Mouse adaptation of the H9N2 avian influenza virus causes the downregulation of genes related to innate immune responses and ubiquitin-mediated proteolysis in mice

Guo, Jing; Gao, Xinxin; Liu, Bao‐Tao; Li, Yubao; Liu, Wenqiang; Jian-biao, LU; Liu, Cheng; Xue, Rui; Li, Xuyong

doi:10.1007/s00430-020-00656-4

Cited by 5 publications

(7 citation statements)

References 52 publications

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“…Primers are shown in Supplementary Table S4. Target gene expression were normalized to the reference endogenous glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene and calculated using the 2-ΔΔCT method (Livak and Schmittgen, 2001;Guo et al, 2020).…”

Section: Real-time Polymerase Chain Reaction (Qpcr)mentioning

confidence: 99%

Differences in Highly Pathogenic H5N6 Avian Influenza Viral Pathogenicity and Inflammatory Response in Chickens and Ducks

Wang

Luo

et al. 2021

Front. Microbiol.

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Infection with H5N6 highly pathogenic avian influenza virus caused high mortality in chickens, while ducks often appear to be asymptomatic. But, some recent H5Nx subtype viruses could cause high mortality in ducks. The variation between different species and the mechanisms by which some H5Nx viruses cause death in ducks requires investigation to identify the key processes in influenza susceptibility and pathogenesis. Here, we characterized two representative H5N6 viruses, A/Pavo cristatus/Jiangxi/JA1/2016 (JA1) and A/Anas crecca/shanghai/SH1/2016 (SH1), and compared their pathogenicity and expression profiles of immune-related genes in chickens and ducks to identify the elements of the host immune-related response that were involved in disease lethality. Results suggested that H5N6 HPAIVs had higher pathogenic and inflammatory effect in chickens than in ducks. Importantly, the TNF-α, IL-6, IFN-γ and iNOS levels were significantly higher in the lung of SH1 infected chickens compared to those of ducks. And we found higher systemic levels of IL-6 induced by JA1 in chickens than in ducks. In addition, our experiments demonstrated that JA1 was associated with greater pathogenicity in ducks were accompanied by the excessive expression of iNOS in the brain. These results are helpful to understand the relationship between the pathogenicity of H5N6 AIVs and inflammatory responses to them in chickens and ducks.

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Section: Real-time Polymerase Chain Reaction (Qpcr)mentioning

confidence: 99%

Differences in Highly Pathogenic H5N6 Avian Influenza Viral Pathogenicity and Inflammatory Response in Chickens and Ducks

Wang

Luo

et al. 2021

Front. Microbiol.

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“…SUMO1 and ubiquitin compete for binding to the target protein. When the SUMO1 protein does not sumoylate the target protein, ubiquitin has the opportunity to bind and thereby degrade the target protein ( 31 , 46 ). To investigate whether the degradation of M1 protein bearing the mutation A215T is linked to ubiquitination, 293T cells were cotransfected with HA-tagged wild-type or mutant M1 plasmids and a Flag-tagged ubiquitin-expressing plasmid, and the cells were then treated with MG132 (a 26S proteasome inhibitor).…”

Section: Resultsmentioning

confidence: 99%

“…The ORFs for ubiquitin (Ub) were amplified from human A549 cDNA by PCR with a 5′ primer that introduced a Flag tag with a NheI site and a 3′ primer that introduced a CalI site. Sequencing was performed to confirm the identity of all plasmids ( 31 , 46 ). The 239T cells were (i) cotransfected with the expression plasmids of Ubc9, SUMO1, and HA-M1, (ii) cotransfected with the expression plasmids of Ubc9 and HA-SUMO1 and then infected with four viruses, and (iii) cotransfected with the expression plasmids of Flag-Ub and HA-M1 and treated with MG132 (M7449; Sigma) 18 h after transfection.…”

Section: Methodsmentioning

confidence: 99%

SUMOylation of Matrix Protein M1 and Filamentous Morphology Collectively Contribute to the Replication and Virulence of Highly Pathogenic H5N1 Avian Influenza Viruses in Mammals

