Nipah virus (NiV) is a highly pathogenic paramyxovirus causing frequently lethal encephalitis in humans. The NiV genome is encapsidated by the nucleocapsid (N) protein. RNA synthesis is mediated by the viral RNA-dependent RNA polymerase (RdRP), consisting of the polymerase (L) protein complexed with the homo-tetrameric phosphoprotein (P). The advance of the polymerase along its template requires iterative dissolution and reformation of transient interactions between P and N protomers in a highly regulated process that remains poorly understood. This study applied functional and biochemical NiV polymerase assays to the problem. We mapped three distinct protein interfaces on the C-terminal P-X domain (P-XD), which form a triangular prism and engage L, the C-terminal N tail, and the globular N core, respectively. Transcomplementation assays using NiV L and N-tail binding-deficient mutants revealed that only one XD of a P tetramer binds to L, whereas three must be available for N-binding for efficient polymerase activity. The dissolution of the N-tail complex with P-XD was coordinated by a transient interaction between N-core and the α-1/2 face of this XD but not unoccupied XDs of the P tetramer, creating a timer for coordinated polymerase advance.
Importance: Mononegaviruses comprise major human pathogens such as the Ebola virus, rabies virus, respiratory syncytial virus, measles virus, and Nipah virus (NiV). For replication and transcription, their polymerase complexes must negotiate a protein-encapsidated RNA genome, which requires the highly coordinated continuous formation and resolution of protein-protein interfaces as the polymerase advances along the template. The viral P protein assumes a central role in this process, but the molecular mechanism of ensuring polymerase mobility is poorly understood. Studying NiV polymerase complexes, we applied functional and biochemical assays to map three distinct interfaces in the NiV P XD and identified transient interactions between XD and the nucleocapsid core as instrumental in coordinating polymerase advance. These results define a conserved molecular principle regulating paramyxovirus polymerase dynamics and illuminate a promising druggable target for the structure-guided development of broad-spectrum polymerase inhibitors.
尼帕病毒(NiV)是一种高致病性副黏液病毒,经常导致人类患上致命的脑炎。NiV 基因组由核壳蛋白(N)封装。RNA 合成由病毒 RNA 依赖性 RNA 聚合酶(RdRP)介导,RdRP 由聚合酶(L)蛋白与同型四聚体磷蛋白(P)复合物组成。聚合酶沿着模板前进需要 P 和 N 原体之间瞬时相互作用的反复溶解和重组,这一过程受到高度调控,但人们对这一过程仍然知之甚少。本研究应用功能和生化 NiV 聚合酶测定法来解决这一问题。我们在 C 端 P-X 结构域(P-XD)上绘制了三个不同的蛋白质界面,它们形成一个三角形棱柱,分别与 L、C 端 N 尾部和球状 N 核心接触。利用 NiV L 和 N-尾结合缺陷突变体进行的转补试验表明,P 四聚体中只有一个 XD 与 L 结合,而要实现高效的聚合酶活性,必须有三个 XD 与 N 结合。N-尾与P-XD复合物的溶解是通过N-核与该XD的α-1/2面而不是P四聚体未占据的XD之间的瞬时相互作用来协调的,这为聚合酶的协调推进创造了一个计时器:单核病毒包括埃博拉病毒、狂犬病病毒、呼吸道合胞病毒、麻疹病毒和尼帕病毒(NiV)等主要人类病原体。为了进行复制和转录,它们的聚合酶复合物必须与蛋白质包被的 RNA 基因组进行协商,这就要求聚合酶沿着模板前进时高度协调地不断形成和解决蛋白质与蛋白质之间的界面。病毒 P 蛋白在这一过程中发挥着核心作用,但确保聚合酶流动性的分子机制却鲜为人知。在研究NiV聚合酶复合物时,我们应用功能和生化检测方法绘制了NiV P XD的三个不同界面,并确定了XD与核壳核心之间的瞬时相互作用有助于协调聚合酶的前进。这些结果确定了调控副粘病毒聚合酶动力学的保守分子原理,并为以结构为导向开发广谱聚合酶抑制剂提供了一个有希望的药物靶点。
{"title":"A three-way interface of the Nipah virus phosphoprotein X-domain coordinates polymerase movement along the viral genome.","authors":"Josef D Wolf, Richard K Plemper","doi":"10.1128/jvi.00986-24","DOIUrl":"https://doi.org/10.1128/jvi.00986-24","url":null,"abstract":"<p><p>Nipah virus (NiV) is a highly pathogenic paramyxovirus causing frequently lethal encephalitis in humans. The NiV genome is encapsidated by the nucleocapsid (N) protein. RNA synthesis is mediated by the viral RNA-dependent RNA polymerase (RdRP), consisting of the polymerase (L) protein complexed with the homo-tetrameric phosphoprotein (P). The advance of the polymerase along its template requires iterative dissolution and reformation of transient interactions between P and N protomers in a highly regulated process that remains poorly understood. This study applied functional and biochemical NiV polymerase assays to the problem. We mapped three distinct protein interfaces on the C-terminal P-X domain (P-XD), which form a triangular prism and engage L, the C-terminal N tail, and the globular N core, respectively. Transcomplementation assays using NiV L and N-tail binding-deficient mutants revealed that only one XD of a P tetramer binds to L, whereas three must be available for N-binding for efficient polymerase activity. The dissolution of the N-tail complex with P-XD was coordinated by a transient interaction between N-core and the α-1/2 face of this XD but not unoccupied XDs of the <i>P</i> tetramer, creating a timer for coordinated polymerase advance.