This year, avian influenza (AI) has spread like wildfire across thousands of poultry farms, infecting more than 48 million birds in the USA. Even though AI is considered to have a low risk for transmission to humans, according to the Centers for Disease Control and Prevention, similar viruses in other countries have made humans ill and caused death in some cases. The outbreak’s rapid escalation has spurred the increase of biosecurity efforts by culling flocks of bird in farms in which the virus has been detected. Although, the biggest impact of this outbreak has been economic, health concerns are never far behind because of the possibility that this highly mutable virus could one day spread among humans and spawn an influenza pandemic.
Genetically Modified Chickens
Dr. Helen Sang’s (Roslin Institute, Edinburgh, Scotland) and Dr. Laurence Tiley’s (University of Cambridge, UK) research teams recently developed a novel method of conferring resistance to influenza A (which causes AI) in chickens through genetic engineering. The authors tested whether transgenic chickens could reduce the transmission of H5N1, a highly pathogenic type of AI. In this study, the authors introduced a short hairpin RNA molecule containing the recognition sequence for the enzyme, viral polymerase, required for viral replication and packaging. The RNA, termed decoy RNA (D5), expresses the 8 common sequences of the influenza A viral genome. When the influenza A virus infects cells, the inserted RNA acts as a decoy to which viral polymerase binds instead of replicating the virus. In effect, the decoy RNA silences the expression of viral polymerase and suppresses the transmission of the influenza virus.
Experimental Design
In the first experiment, the researchers tested the susceptibility of chickens towards an AI infection and its transmission in transgenic chickens by directly infecting transgenic and non-transgenic birds with a high dose of H5N1 and housing with uninfected birds. The results indicated that the susceptibility to the AI virus after a direct infection was similar for transgenic and non-transgenic birds but there was a reduction in the transmission of the AI virus from transgenic birds to other birds.
In the second experiment, the scientists determined if the results obtained in experiment 1 reflected reduced levels of virus shedding from the transgenic challenge group or reduced susceptibility to infection via contact exposure to the infected birds. Transgenic and non-transgenic birds were infected with a lower dose than that used in the first experiment. Again, directly infected birds (non-transgenic and transgenic) succumbed to the infection. However, transgenic and non-transgenic birds in contact with directly infected transgenic birds did not become infected. Furthermore, viral RNA was detected in directly infected birds but the virus shed by these birds was not able to infect others.
It is unknown how the transgenic birds infected with H5N1 did not transmit the virus to birds housed with them. Based on the in vitro studies, the researchers hypothesize that the RNA decoys may disrupt replication by direct binding of polymerase. With this elegantly designed study, the researchers provided a proof-of-principle demonstration that genetic modification can be used to prevent AI infection in chickens.
Advantage over Vaccines
Chickens genetically engineered to express resistance to AI could revolutionize biosecurity efforts in the poultry industry. One advantage of genetic modification over vaccines is that the decoy 5 RNA corresponds to an absolutely conserved sequence that is essential for the regulation of viral transcription, replication and packaging for all subtypes of the influenza A virus. Vaccines can protect against clinical disease. However, they are only effective for one subtype and provide reduced protection for subtypes to which they are not well matched, allowing for the virus to spread. To keep up with viral evolution, vaccines would have to be updated frequently. Decoy 5 RNA confers the potential to develop chickens with resistance to many different strains of influenza A. To overcome the resistance conferred by the decoy RNA, the virus would have to create mutations on all eight genome segments simultaneously, a scenario that is highly improbable.
Stay tuned for our upcoming article that will address just how safe transgenic chickens may be and the possible risks associated with genetically modified organisms (GMOs).
References:
World Health Organization (WHO). FAQs: H5N1 influenza. http://www.who.int/influenza/human_animal_interface/avian_influenza/h5n1_research/faqs/en/. Visited August 1, 2015
Lyall J, Irvine RM, Sherman A, McKinley TJ, Núñez A, Purdie A, Outtrim L, Brown IH, Rolleston-Smith G, Sang H, Tiley L. 2011. Suppression of avian influenza transmission in genetically modified chickens. Science. 331(6014):223-6
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