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Article ; Online: Kaposi's sarcoma-associated herpesvirus (KSHV) utilizes the NDP52/CALCOCO2 selective autophagy receptor to disassemble processing bodies.

Robinson, Carolyn-Ann / Singh, Gillian K / Kleer, Mariel / Katsademas, Thalia / Castle, Elizabeth L / Boudreau, Bre Q / Corcoran, Jennifer A

PLoS pathogens

2023 Volume 19, Issue 1, Page(s) e1011080

Abstract: Kaposi's sarcoma-associated herpesvirus (KSHV) causes the inflammatory and angiogenic endothelial cell neoplasm, Kaposi's sarcoma (KS). We previously demonstrated that the KSHV Kaposin B (KapB) protein promotes inflammation via the disassembly of ... ...

Abstract	Kaposi's sarcoma-associated herpesvirus (KSHV) causes the inflammatory and angiogenic endothelial cell neoplasm, Kaposi's sarcoma (KS). We previously demonstrated that the KSHV Kaposin B (KapB) protein promotes inflammation via the disassembly of cytoplasmic ribonucleoprotein granules called processing bodies (PBs). PBs modify gene expression by silencing or degrading labile messenger RNAs (mRNAs), including many transcripts that encode inflammatory or angiogenic proteins associated with KS disease. Although our work implicated PB disassembly as one of the causes of inflammation during KSHV infection, the precise mechanism used by KapB to elicit PB disassembly was unclear. Here we reveal a new connection between the degradative process of autophagy and PB disassembly. We show that both latent KSHV infection and KapB expression enhanced autophagic flux via phosphorylation of the autophagy regulatory protein, Beclin. KapB was necessary for this effect, as infection with a recombinant virus that does not express the KapB protein did not induce Beclin phosphorylation or autophagic flux. Moreover, we showed that PB disassembly mediated by KSHV or KapB, depended on autophagy genes and the selective autophagy receptor NDP52/CALCOCO2 and that the PB scaffolding protein, Pat1b, co-immunoprecipitated with NDP52. These studies reveal a new role for autophagy and the selective autophagy receptor NDP52 in promoting PB turnover and the concomitant synthesis of inflammatory molecules during KSHV infection.
MeSH term(s)	Humans ; Autophagy ; Endothelial Cells/metabolism ; Herpesviridae Infections/metabolism ; Herpesvirus 8, Human/genetics ; Processing Bodies ; Sarcoma, Kaposi ; Nuclear Proteins/metabolism
Chemical Substances	Nuclear Proteins
Language	English
Publishing date	2023-01-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1011080
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: A Panel of Kaposi's Sarcoma-Associated Herpesvirus Mutants in the Polycistronic Kaposin Locus for Precise Analysis of Individual Protein Products.

Kleer, Mariel / MacNeil, Grant / Adam, Nancy / Pringle, Eric S / Corcoran, Jennifer A

Journal of virology

2021 Volume 96, Issue 5, Page(s) e0156021

Abstract: Kaposi's sarcoma-associated herpesvirus (KSHV) is the cause of several human cancers, including the endothelial cell (EC) malignancy, Kaposi's sarcoma. Unique KSHV genes absent from other human herpesvirus genomes, the "K-genes," are important for KSHV ... ...

Abstract	Kaposi's sarcoma-associated herpesvirus (KSHV) is the cause of several human cancers, including the endothelial cell (EC) malignancy, Kaposi's sarcoma. Unique KSHV genes absent from other human herpesvirus genomes, the "K-genes," are important for KSHV replication and pathogenesis. Among these, the kaposin transcript is highly expressed in all phases of infection, but its complex polycistronic nature has hindered functional analysis to date. At least three proteins are produced from the kaposin transcript: Kaposin A (KapA), B (KapB), and C (KapC). To determine the relative contributions of kaposin proteins during KSHV infection, we created a collection of mutant viruses unable to produce kaposin proteins individually or in combination. In previous work, we showed KapB alone recapitulated the elevated proinflammatory cytokine transcripts associated with KS via the disassembly of RNA granules called processing bodies (PBs). Using the new ΔKapB virus, we showed that KapB was necessary for this effect during latent KSHV infection. Moreover, we observed that despite the ability of all kaposin-deficient latent iSLK cell lines to produce virions, all displayed low viral episome copy number, a defect that became more pronounced after primary infection of naive ECs. For ΔKapB, provision of KapB in
MeSH term(s)	Cell Line, Tumor ; Herpesvirus 8, Human/genetics ; Herpesvirus 8, Human/metabolism ; Humans ; Mutation ; Sarcoma, Kaposi/virology ; Viral Proteins/genetics ; Viral Proteins/metabolism ; Virus Latency/genetics
Chemical Substances	Viral Proteins ; kaposin B protein, Human herpesvirus 8
Language	English
Publishing date	2021-12-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.01560-21
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Article ; Online: Nsp1 proteins of human coronaviruses HCoV-OC43 and SARS-CoV2 inhibit stress granule formation.