</p><p><strong>Importance: </strong>Mononegaviruses comprise major human pathogens such as the Ebola virus, rabies virus, respiratory syncytial virus, measles virus, and Nipah virus (NiV). For replication and transcription, their polymerase complexes must negotiate a protein-encapsidated RNA genome, which requires the highly coordinated continuous formation and resolution of protein-protein interfaces as the polymerase advances along the template. The viral P protein assumes a central role in this process, but the molecular mechanism of ensuring polymerase mobility is poorly understood. Studying NiV polymerase complexes, we applied functional and biochemical assays to map three distinct interfaces in the NiV P XD and identified transient interactions between XD and the nucleocapsid core as instrumental in coordinating polymerase advance. These results define a conserved molecular principle regulating paramyxovirus polymerase dynamics and illuminate a promising druggable target for the structure-guided development of broad-spectrum polymerase inhibitors.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142126089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Weiying Zhang, Tricia L Nilles, Jay H Bream, Huifen Li, Eslam Malash, Susan Langan, Sean X Leng, Joseph B Margolick
Cytomegalovirus (CMV)-seropositive adults have large T cell responses to a wide range of CMV proteins; these responses have been associated with chronic inflammation and frailty in people with or without HIV infection. We analyzed the relationships between chronic HIV infection, frailty, and the breadth and polyfunctionality of CD4 and CD8 T cell responses to CMV. Peripheral blood mononuclear cells from 42 men (20 without HIV and 22 with virologically suppressed HIV) in the Multicenter AIDS Cohort Study (MACS) were stimulated with peptide pools spanning 19 CMV open reading frames (ORFs). As measured by flow cytometry and intracellular cytokine staining for IFN-γ, TNF-α, and IL-2, CD8 T cells from men with HIV responded to significantly more CMV ORFs than those from men without HIV. This was primarily due to a broader response to ORFs that are expressed during the late phase of CMV replication. The number of ORFs to which a participant's T cells responded was positively correlated with the sum of all that individual's T cell responses; these correlations were weaker in men with than without HIV. Polyfunctional CMV-specific CD4 responses (production of more than one cytokine) were significantly lower in men with than without HIV. Frailty status did not substantially affect the breadth or magnitude of the CMV-specific T cell responses. These results suggest that immune control of CMV infection is affected more by chronic HIV infection than by frailty. The differences between men with and without HIV were similar to those reported between young and older adults without HIV.
Importance: T cell responses to chronic cytomegalovirus (CMV) infection have significant biological and clinical implications in HIV infection and aging. Here, we systematically analyzed the breadth, magnitude, and polyfunctionality of T cell responses to multiple CMV antigens in men with and without HIV in the Multicenter AIDS Cohort Study (MACS), a longstanding study of the natural and treated history of HIV-1 infection in men who have sex with men. We found that the breadth and polyfunctionality of T cell responses to CMV were different between men with chronic, treated HIV and those without HIV. The reason for these differences is unknown, but these findings suggest that people with treated HIV may have more frequent CMV reactivation than people without HIV. Differences between people with and without HIV also resembled differences reported between young and older adults without HIV, supporting a role for the immune responses to CMV in the aging process.
