Swine ANP32A supports avian influenza virus polymerase

Peacock, Thomas P.; Swann, Olivia C.; Staller, Ecco; Leung, P. Brian; Goldhill, Daniel H.; Zhou, Hongbo; Long, Jason S.; Barclay, William

doi:10.1101/2020.01.24.916916

Cited by 5 publications

(2 citation statements)

References 32 publications

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“…Intermediary hosts, such as pigs, play a role in the adaptation of IAVs by acting as a “mixing vessel” and facilitating reassortment, as expression of both α2,3 and α2,6 linked SAs enables them to be simultaneously infected by both human and avian influenza viruses ( 17 ) ( Figure 2 ). In addition, swine ANP32A has been shown to support replication with the avian virus polymerase ( 18 ), further supporting the role for pigs as “mixing vessels” for the emergence of reassortant viruses with pandemic potential ( 18 ). The process of antigenic drift can also contribute to the adaptation of avian influenza virus HAs, by facilitating a switch in preference for α2,3 linked SAs to α2,6 linked SAs, or in the viral polymerase (mutation PB2-E627K) ( 19 , 20 ).…”

Section: Introductionmentioning

confidence: 86%

Adenoviral Vectors as Vaccines for Emerging Avian Influenza Viruses

et al. 2021

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It is evident that the emergence of infectious diseases, which have the potential for spillover from animal reservoirs, pose an ongoing threat to global health. Zoonotic transmission events have increased in frequency in recent decades due to changes in human behavior, including increased international travel, the wildlife trade, deforestation, and the intensification of farming practices to meet demand for meat consumption. Influenza A viruses (IAV) possess a number of features which make them a pandemic threat and a major concern for human health. Their segmented genome and error-prone process of replication can lead to the emergence of novel reassortant viruses, for which the human population are immunologically naïve. In addition, the ability for IAVs to infect aquatic birds and domestic animals, as well as humans, increases the likelihood for reassortment and the subsequent emergence of novel viruses. Sporadic spillover events in the past few decades have resulted in human infections with highly pathogenic avian influenza (HPAI) viruses, with high mortality. The application of conventional vaccine platforms used for the prevention of seasonal influenza viruses, such as inactivated influenza vaccines (IIVs) or live-attenuated influenza vaccines (LAIVs), in the development of vaccines for HPAI viruses is fraught with challenges. These issues are associated with manufacturing under enhanced biosafety containment, and difficulties in propagating HPAI viruses in embryonated eggs, due to their propensity for lethality in eggs. Overcoming manufacturing hurdles through the use of safer backbones, such as low pathogenicity avian influenza viruses (LPAI), can also be a challenge if incompatible with master strain viruses. Non-replicating adenoviral (Ad) vectors offer a number of advantages for the development of vaccines against HPAI viruses. Their genome is stable and permits the insertion of HPAI virus antigens (Ag), which are expressed in vivo following vaccination. Therefore, their manufacture does not require enhanced biosafety facilities or procedures and is egg-independent. Importantly, Ad vaccines have an exemplary safety and immunogenicity profile in numerous human clinical trials, and can be thermostabilized for stockpiling and pandemic preparedness. This review will discuss the status of Ad-based vaccines designed to protect against avian influenza viruses with pandemic potential.

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Section: Introductionmentioning

confidence: 86%

Adenoviral Vectors as Vaccines for Emerging Avian Influenza Viruses

et al. 2021

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“…We have previously described a method to measure the capacity of mutated ANP32 proteins to act as pro-viral factors for influenza polymerase activity. This is achieved by exogenous expression of the cloned mutants in human eHAP cells lacking ANP32A and ANP32B (dKO), in which influenza polymerase is unable to function in absence of complementing ANP32 [39,56]. Here we expressed each natural ANP32A or ANP32B variant and tested its ability to support reconstituted polymerases from a 2009 pandemic H1N1 isolate (A/England/195/2009; hereafter 'Eng/195') or a seasonal H3N2 virus (A/Victoria/3/75; hereafter 'Vic/75') in minigenome reporter assays (Fig.…”

Section: Natural Variants Of Anp32 Proteins Affect Support Of Flupol Activitymentioning

confidence: 99%

A natural variant in ANP32B impairs influenza virus replication in human cells

Staller

Sheppard

Baillon

et al. 2021

Journal of General Virology

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Viruses require host factors to support their replication, and genetic variation in such factors can affect susceptibility to infectious disease. Influenza virus replication in human cells relies on ANP32 proteins, which are involved in assembly of replication-competent dimeric influenza virus polymerase (FluPol) complexes. Here, we investigate naturally occurring single nucleotide variants (SNV) in the human Anp32A and Anp32B genes. We note that variant rs182096718 in Anp32B is found at a higher frequency than other variants in either gene. This SNV results in a D130A substitution in ANP32B, which is less able to support FluPol activity than wild-type ANP32B and binds FluPol with lower affinity. Interestingly, ANP32B-D130A exerts a dominant negative effect over wild-type ANP32B and interferes with the functionally redundant paralogue ANP32A. FluPol activity and virus replication are attenuated in CRISPR-edited cells expressing wild-type ANP32A and mutant ANP32B-D130A. We propose a model in which the D130A mutation impairs FluPol dimer formation, thus resulting in compromised replication. We suggest that both homozygous and heterozygous carriers of rs182096718 may have some genetic protection against influenza viruses.

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A rare variant in ANP32B impairs influenza virus replication in human cells

Staller

Baillon

Frise

et al. 2020

Preprint

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SUMMARYViruses require host factors to support their replication, and genetic variation in such factors can affect susceptibility to infectious disease. Influenza virus replication in human cells relies on ANP32 proteins, which serve essential but redundant roles to support influenza virus polymerase activity. Here, we investigate naturally occurring single nucleotide variants (SNV) in the human Anp32A and Anp32B genes. We note that variant rs182096718 in Anp32B is found at a higher frequency than other variants in either gene. This variant results in a D130A substitution in ANP32B, which is less able to support influenza virus polymerase (FluPol) activity than wildtype ANP32B. Using a split luciferase binding assay, we also show reduced interaction between ANP32B-D130A and FluPol. We then use CRISPR/Cas9 genome editing to generate the mutant homozygous genotype in human eHAP cells, and show that FluPol activity and virus replication are attenuated in cells expressing wildtype ANP32A and mutant ANP32B-D130A. This is in contrast to cells that completely lack expression of ANP32B where no attenuation is seen. We conclude that ANP32B-D130A exerts a dominant negative effect on the pro-viral activity of ANP32A in cells, and suggest that carriers of rs182096718 may have some genetic protection against influenza viruses.

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Swine ANP32A supports avian influenza virus polymerase

Cited by 5 publications

References 32 publications

Adenoviral Vectors as Vaccines for Emerging Avian Influenza Viruses

Adenoviral Vectors as Vaccines for Emerging Avian Influenza Viruses

A natural variant in ANP32B impairs influenza virus replication in human cells

A rare variant in ANP32B impairs influenza virus replication in human cells

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