Dolliver, Stacia M / Kleer, Mariel / Bui-Marinos, Maxwell P / Ying, Shan / Corcoran, Jennifer A / Khaperskyy, Denys A

PLoS pathogens

2022 Volume 18, Issue 12, Page(s) e1011041

Abstract: Stress granules (SGs) are cytoplasmic condensates that often form as part of the cellular antiviral response. Despite the growing interest in understanding the interplay between SGs and other biological condensates and viral replication, the role of SG ... ...

Abstract	Stress granules (SGs) are cytoplasmic condensates that often form as part of the cellular antiviral response. Despite the growing interest in understanding the interplay between SGs and other biological condensates and viral replication, the role of SG formation during coronavirus infection remains poorly understood. Several proteins from different coronaviruses have been shown to suppress SG formation upon overexpression, but there are only a handful of studies analyzing SG formation in coronavirus-infected cells. To better understand SG inhibition by coronaviruses, we analyzed SG formation during infection with the human common cold coronavirus OC43 (HCoV-OC43) and the pandemic SARS-CoV2. We did not observe SG induction in infected cells and both viruses inhibited eukaryotic translation initiation factor 2α (eIF2α) phosphorylation and SG formation induced by exogenous stress. Furthermore, in SARS-CoV2 infected cells we observed a sharp decrease in the levels of SG-nucleating protein G3BP1. Ectopic overexpression of nucleocapsid (N) and non-structural protein 1 (Nsp1) from both HCoV-OC43 and SARS-CoV2 inhibited SG formation. The Nsp1 proteins of both viruses inhibited arsenite-induced eIF2α phosphorylation, and the Nsp1 of SARS-CoV2 alone was sufficient to cause a decrease in G3BP1 levels. This phenotype was dependent on the depletion of cytoplasmic mRNA mediated by Nsp1 and associated with nuclear accumulation of the SG-nucleating protein TIAR. To test the role of G3BP1 in coronavirus replication, we infected cells overexpressing EGFP-tagged G3BP1 with HCoV-OC43 and observed a significant decrease in virus replication compared to control cells expressing EGFP. The antiviral role of G3BP1 and the existence of multiple SG suppression mechanisms that are conserved between HCoV-OC43 and SARS-CoV2 suggest that SG formation may represent an important antiviral host defense that coronaviruses target to ensure efficient replication.
MeSH term(s)	Humans ; Coronavirus OC43, Human/metabolism ; COVID-19/metabolism ; Cytoplasmic Granules/metabolism ; DNA Helicases/metabolism ; Poly-ADP-Ribose Binding Proteins/genetics ; Poly-ADP-Ribose Binding Proteins/metabolism ; RNA Helicases/genetics ; RNA Helicases/metabolism ; RNA Recognition Motif Proteins/metabolism ; RNA, Viral/metabolism ; SARS-CoV-2/metabolism ; Stress Granules
Chemical Substances	DNA Helicases (EC 3.6.4.-) ; G3BP1 protein, human (EC 3.6.4.12) ; Poly-ADP-Ribose Binding Proteins ; RNA Helicases (EC 3.6.4.13) ; RNA Recognition Motif Proteins ; RNA, Viral ; SH2D3A protein, human
Language	English
Publishing date	2022-12-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1011041
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Human coronaviruses disassemble processing bodies.