巨细胞病毒(CMV)血清反应阳性的成年人会对多种 CMV 蛋白产生大量 T 细胞反应;这些反应与感染或未感染 HIV 的人的慢性炎症和虚弱有关。我们分析了慢性 HIV 感染、虚弱与 CD4 和 CD8 T 细胞对 CMV 反应的广度和多功能性之间的关系。我们用跨越 19 个 CMV 开放阅读框 (ORF) 的肽池刺激了多中心艾滋病队列研究 (MACS) 中 42 名男性(20 人未感染 HIV,22 人感染了病毒学抑制的 HIV)的外周血单核细胞。通过流式细胞术和细胞内 IFN-γ、TNF-α、IL-2 等细胞因子染色测量,感染 HIV 的男性 CD8 T 细胞对 CMV ORFs 的反应明显多于未感染 HIV 的男性 CD8 T 细胞。这主要是由于对 CMV 复制晚期表达的 ORF 的反应更广泛。受试者的 T 细胞对 ORFs 的反应数量与该受试者所有 T 细胞反应的总和呈正相关;在感染 HIV 的男性中,这种相关性比未感染 HIV 的男性弱。CMV特异性CD4多功能反应(产生一种以上的细胞因子)在感染艾滋病毒的男性中明显低于未感染艾滋病毒的男性。虚弱状态对CMV特异性T细胞反应的广度和强度没有实质性影响。这些结果表明,CMV 感染的免疫控制受慢性 HIV 感染的影响比受体弱的影响更大。感染艾滋病毒和未感染艾滋病毒的男性之间的差异与未感染艾滋病毒的年轻人和老年人之间的差异相似:T细胞对慢性巨细胞病毒(CMV)感染的反应对HIV感染和衰老具有重要的生物学和临床意义。在此,我们系统分析了多中心艾滋病队列研究(MACS)中感染和未感染 HIV 的男性对多种 CMV 抗原的 T 细胞反应的广度、强度和多功能性,MACS 是一项长期研究男男性行为者 HIV-1 感染自然史和治疗史的研究。我们发现,慢性、接受过治疗的 HIV 感染者与未感染 HIV 的男性之间对 CMV 的 T 细胞反应在广度和多功能性上存在差异。造成这些差异的原因尚不清楚,但这些发现表明,接受过治疗的 HIV 感染者可能比未感染 HIV 的人更容易再次感染 CMV。艾滋病病毒感染者和非艾滋病病毒感染者之间的差异也类似于未感染艾滋病病毒的年轻人和老年人之间的差异,这支持了CMV免疫反应在衰老过程中的作用。
{"title":"Breadth and polyfunctionality of T cell responses to human cytomegalovirus in men who have sex with men: relationship with HIV infection and frailty.","authors":"Weiying Zhang, Tricia L Nilles, Jay H Bream, Huifen Li, Eslam Malash, Susan Langan, Sean X Leng, Joseph B Margolick","doi":"10.1128/jvi.01167-24","DOIUrl":"https://doi.org/10.1128/jvi.01167-24","url":null,"abstract":"<p><p>Cytomegalovirus (CMV)-seropositive adults have large T cell responses to a wide range of CMV proteins; these responses have been associated with chronic inflammation and frailty in people with or without HIV infection. We analyzed the relationships between chronic HIV infection, frailty, and the breadth and polyfunctionality of CD4 and CD8 T cell responses to CMV. Peripheral blood mononuclear cells from 42 men (20 without HIV and 22 with virologically suppressed HIV) in the Multicenter AIDS Cohort Study (MACS) were stimulated with peptide pools spanning 19 CMV open reading frames (ORFs). As measured by flow cytometry and intracellular cytokine staining for IFN-γ, TNF-α, and IL-2, CD8 T cells from men with HIV responded to significantly more CMV ORFs than those from men without HIV. This was primarily due to a broader response to ORFs that are expressed during the late phase of CMV replication. The number of ORFs to which a participant's T cells responded was positively correlated with the sum of all that individual's T cell responses; these correlations were weaker in men with than without HIV. Polyfunctional CMV-specific CD4 responses (production of more than one cytokine) were significantly lower in men with than without HIV. Frailty status did not substantially affect the breadth or magnitude of the CMV-specific T cell responses. These results suggest that immune control of CMV infection is affected more by chronic HIV infection than by frailty. The differences between men with and without HIV were similar to those reported between young and older adults without HIV.</p><p><strong>Importance: </strong>T cell responses to chronic cytomegalovirus (CMV) infection have significant biological and clinical implications in HIV infection and aging. Here, we systematically analyzed the breadth, magnitude, and polyfunctionality of T cell responses to multiple CMV antigens in men with and without HIV in the Multicenter AIDS Cohort Study (MACS), a longstanding study of the natural and treated history of HIV-1 infection in men who have sex with men. We found that the breadth and polyfunctionality of T cell responses to CMV were different between men with chronic, treated HIV and those without HIV. The reason for these differences is unknown, but these findings suggest that people with treated HIV may have more frequent CMV reactivation than people without HIV. Differences between people with and without HIV also resembled differences reported between young and older adults without HIV, supporting a role for the immune responses to CMV in the aging process.