann, 2004). Intrabody transfection not only has been used in vitro against viruses (such as human immunodeficiency virus (HIV), tick-borne flavivirus, hepatitis C virus), bacteriotoxins and nematode secretions (Kontermann, 2004), but also in oncology, neurodegenerative diseases and transplant rejection (Stocks, 2005). The use of intrabodies against the rabies virus, which causes fatal encephalitis and for which only one highly unsuccessful antiviral treatment is available, also shows the therapeutic potential of this approach (Kaku et al., 2011). Finding effective ways to fight influenza is a difficult but absolutely essential task. The emergence of the H1N1 influenza A virus in 2009 in North America and the avian H5N1 in 1997 and H7N7 1090-0233/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tvjl.2013.10.016
influenza A virus in 2013 in China (To et al., 2013) reminds the public and animal health authorities worldwide of the need for vaccines and antivirals as a way to avoid a highly devastating human influenza pandemic, such as the one of 1918, as well as outbreaks of avian influenza that could devastate the poultry industry. Neuraminidase inhibitors such as oseltamivir, which blocks virus release from infected cells, and M2 proton channel blockers such as adamantanes, which inhibit virus uncoating in endosomes, are the only licensed antivirals for human treatment against influenza (Vanderlinden and Naesens, 2013). Yet virus strains resistant to both antiviral classes harboring neuraminidase and M2 amino acid substitutions are known to emerge (Yen et al., 2013), which demonstrates the efficacy of the viral mutation rate, allowing viruses to circumvent these antivirals. However, antiviral strategies also mutate. RNA interference (RNAi), a part of the natural protein expression regulatory system of eukaryotic cells, is increasingly being used as an antiviral platform via transient (with liposomes) or permanent (with viral vectors) transfection of cells with short-hairpin or short-interfering RNAs that trigger mRNA degradation in the cytoplasm. At first glance, RNAi was an excellent choice as a new strategy to defeat influenza: in vivo models showed that the virus can indeed be inhibited with short-interfering RNAs targeted to the viral polymerases and NP, M and NS mRNAs (Baric, 2010). If it is truly that effective, why is RNAi not being extensively used to treat or prevent influenza? The answer is very much the same as the reason why vaccine formulations are continually changed: the influenza virus rapidly evolves, leading to such great genetic diversity that the sequence-dependent RNAi mechanism cannot be sufficiently triggered with only a few short-hairpin or short-interfering RNA types. The work of Fujiomoto et al. (2013) is an exceptional attempt to improve the set of anti-influenza antivirals. The authors successfully transfected MDCK cells with plasmids containing genes for the heavy and light chains of anti-PB2 (one of the influenza A virus basic polymerases) monoclonal antibodies targeting a highly conserved epitope of this protein. They demonstrated that these partial antibodies were effectively produced in the cytoplasm and were able to block PB2 nuclear transportation, thus inhibiting viral RNA synthesis and making cells resistant to the virus. The probability of a generic, single antiviral-based treatment for influenza seems quite improbable at the present time. A combination of approaches that target different steps of the infection, including constantly changing vaccine formulations and effective ways to deliver these to large populations of humans and livestock need to be taken into account, as well as the fact that influenza viruses mutate very rapidly. But antivirals will mutate along.
8
Guest Editorial / The Veterinary Journal 199 (2014) 7–8
Paulo E. Brandão Department of Preventive Veterinary Medicine and Animal Health, School of Veterinary Medicine, University of São Paulo, CEP 05508-270 São Paulo, SP, Brazil E-mail address: [email protected]
References
Baric, S., 2010. SiRNA for influenza therapy. Viruses 2, 1448–1457. Fujiomoto, Y., Ozaki, K., Maeda, M., Nishijima, K., Takakuwa, H., Ostuki, K., Kida, H., Ono, E., 2013. Resistance to influenza A virus infection in transformed cell lines expressing an anti-PB2 monoclonal antibody. The Veterinary Journal 198, 487– 493.
Kaku, Y., Noguchi, A., Hotta, K., Yamada, A., Inoue, S., 2011. Inhibition of rabies virus propagation in mouse neuroblastoma cells by an intrabody against the viral phosphoprotein. Antiviral Research 91, 64–71. Kontermann, R.E., 2004. Intrabodies as therapeutic agents. Methods 34, 163–170. Morens, D.M., North, M., Taubenberger, J.K., 2010. Eyewitness accounts of the 1510 influenza pandemic in Europe. Lancet 376, 1894–1895. Stocks, M., 2005. Intrabodies as drug discovery tools and therapeutics. Current Opinion in Chemical Biology 9, 359–365. To, K., Chan, J.F., Chen, H., Li, L., Yuen, K.Y., 2013. The emergence of influenza A H7N9 in human beings 16 years after influenza A H5N1: A tale of two cities. Lancet Infectious Diseases 13, 809–821. Vanderlinden, E., Naesens, L., 2013. Emerging antiviral strategies to interfere with influenza virus entry. Medicinal Research Reviews. http://dx.doi.org/10.1002/ med.21289. Yen, H.L., McKimm-Breschkin, J.L., Choy, K.T., Wong, D.D., Cheung, P.P., Zhou, J., Ng, I.H., Zhu, H., Webby, R.J., Guan, Y., et al, 2013. Resistance to neuraminidase inhibitors conferred by an R292K mutation in a human influenza virus H7N9 isolate can be masked by a mixed R/K viral population. MBio 4, http:// dx.doi.org/pii: e00396-13. 10.1128/mBio. 00396-13.