Kleer, Mariel / Mulloy, Rory P / Robinson, Carolyn-Ann / Evseev, Danyel / Bui-Marinos, Maxwell P / Castle, Elizabeth L / Banerjee, Arinjay / Mubareka, Samira / Mossman, Karen / Corcoran, Jennifer A

PLoS pathogens

2022 Volume 18, Issue 8, Page(s) e1010724

Abstract: A dysregulated proinflammatory cytokine response is characteristic of severe coronavirus infections caused by SARS-CoV-2, yet our understanding of the underlying mechanism responsible for this imbalanced immune response remains incomplete. Processing ... ...

Abstract	A dysregulated proinflammatory cytokine response is characteristic of severe coronavirus infections caused by SARS-CoV-2, yet our understanding of the underlying mechanism responsible for this imbalanced immune response remains incomplete. Processing bodies (PBs) are cytoplasmic membraneless ribonucleoprotein granules that control innate immune responses by mediating the constitutive decay or suppression of mRNA transcripts, including many that encode proinflammatory cytokines. PB formation promotes turnover or suppression of cytokine RNAs, whereas PB disassembly corresponds with the increased stability and/or translation of these cytokine RNAs. Many viruses cause PB disassembly, an event that can be viewed as a switch that rapidly relieves cytokine RNA repression and permits the infected cell to respond to viral infection. Prior to this submission, no information was known about how human coronaviruses (CoVs) impacted PBs. Here, we show SARS-CoV-2 and the common cold CoVs, OC43 and 229E, induced PB loss. We screened a SARS-CoV-2 gene library and identified that expression of the viral nucleocapsid (N) protein from SARS-CoV-2 was sufficient to mediate PB disassembly. RNA fluorescent in situ hybridization revealed that transcripts encoding TNF and IL-6 localized to PBs in control cells. PB loss correlated with the increased cytoplasmic localization of these transcripts in SARS-CoV-2 N protein-expressing cells. Ectopic expression of the N proteins from five other human coronaviruses (OC43, MERS, 229E, NL63 and SARS-CoV) did not cause significant PB disassembly, suggesting that this feature is unique to SARS-CoV-2 N protein. These data suggest that SARS-CoV-2-mediated PB disassembly contributes to the dysregulation of proinflammatory cytokine production observed during severe SARS-CoV-2 infection.
MeSH term(s)	COVID-19 ; Coronavirus OC43, Human ; Cytokines ; Humans ; In Situ Hybridization, Fluorescence ; Processing Bodies ; RNA ; SARS-CoV-2
Chemical Substances	Cytokines ; RNA (63231-63-0)
Language	English
Publishing date	2022-08-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1010724
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Article ; Online: Nsp1 proteins of human coronaviruses HCoV-OC43 and SARS-CoV2 inhibit stress granule formation

Dolliver, Stacia M. / Kleer, Mariel / Bui-Marinos, Maxwell P. / Ying, Shan / Corcoran, Jennifer A. / Khaperskyy, Denys A.

bioRxiv

Abstract	Stress granules (SGs) are cytoplasmic condensates that often form as part of the cellular antiviral response. Despite the growing interest in understanding the interplay between SGs and other biological condensates and viral replication, the role of SG formation during coronavirus infection remains poorly understood. Several proteins from different coronaviruses have been shown to suppress SG formation upon overexpression, but there are only a handful of studies analyzing SG formation in coronavirus-infected cells. To better understand SG inhibition by coronaviruses, we analyzed SG formation during infection with the human common cold coronavirus OC43 (HCoV-OC43) and the highly pathogenic SARS-CoV2. We did not observe SG induction in infected cells and both viruses inhibited eukaryotic translation initiation factor 2α (eIF2α) phosphorylation and SG formation induced by exogenous stress (e.g. sodium arsenite treatment). Furthermore, in SARS-CoV2 infected cells we observed a sharp decrease in the levels of SG-nucleating protein G3BP1. Ectopic overexpression of nucleocapsid (N) and non-structural protein 1 (Nsp1) from both HCoV-OC43 and SARS-CoV-2 inhibited SG formation. The Nsp1 proteins of both viruses inhibited arsenite-induced eIF2α phosphorylation, and the Nsp1 of SARS-CoV2 alone was sufficient to cause decrease in G3BP1 levels. This phenotype was dependent on the depletion of cytoplasmic mRNA mediated by Nsp1 and associated with nuclear retention of the SG-nucleating protein TIAR. To test the role of G3BP1 in coronavirus replication, we infected cells overexpressing EGFP-tagged G3BP1 with HCoV-OC43 and observed a significant decrease in infection compared to control cells expressing EGFP. The antiviral role of G3BP1 and the existence of multiple SG suppression mechanisms that are conserved between HCoV-OC43 and SARS-CoV2 suggest that SG formation may represent an important antiviral host defense that coronaviruses target to ensure efficient replication.
Keywords	covid19
Language	English
Publishing date	2022-05-02
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2022.05.02.490272
Database	COVID19

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Article ; Online: Stress Granule-Inducing Eukaryotic Translation Initiation Factor 4A Inhibitors Block Influenza A Virus Replication.