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142126090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Isabella L M Aquino, Erik Sousa Reis, Rafaella Oliveira Almeida Mattos Moreira, Nídia Esther Colquehuanca Arias, Matheus Gomes Barcelos, Victória Fulgêncio Queiroz, Raquel Duque do Nascimento Arifa, Larissa Mendes Barbosa Lucas, Juliana Miranda Tatara, Daniele G Souza, Adriana Costa, Luiz Rosa, Gabriel M F Almeida, Erna Geessien Kroon, Jônatas S Abrahão
In the context of the virosphere, viral particles can compete for host cells. In this scenario, some viruses block the entry of exogenous virions upon infecting a cell, a phenomenon known as superinfection inhibition. The molecular mechanisms associated with superinfection inhibition vary depending on the viral species and the host, but generally, blocking superinfection ensures the genetic supremacy of the virus's progeny that first infects the cell. Giant amoeba-infecting viruses have attracted the scientific community's attention due to the complexity of their particles and genomes. However, there are no studies on the occurrence of superinfection and its inhibition induced by giant viruses. This study shows that mimivirus, moumouvirus, and megavirus, exhibit different strategies related to the infection of Acanthamoeba. For the first time, we have reported that mimivirus and moumouvirus induce superinfection inhibition in amoebas. Interestingly, megaviruses do not exhibit this ability, allowing continuous entry of exogenous virions into infected amoebas. Our investigation into the mechanisms behind superinfection blockage reveals that mimivirus and moumouvirus inhibit amoebic phagocytosis, leading to significant changes in the morphology and activity of the host cells. In contrast, megavirus-infected amoebas continue incorporating newly formed virions, negatively affecting the available viral progeny. This effect, however, is reversible with chemical inhibition of phagocytosis. This work contributes to the understanding of superinfection and its inhibition in mimivirus, moumouvirus, and megavirus, demonstrating that despite their evolutionary relatedness, these viruses exhibit profound differences in their interactions with their hosts.IMPORTANCESome viruses block the entry of new virions upon infecting a cell, a phenomenon known as superinfection inhibition. Superinfection inhibition in giant viruses has yet to be studied. This study reveals that even closely related viruses, such as mimivirus, moumouvirus, and megavirus, have different infection strategies for Acanthamoeba. For the first time, we have reported that mimivirus and moumouvirus induce superinfection inhibition in amoebas. In contrast, megaviruses do not exhibit this ability, allowing continuous entry of exogenous virions into infected amoebas. Our investigation shows that mimivirus and moumouvirus inhibit amoebic phagocytosis, causing significant changes in host cell morphology and activity. Megavirus-infected amoebas, however, continue incorporating newly formed viruses, affecting viral progeny. This research enhances our understanding of superinfection inhibition in these viruses, highlighting their differences in host interactions.
