Influenza A virus (IAV) is a worldwide distributed pathogen able to infect many species of avian and mammals, including humans and pigs. Its genome is characterized by having 8 RNA negative sense segments: the polymerases (PB2, PB1, and PA), the hemagglutinin (HA), the nucleoprotein (NP), the neuraminidase (NA), matrix (M), and the segment that code for the non-structural proteins (NS). IAV polymerases, such as other RNA viruses, have a low proofreading activity, thus virus genome accumulates a great deal of point mutation on a short time scale. Besides, genomic reassortment events are feasible when two different IAV subtypes simultaneously coinfect the same host. These genetic mechanisms are a source of high genetic diversity, which provides plasticity to the virus, being able to quickly adapt in changing environments. Virus evolution can make that virus achieve new antigenic patterns, being no longer recognized by the previous host immunity, generating seasonal epidemic and pandemic IAVs. In 2009 a swine-origin A(H1N1)pdm09 strain arose, harbouring swine, human and avian influenza segments, and caused the last IAV pandemic. This outbreak, highlighted the hypothesis of pigs as “mixing vessels”, playing an important role in the adaptation of avian viruses to humans, as pigs could be infected by both IAVs. Currently, there are 3 dominant subtypes of swine influenza virus (SIV) circulating in pigs: H1N1, H3N2, and H1N2. To control SIV, the most widely used strategy in Europe, although limited, is the application of trivalent vaccines. The immunity provided by this vaccine is not complete, allowing virus replication and hence evolving, which could generate escape mutants. Therefore, SIV poses a continuous threat to both, animal and human health, since its evolution can affect its antigenicity, host range, virulence, antiviral resistance, and pathogenesis. Due to all these antecedents, in this doctoral thesis, the evolutionary dynamics of SIV viral populations have been studied in a pig model with pre-existing immunity against the virus by next sequencing technology. The first study evaluates the evolution of the Eurasian “avian-like” (EA) H1N1 virus in vaccinated and nonvaccinated animals. Positive selection was the main evolution force detected in samples collected from vaccinated animals, where important mutations were reported in HA, NS1, and NP. In the second study, the evolution of the “human-like” H3N2 virus was analyzed in vaccinated and nonvaccinated animals that had previously recovered from an unexpected natural infection with the A(H1N1)pdm09 virus. In both scenarios, natural selection was influencing virus evolution, finding proportionally more nonsynonymous substitutions in HA and NA in viruses recovered from vaccinated animals. In the last chapter, the impact of the vaccine on genome reassortment and genetic drift during an experimental coinfection with H1N1 EA and H3N2 “human-like” has been studied. Results showed a minor possibility of reassortment events in vaccinated animals. On the other hand, the greatest genetic diversification was detected in H1N1 subtype in vaccinated animals, reporting substitutions that may play an important role in the evasion of the immune response in the HA and NA. The results obtained in this doctoral thesis corroborate the enormous capacity of mutation and adaptation of SIV. Different evolutionary patterns found in vaccinated and nonvaccinated animals were detected, providing a novel insight of SIV evolution under different scenarios.
| Date of Award | 16 Dec 2022 |
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| Original language | English |
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| Supervisor | Joaquim Segales Coma (Director), José Ignacio Núñez Garrote (Director) & Ayub Darji (Director) |
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