Slaine, Patrick D / Kleer, Mariel / Smith, Nathan K / Khaperskyy, Denys A / McCormick, Craig

Viruses

2017 Volume 9, Issue 12

Abstract: Eukaryotic translation initiation factor 4A (eIF4A) is a helicase that facilitates assembly of the translation preinitiation complex by unwinding structured mRNA 5' untranslated regions. Pateamine A (PatA) and silvestrol are natural products that disrupt ...

Abstract	Eukaryotic translation initiation factor 4A (eIF4A) is a helicase that facilitates assembly of the translation preinitiation complex by unwinding structured mRNA 5' untranslated regions. Pateamine A (PatA) and silvestrol are natural products that disrupt eIF4A function and arrest translation, thereby triggering the formation of cytoplasmic aggregates of stalled preinitiation complexes known as stress granules (SGs). Here we examined the effects of eIF4A inhibition by PatA and silvestrol on influenza A virus (IAV) protein synthesis and replication in cell culture. Treatment of infected cells with either PatA or silvestrol at early times post-infection resulted in SG formation, arrest of viral protein synthesis and failure to replicate the viral genome. PatA, which irreversibly binds to eIF4A, sustained long-term blockade of IAV replication following drug withdrawal, and inhibited IAV replication at concentrations that had minimal cytotoxicity. By contrast, the antiviral effects of silvestrol were fully reversible; drug withdrawal caused rapid SG dissolution and resumption of viral protein synthesis. IAV inhibition by silvestrol was invariably associated with cytotoxicity. PatA blocked replication of genetically divergent IAV strains, suggesting common dependence on host eIF4A activity. This study demonstrates that the core host protein synthesis machinery can be targeted to block viral replication.
MeSH term(s)	A549 Cells ; Antiviral Agents/metabolism ; Enzyme Inhibitors/metabolism ; Epoxy Compounds/metabolism ; Eukaryotic Initiation Factor-4A/antagonists & inhibitors ; Humans ; Influenza A virus/physiology ; Macrolides/metabolism ; Protein Biosynthesis/drug effects ; Thiazoles/metabolism ; Triterpenes/metabolism ; Virus Replication/drug effects
Chemical Substances	Antiviral Agents ; Enzyme Inhibitors ; Epoxy Compounds ; Macrolides ; Thiazoles ; Triterpenes ; pateamine A ; silvestrol ; Eukaryotic Initiation Factor-4A (EC 2.7.7.-)
Language	English
Publishing date	2017--18
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v9120388
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Article ; Online: Thiopurines activate an antiviral unfolded protein response that blocks influenza A virus glycoprotein accumulation.

Slaine, Patrick D / Kleer, Mariel / Duguay, Brett A / Pringle, Eric S / Kadijk, Eileigh / Ying, Shan / Balgi, Aruna / Roberge, Michel / McCormick, Craig / Khaperskyy, Denys A

Journal of virology

2021 Volume 95, Issue 11

Abstract: Influenza A viruses (IAVs) utilize host shutoff mechanisms to limit antiviral gene expression and redirect translation machinery to the synthesis of viral proteins. Previously, we showed that IAV replication is sensitive to protein synthesis inhibitors ... ...