Guo

Chen

et al. 2022

J Virol

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The matrix protein (M1) of influenza A virus plays an important role in replication, assembly, and budding. A previous study found that aspartic acid (D) at position 30 and alanine (A) at position 215 of M1 contribute to the high pathogenicity of H5N1 viruses in mice, and double mutations of D to asparagine (N) at position 30 (D30N) and A to threonine (T) at position 215 (A215T) in M1 dramatically attenuate H5N1 viruses in mice. However, the underlying mechanisms by which these M1 mutations attenuate the virulence of H5N1 viruses are unknown. Here, we found that the amino acid mutation A215T eliminates the SUMOylation of M1 by reducing its interaction with the host SUMO1 protein, significantly reducing the stability of M1, slowing the export of the M1-vRNP complex from the nucleus to the cytoplasm, and reducing viral replication in MDCK cells. We further found that the D30N mutation in M1 alters the shape of progeny viruses from filamentous to spherical virions. Our findings reveal an essential role for M1 215A SUMOylation and M1 30D-related filamentous morphology in the pathogenesis of avian influenza viruses, which could be targeted in novel antiviral drug designs. Importance Identification of the pathogenic mechanism of highly pathogenic avian influenza viruses in mammals is helpful to develop novel anti-influenza virus strategies. Two amino acid mutations (D30N and A215T) in M1 were found to collectively attenuate H5N1 influenza viruses in mice, but the underlying mechanism remained unknown. This study found that the A215T mutation significantly decreases the SUMOylation of M1, which in turn attenuates the replication of H5N1 virus in mammalian cells. The D30N mutation in M1 was found to change the virion shape from filamentous to spherical. These findings are important for understanding the molecular mechanism of virulence of highly pathogenic avian influenza viruses in mammals.

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Section: Discussionmentioning

confidence: 99%

“…In nature, the adaptive evolution of the AIV in new hosts occurs regularly, and the viruses acquire new replicative ability, pathogenicity, transmissibility, antigenicity, and receptor‐binding properties by undergoing adaptive evolution in the new host. Research had manifested that if a novel virus is generated via adaptation from avians to humans; this virus may be virulent in mammals (Guo et al., 2020). The results in our study showed that viruses with PB2‐588V were adaptable to both avians and mammals, while the viruses with other mutations showed different adaptations to mice and chickens, as for instance, did PB2‐L648V, which was highly adaptable to mice but could not be detected in the trachea of chickens, implying that there are two different types of mutation, and PB2‐A588V may be preferentially selected during the viral adaptation of avian influenza in mammals.…”

Section: Discussionmentioning

confidence: 99%

The PB2 co‐adaptation of H10N8 avian influenza virus increases the pathogenicity to chickens and mice

Xiao

et al. 2021

Transbounding Emerging Dis

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Avian influenza (AI) is an important zoonotic disease, which can be transmitted across species barriers to other hosts, especially humans, posing a serious threat to the poultry industry and public health. In recent years, human cases infected with the H10N8, H9N2, and H7N9 of avian influenza viruses (AIVs) have been identified frequently as have the internal genes of H7N9 and H10N8, which are derived from H9N2 viruses.The adaptive mutation of the PB2 gene is an important way for the H10N8, H9N2, and H7N9 AIVs to spread across species to adapt to new hosts. Several well-known adaptive mutations in the PB2 gene, such as E627K, D701N, and A588V, significantly enhanced the virulence of the AIVs in mammals. However, the co-adaptation of AIVs to avian and mammalian hosts is rarely studied. In this study, we found that the mutations of PB2-I292V, PB2-R389K, PB2-A588V, PB2-T598M/V, PB2-L648V, and PB2-T676M substitutions significantly increased after 2012. In addition, in our previous studies, we found that the human-origin and avian-origin of H10N8 AIVs with very high homology also have these six mutation differences in PB2 gene, and the avianorigin H10N8 strain known as JX102 with all the key amino acids on the PB2 protein in the pre-evolutionary stage, so JX102 was chosen as a model strain. Among them, PB2-A588V significantly enhanced the activity of polymerase in avian and mammalian cells. Notably, animal experiments showed that PB2-A588V substitution increased the pathogenicity and transmissibility in chickens and the virulence of mice. The combined mutations of PB2-F6 (including PB2-I292V, PB2-R389K, PB2-A588V, PB2-T598M, PB2-L648V, and PB2-T676M) obtained higher adaptability of AIVs in avians and mammals than that of the single mutation of PB2-A588V, which suggested that the PB2 588 site is a key co-adaptation site and that synergies with other mutation sites can further enhance this co-adaptability. The results of this study show that the emergence of co-adaptation not only increases the threat to avians and mammals but may also contribute to a pandemic among avians and cross the interspecies barrier to mammals.

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Mouse adaptation of the H9N2 avian influenza virus causes the downregulation of genes related to innate immune responses and ubiquitin-mediated proteolysis in mice

Cited by 5 publications

References 52 publications

Differences in Highly Pathogenic H5N6 Avian Influenza Viral Pathogenicity and Inflammatory Response in Chickens and Ducks

Differences in Highly Pathogenic H5N6 Avian Influenza Viral Pathogenicity and Inflammatory Response in Chickens and Ducks

SUMOylation of Matrix Protein M1 and Filamentous Morphology Collectively Contribute to the Replication and Virulence of Highly Pathogenic H5N1 Avian Influenza Viruses in Mammals

The PB2 co‐adaptation of H10N8 avian influenza virus increases the pathogenicity to chickens and mice

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