{"title":"Giant viruses inhibit superinfection by downregulating phagocytosis in <i>Acanthamoeba</i>.","authors":"Isabella L M Aquino, Erik Sousa Reis, Rafaella Oliveira Almeida Mattos Moreira, Nídia Esther Colquehuanca Arias, Matheus Gomes Barcelos, Victória Fulgêncio Queiroz, Raquel Duque do Nascimento Arifa, Larissa Mendes Barbosa Lucas, Juliana Miranda Tatara, Daniele G Souza, Adriana Costa, Luiz Rosa, Gabriel M F Almeida, Erna Geessien Kroon, Jônatas S Abrahão","doi":"10.1128/jvi.01045-24","DOIUrl":"https://doi.org/10.1128/jvi.01045-24","url":null,"abstract":"<p><p>In the context of the virosphere, viral particles can compete for host cells. In this scenario, some viruses block the entry of exogenous virions upon infecting a cell, a phenomenon known as superinfection inhibition. The molecular mechanisms associated with superinfection inhibition vary depending on the viral species and the host, but generally, blocking superinfection ensures the genetic supremacy of the virus's progeny that first infects the cell. Giant amoeba-infecting viruses have attracted the scientific community's attention due to the complexity of their particles and genomes. However, there are no studies on the occurrence of superinfection and its inhibition induced by giant viruses. This study shows that mimivirus, moumouvirus, and megavirus, exhibit different strategies related to the infection of <i>Acanthamoeba</i>. For the first time, we have reported that mimivirus and moumouvirus induce superinfection inhibition in amoebas. Interestingly, megaviruses do not exhibit this ability, allowing continuous entry of exogenous virions into infected amoebas. Our investigation into the mechanisms behind superinfection blockage reveals that mimivirus and moumouvirus inhibit amoebic phagocytosis, leading to significant changes in the morphology and activity of the host cells. In contrast, megavirus-infected amoebas continue incorporating newly formed virions, negatively affecting the available viral progeny. This effect, however, is reversible with chemical inhibition of phagocytosis. This work contributes to the understanding of superinfection and its inhibition in mimivirus, moumouvirus, and megavirus, demonstrating that despite their evolutionary relatedness, these viruses exhibit profound differences in their interactions with their hosts.IMPORTANCESome viruses block the entry of new virions upon infecting a cell, a phenomenon known as superinfection inhibition. Superinfection inhibition in giant viruses has yet to be studied. This study reveals that even closely related viruses, such as mimivirus, moumouvirus, and megavirus, have different infection strategies for <i>Acanthamoeba</i>. For the first time, we have reported that mimivirus and moumouvirus induce superinfection inhibition in amoebas. In contrast, megaviruses do not exhibit this ability, allowing continuous entry of exogenous virions into infected amoebas. Our investigation shows that mimivirus and moumouvirus inhibit amoebic phagocytosis, causing significant changes in host cell morphology and activity. Megavirus-infected amoebas, however, continue incorporating newly formed viruses, affecting viral progeny. This research enhances our understanding of superinfection inhibition in these viruses, highlighting their differences in host interactions.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142120157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Minhui Guan, Thomas J DeLiberto, Aijing Feng, Jieze Zhang, Tao Li, Shuaishuai Wang, Lei Li, Mary Lea Killian, Beatriz Praena, Emily Giri, Shelagh T Deliberto, Jun Hang, Alicia Olivier, Mia Kim Torchetti, Yizhi Jane Tao, Colin Parrish, Xiu-Feng Wan
Between 2013 and 2018, the novel A/Anhui/1/2013 (AH/13)-lineage H7N9 virus caused at least five waves of outbreaks in humans, totaling 1,567 confirmed human cases in China. Surveillance data indicated a disproportionate distribution of poultry infected with this AH/13-lineage virus, and laboratory experiments demonstrated that this virus can efficiently spread among chickens but not among Pekin ducks. The underlying mechanism of this selective transmission remains unclear. In this study, we demonstrated the absence of Neu5Gc expression in chickens across all respiratory and gastrointestinal tissues. However, Neu5Gc expression varied among different duck species and even within the tissues of the same species. The AH/13-lineage viruses exclusively bind to acetylneuraminic acid (Neu5Ac), in contrast to wild waterbird H7 viruses that bind both Neu5Ac and N-glycolylneuraminic acid (Neu5Gc). The level of Neu5Gc expression influences H7 virus replication and facilitates adaptive mutations in these viruses. In summary, our findings highlight the critical role of Neu5Gc in affecting the host range and interspecies transmission dynamics of H7 viruses among avian species.IMPORTANCEMigratory waterfowl, gulls, and shorebirds are natural reservoirs for influenza A viruses (IAVs) that can occasionally spill over to domestic poultry, and ultimately humans. This study showed wild-type H7 IAVs from waterbirds initially bind to glycan receptors terminated with N-acetylneuraminic acid (Neu5Ac) or N-glycolylneuraminic acid (Neu5Gc). However, after enzootic transmission in chickens, the viruses exclusively bind to Neu5Ac. The absence of Neu5Gc expression in gallinaceous poultry, particularly chickens, exerts selective pressure, shaping IAV populations, and promoting the acquisition of adaptive amino acid substitutions in the hemagglutinin protein. This results in the loss of Neu5Gc binding and an increase in virus transmissibility in gallinaceous poultry, particularly chickens. Consequently, the transmission capability of these poultry-adapted H7 IAVs in wild water birds decreases. Timely intervention, such as stamping out, may help reduce virus adaptation to domestic chicken populations and lower the risk of enzootic outbreaks, including those caused by IAVs exhibiting high pathogenicity.