Abstract	Influenza A viruses (IAVs) utilize host shutoff mechanisms to limit antiviral gene expression and redirect translation machinery to the synthesis of viral proteins. Previously, we showed that IAV replication is sensitive to protein synthesis inhibitors that block translation initiation and induce formation of cytoplasmic condensates of untranslated messenger ribonucleoprotein complexes called stress granules (SGs). In this study, using an image-based high-content screen, we identified two thiopurines, 6-thioguanine (6-TG) and 6-thioguanosine (6-TGo), that triggered SG formation in IAV-infected cells and blocked IAV replication in a dose-dependent manner without eliciting SG formation in uninfected cells. 6-TG and 6-TGo selectively disrupted the synthesis and maturation of IAV glycoproteins hemagglutinin (HA) and neuraminidase (NA) without affecting the levels of the viral RNAs that encode them. By contrast, these thiopurines had minimal effect on other IAV proteins or the global host protein synthesis. Disruption of IAV glycoprotein accumulation by 6-TG and 6-TGo correlated with activation of unfolded protein response (UPR) sensors activating transcription factor-6 (ATF6), inositol requiring enzyme-1 (IRE1) and PKR-like endoplasmic reticulum kinase (PERK), leading to downstream UPR gene expression. Treatment of infected cells with the chemical chaperone 4-phenylbutyric acid diminished thiopurine-induced UPR activation and partially restored the processing and accumulation of HA and NA. By contrast, chemical inhibition of the integrated stress response downstream of PERK restored accumulation of NA monomers but did not restore processing of viral glycoproteins. Genetic deletion of PERK enhanced the antiviral effect of 6-TG without causing overt cytotoxicity, suggesting that while UPR activation correlates with diminished viral glycoprotein accumulation, PERK could limit the antiviral effects of drug-induced ER stress. Taken together, these data indicate that 6-TG and 6-TGo are effective host-targeted antivirals that trigger the UPR and selectively disrupt accumulation of viral glycoproteins.
Language	English
Publishing date	2021-03-24
Publishing country	United States
Document type	Journal Article
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.00453-21
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Article ; Online: Human coronaviruses disassemble processing bodies

Robinson, Carolyn-Ann / Kleer, Mariel / Mulloy, Rory P. / Castle, Elizabeth L. / Boudreau, Bre Q. / Corcoran, Jennifer A.

bioRxiv

Abstract: The Coronaviridae are a family of viruses with large RNA genomes. Seven coronaviruses (CoVs) have been shown to infect humans, including the recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease ... ...

Abstract	The Coronaviridae are a family of viruses with large RNA genomes. Seven coronaviruses (CoVs) have been shown to infect humans, including the recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease of 2019 (COVID-19). The host response to CoV infection is complex and regulated, in part, by intracellular antiviral signaling pathways triggered in the first cells that are infected. Emerging evidence suggests that CoVs hijack these antiviral responses to reshape the production of interferons and proinflammatory cytokines. Processing bodies (PBs) are membraneless ribonucleoprotein granules that mediate decay or translational suppression of cellular mRNAs; this is particularly relevant for proinflammatory cytokine mRNA which normally reside in PBs and are repressed. Emerging evidence also suggests that PBs or their components play important direct-acting antiviral roles, providing a compelling reason for their frequent disassembly by many viruses. No information is known about how human CoVs impact PBs. Here, we provide data to show that infection with the human CoV, OC43, causes PB disassembly. Moreover, we show that several SARS-CoV-2 gene products also mediate PB loss and virus-induced PB loss correlates with elevated levels of proinflammatory cytokine mRNAs that would normally be repressed in PBs. Finally, we demonstrate that stimulating PB formation prior to OC43 infection restricts viral replication. These data suggest that SARS-CoV-2 and other CoVs disassemble PBs during infection to support viral replication and evade innate immune responses. As an unintended side effect, the disassembly of PBs enhances translation of proinflammatory cytokine mRNAs which normally reside in PBs, thereby reshaping the subsequent immune response.
Keywords	covid19
Publisher	BioRxiv; WHO
Document type	Article ; Online
DOI	10.1101/2020.11.08.372995
Database	COVID19

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Article ; Online: Human coronaviruses disassemble processing bodies

Robinson, Carolyn-Ann / Kleer, Mariel / Mulloy, Rory P. / Castle, Elizabeth L. / Boudreau, Bre Q. / Corcoran, Jennifer A.

