Evolution of highly pathogenic H5N1 influenza A virus in the central nervous system of ferrets.
Central nervous system (CNS) disease is the most common extra-respiratory tract complication of influenza A virus infections in humans. Remarkably, zoonotic highly pathogenic avian influenza (HPAI) H5N1 virus infections are more often associated with CNS disease than infections with seasonal influen...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2023-03-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1011214 |
| _version_ | 1827968544152748032 |
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| author | Jurre Y Siegers Lucas Ferreri Dirk Eggink Edwin J B Veldhuis Kroeze Aartjan J W Te Velthuis Marco van de Bildt Lonneke Leijten Peter van Run Dennis de Meulder Theo Bestebroer Mathilde Richard Thijs Kuiken Anice C Lowen Sander Herfst Debby van Riel |
| author_facet | Jurre Y Siegers Lucas Ferreri Dirk Eggink Edwin J B Veldhuis Kroeze Aartjan J W Te Velthuis Marco van de Bildt Lonneke Leijten Peter van Run Dennis de Meulder Theo Bestebroer Mathilde Richard Thijs Kuiken Anice C Lowen Sander Herfst Debby van Riel |
| author_sort | Jurre Y Siegers |
| collection | DOAJ |
| description | Central nervous system (CNS) disease is the most common extra-respiratory tract complication of influenza A virus infections in humans. Remarkably, zoonotic highly pathogenic avian influenza (HPAI) H5N1 virus infections are more often associated with CNS disease than infections with seasonal influenza viruses. Evolution of avian influenza viruses has been extensively studied in the context of respiratory infections, but evolutionary processes in CNS infections remain poorly understood. We have previously observed that the ability of HPAI A/Indonesia/5/2005 (H5N1) virus to replicate in and spread throughout the CNS varies widely between individual ferrets. Based on these observations, we sought to understand the impact of entrance into and replication within the CNS on the evolutionary dynamics of virus populations. First, we identified and characterized three substitutions-PB1 E177G and A652T and NP I119M - detected in the CNS of a ferret infected with influenza A/Indonesia/5/2005 (H5N1) virus that developed a severe meningo-encephalitis. We found that some of these substitutions, individually or collectively, resulted in increased polymerase activity in vitro. Nevertheless, in vivo, the virus bearing the CNS-associated mutations retained its capacity to infect the CNS but showed reduced dispersion to other anatomical sites. Analyses of viral diversity in the nasal turbinate and olfactory bulb revealed the lack of a genetic bottleneck acting on virus populations accessing the CNS via this route. Furthermore, virus populations bearing the CNS-associated mutations showed signs of positive selection in the brainstem. These features of dispersion to the CNS are consistent with the action of selective processes, underlining the potential for H5N1 viruses to adapt to the CNS. |
| first_indexed | 2024-04-09T18:23:13Z |
| format | Article |
| id | doaj.art-6b06d78f37544d44bd9dcafbc3513635 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-04-09T18:23:13Z |
| publishDate | 2023-03-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-6b06d78f37544d44bd9dcafbc35136352023-04-12T05:31:28ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742023-03-01193e101121410.1371/journal.ppat.1011214Evolution of highly pathogenic H5N1 influenza A virus in the central nervous system of ferrets.Jurre Y SiegersLucas FerreriDirk EgginkEdwin J B Veldhuis KroezeAartjan J W Te VelthuisMarco van de BildtLonneke LeijtenPeter van RunDennis de MeulderTheo BestebroerMathilde RichardThijs KuikenAnice C LowenSander HerfstDebby van RielCentral nervous system (CNS) disease is the most common extra-respiratory tract complication of influenza A virus infections in humans. Remarkably, zoonotic highly pathogenic avian influenza (HPAI) H5N1 virus infections are more often associated with CNS disease than infections with seasonal influenza viruses. Evolution of avian influenza viruses has been extensively studied in the context of respiratory infections, but evolutionary processes in CNS infections remain poorly understood. We have previously observed that the ability of HPAI A/Indonesia/5/2005 (H5N1) virus to replicate in and spread throughout the CNS varies widely between individual ferrets. Based on these observations, we sought to understand the impact of entrance into and replication within the CNS on the evolutionary dynamics of virus populations. First, we identified and characterized three substitutions-PB1 E177G and A652T and NP I119M - detected in the CNS of a ferret infected with influenza A/Indonesia/5/2005 (H5N1) virus that developed a severe meningo-encephalitis. We found that some of these substitutions, individually or collectively, resulted in increased polymerase activity in vitro. Nevertheless, in vivo, the virus bearing the CNS-associated mutations retained its capacity to infect the CNS but showed reduced dispersion to other anatomical sites. Analyses of viral diversity in the nasal turbinate and olfactory bulb revealed the lack of a genetic bottleneck acting on virus populations accessing the CNS via this route. Furthermore, virus populations bearing the CNS-associated mutations showed signs of positive selection in the brainstem. These features of dispersion to the CNS are consistent with the action of selective processes, underlining the potential for H5N1 viruses to adapt to the CNS.https://doi.org/10.1371/journal.ppat.1011214 |
| spellingShingle | Jurre Y Siegers Lucas Ferreri Dirk Eggink Edwin J B Veldhuis Kroeze Aartjan J W Te Velthuis Marco van de Bildt Lonneke Leijten Peter van Run Dennis de Meulder Theo Bestebroer Mathilde Richard Thijs Kuiken Anice C Lowen Sander Herfst Debby van Riel Evolution of highly pathogenic H5N1 influenza A virus in the central nervous system of ferrets. PLoS Pathogens |
| title | Evolution of highly pathogenic H5N1 influenza A virus in the central nervous system of ferrets. |
| title_full | Evolution of highly pathogenic H5N1 influenza A virus in the central nervous system of ferrets. |
| title_fullStr | Evolution of highly pathogenic H5N1 influenza A virus in the central nervous system of ferrets. |
| title_full_unstemmed | Evolution of highly pathogenic H5N1 influenza A virus in the central nervous system of ferrets. |
| title_short | Evolution of highly pathogenic H5N1 influenza A virus in the central nervous system of ferrets. |
| title_sort | evolution of highly pathogenic h5n1 influenza a virus in the central nervous system of ferrets |
| url | https://doi.org/10.1371/journal.ppat.1011214 |
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