{"title":"Neu5Gc binding loss of subtype H7 influenza A virus facilitates adaptation to gallinaceous poultry following transmission from waterbirds.","authors":"Minhui Guan, Thomas J DeLiberto, Aijing Feng, Jieze Zhang, Tao Li, Shuaishuai Wang, Lei Li, Mary Lea Killian, Beatriz Praena, Emily Giri, Shelagh T Deliberto, Jun Hang, Alicia Olivier, Mia Kim Torchetti, Yizhi Jane Tao, Colin Parrish, Xiu-Feng Wan","doi":"10.1128/jvi.00119-24","DOIUrl":"https://doi.org/10.1128/jvi.00119-24","url":null,"abstract":"<p><p>Between 2013 and 2018, the novel A/Anhui/1/2013 (AH/13)-lineage H7N9 virus caused at least five waves of outbreaks in humans, totaling 1,567 confirmed human cases in China. Surveillance data indicated a disproportionate distribution of poultry infected with this AH/13-lineage virus, and laboratory experiments demonstrated that this virus can efficiently spread among chickens but not among Pekin ducks. The underlying mechanism of this selective transmission remains unclear. In this study, we demonstrated the absence of Neu5Gc expression in chickens across all respiratory and gastrointestinal tissues. However, Neu5Gc expression varied among different duck species and even within the tissues of the same species. The AH/13-lineage viruses exclusively bind to acetylneuraminic acid (Neu5Ac), in contrast to wild waterbird H7 viruses that bind both Neu5Ac and N-glycolylneuraminic acid (Neu5Gc). The level of Neu5Gc expression influences H7 virus replication and facilitates adaptive mutations in these viruses. In summary, our findings highlight the critical role of Neu5Gc in affecting the host range and interspecies transmission dynamics of H7 viruses among avian species.IMPORTANCEMigratory waterfowl, gulls, and shorebirds are natural reservoirs for influenza A viruses (IAVs) that can occasionally spill over to domestic poultry, and ultimately humans. This study showed wild-type H7 IAVs from waterbirds initially bind to glycan receptors terminated with N-acetylneuraminic acid (Neu5Ac) or N-glycolylneuraminic acid (Neu5Gc). However, after enzootic transmission in chickens, the viruses exclusively bind to Neu5Ac. The absence of Neu5Gc expression in gallinaceous poultry, particularly chickens, exerts selective pressure, shaping IAV populations, and promoting the acquisition of adaptive amino acid substitutions in the hemagglutinin protein. This results in the loss of Neu5Gc binding and an increase in virus transmissibility in gallinaceous poultry, particularly chickens. Consequently, the transmission capability of these poultry-adapted H7 IAVs in wild water birds decreases. Timely intervention, such as stamping out, may help reduce virus adaptation to domestic chicken populations and lower the risk of enzootic outbreaks, including those caused by IAVs exhibiting high pathogenicity.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142120158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gang Lu, Zhuang-Xin Ye, Yu-Hua Qi, Jia-Bao Lu, Qian-Zhuo Mao, Ji-Chong Zhuo, Hai-Jian Huang, Yu-Juan He, Yi-Yuan Li, Zhong-Tian Xu, Jian-Ping Chen, Chuan-Xi Zhang, Jun-Min Li
Negevirus is a recently proposed taxon of arthropod-infecting virus, which is associated with plant viruses of two families (Virgaviridae and Kitaviridae). Nevertheless, the evolutionary history of negevirus-host and its relationship with plant viruses remain poorly understood. Endogenous nege-like viral elements (ENVEs) are ancient nege-like viral sequences integrated into the arthropod genomes, which can serve as the molecular fossil records of previous viral infection. In this study, 292 ENVEs were identified in 150 published arthropod genomes, revealing the evolutionary history of nege-like viruses and two related plant virus families. We discovered three novel and eight strains of nege-like viruses in 11 aphid species. Further analysis indicated that 10 ENVEs were detected in six aphid genomes, and they were divided into four types (ENVE1-ENVE4). Orthologous integration and phylogenetic analyses revealed that nege-like viruses had a history of infection of over 60 My and coexisted with aphid ancestors throughout the Cenozoic Era. Moreover, two nege-like viral proteins (CP and SP24) were highly homologous to those of plant viruses in the families Virgaviridae and Kitaviridae. CP- and SP24-derived ENVEs were widely integrated into numerous arthropod genomes. These results demonstrate that nege-like viruses have a long-term coexistence with arthropod hosts and plant viruses of the two families, Virgaviridae and Kitaviridae, which may have evolved from the nege-like virus ancestor through horizontal virus transfer events. These findings broaden our perspective on the history of viral infection in arthropods and the origins of plant viruses.