bioRxiv

Abstract	The Coronaviridae are a family of viruses with large RNA genomes. Seven coronaviruses (CoVs) have been shown to infect humans, including the recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease of 2019 (COVID-19). The host response to CoV infection is complex and regulated, in part, by intracellular antiviral signaling pathways triggered in the first cells that are infected. Emerging evidence suggests that CoVs hijack these antiviral responses to reshape the production of interferons and proinflammatory cytokines. Processing bodies (PBs) are membraneless ribonucleoprotein granules that mediate decay or translational suppression of cellular mRNAs; this is particularly relevant for proinflammatory cytokine mRNA which normally reside in PBs and are repressed. Emerging evidence also suggests that PBs or their components play important direct-acting antiviral roles, providing a compelling reason for their frequent disassembly by many viruses. No information is known about how human CoVs impact PBs. Here, we provide data to show that infection with the human CoV, OC43, causes PB disassembly. Moreover, we show that several SARS-CoV-2 gene products also mediate PB loss and virus-induced PB loss correlates with elevated levels of proinflammatory cytokine mRNAs that would normally be repressed in PBs. Finally, we demonstrate that stimulating PB formation prior to OC43 infection restricts viral replication. These data suggest that SARS-CoV-2 and other CoVs disassemble PBs during infection to support viral replication and evade innate immune responses. As an unintended side effect, the disassembly of PBs enhances translation of proinflammatory cytokine mRNAs which normally reside in PBs, thereby reshaping the subsequent immune response.
Keywords	covid19
Language	English
Publishing date	2020-11-09
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2020.11.08.372995
Database	COVID19

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Article ; Online: Adaptive Mutations in Influenza A/California/07/2009 Enhance Polymerase Activity and Infectious Virion Production.

Slaine, Patrick D / MacRae, Cara / Kleer, Mariel / Lamoureux, Emily / McAlpine, Sarah / Warhuus, Michelle / Comeau, André M / McCormick, Craig / Hatchette, Todd / Khaperskyy, Denys A

Viruses

2018 Volume 10, Issue 5

Abstract: Mice are not natural hosts for influenza A viruses (IAVs), but they are useful models for studying antiviral immune responses and pathogenesis. Serial passage of IAV in mice invariably causes the emergence of adaptive mutations and increased virulence. ... ...

Abstract	Mice are not natural hosts for influenza A viruses (IAVs), but they are useful models for studying antiviral immune responses and pathogenesis. Serial passage of IAV in mice invariably causes the emergence of adaptive mutations and increased virulence. Here, we report the adaptation of IAV reference strain A/California/07/2009(H1N1) (also known as CA/07) in outbred Swiss Webster mice. Serial passage led to increased virulence and lung titers, and dissemination of the virus to brains. We adapted a deep-sequencing protocol to identify and enumerate adaptive mutations across all genome segments. Among mutations that emerged during mouse-adaptation, we focused on amino acid substitutions in polymerase subunits: polymerase basic-1 (PB1) T156A and F740L and polymerase acidic (PA) E349G. These mutations were evaluated singly and in combination in minigenome replicon assays, which revealed that PA E349G increased polymerase activity. By selectively engineering three PB1 and PA mutations into the parental CA/07 strain, we demonstrated that these mutations in polymerase subunits decreased the production of defective viral genome segments with internal deletions and dramatically increased the release of infectious virions from mouse cells. Together, these findings increase our understanding of the contribution of polymerase subunits to successful host adaptation.
MeSH term(s)	Adaptation, Physiological/genetics ; Amino Acid Substitution ; Animals ; Animals, Outbred Strains ; Cells, Cultured ; Disease Models, Animal ; Dogs ; Female ; Genome, Viral ; Humans ; Influenza A Virus, H1N1 Subtype/enzymology ; Influenza A Virus, H1N1 Subtype/genetics ; Influenza A Virus, H1N1 Subtype/pathogenicity ; Influenza A Virus, H1N1 Subtype/physiology ; Influenza, Human/virology ; Mice ; Mutation, Missense ; Protein Conformation ; RNA-Dependent RNA Polymerase/chemistry ; RNA-Dependent RNA Polymerase/genetics ; RNA-Dependent RNA Polymerase/metabolism ; Serial Passage ; Viral Proteins/chemistry ; Viral Proteins/genetics ; Viral Proteins/metabolism ; Virion/metabolism ; Virulence ; Virus Replication
Chemical Substances	Viral Proteins ; RNA-Dependent RNA Polymerase (EC 2.7.7.48)
Language	English
Publishing date	2018-05-18
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v10050272
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