Importance: Although negevirus is phylogenetically related to plant virus, the evolutionary history of negevirus-host and its relationship with plant virus remain largely unknown. In this study, we used endogenous nege-like viral elements (ENVEs) as the molecular fossil records to investigate the history of nege-like viral infection in arthropod hosts and the evolution of two related plant virus families (Virgaviridae and Kitaviridae). Our results showed the infection of nege-like viruses for over 60 My during the arthropod evolution. ENVEs highly homologous to viral sequences in Virgaviridae and Kitaviridae were present in a wide range of arthropod genomes but were absent in plant genomes, indicating that plant viruses in these two families possibly evolved from the nege-like virus ancestor through cross-species horizontal virus transmission. Our findings provide a new perspective on the virus-host coevolution and the origins of plant viruses.
{"title":"Endogenous nege-like viral elements in arthropod genomes reveal virus-host coevolution and ancient history of two plant virus families.","authors":"Gang Lu, Zhuang-Xin Ye, Yu-Hua Qi, Jia-Bao Lu, Qian-Zhuo Mao, Ji-Chong Zhuo, Hai-Jian Huang, Yu-Juan He, Yi-Yuan Li, Zhong-Tian Xu, Jian-Ping Chen, Chuan-Xi Zhang, Jun-Min Li","doi":"10.1128/jvi.00997-24","DOIUrl":"https://doi.org/10.1128/jvi.00997-24","url":null,"abstract":"<p><p>Negevirus is a recently proposed taxon of arthropod-infecting virus, which is associated with plant viruses of two families (<i>Virgaviridae</i> and <i>Kitaviridae</i>). Nevertheless, the evolutionary history of negevirus-host and its relationship with plant viruses remain poorly understood. Endogenous nege-like viral elements (ENVEs) are ancient nege-like viral sequences integrated into the arthropod genomes, which can serve as the molecular fossil records of previous viral infection. In this study, 292 ENVEs were identified in 150 published arthropod genomes, revealing the evolutionary history of nege-like viruses and two related plant virus families. We discovered three novel and eight strains of nege-like viruses in 11 aphid species. Further analysis indicated that 10 ENVEs were detected in six aphid genomes, and they were divided into four types (ENVE1-ENVE4). Orthologous integration and phylogenetic analyses revealed that nege-like viruses had a history of infection of over 60 My and coexisted with aphid ancestors throughout the Cenozoic Era. Moreover, two nege-like viral proteins (CP and SP24) were highly homologous to those of plant viruses in the families <i>Virgaviridae</i> and <i>Kitaviridae</i>. CP- and SP24-derived ENVEs were widely integrated into numerous arthropod genomes. These results demonstrate that nege-like viruses have a long-term coexistence with arthropod hosts and plant viruses of the two families, <i>Virgaviridae</i> and <i>Kitaviridae</i>, which may have evolved from the nege-like virus ancestor through horizontal virus transfer events. These findings broaden our perspective on the history of viral infection in arthropods and the origins of plant viruses.</p><p><strong>Importance: </strong>Although negevirus is phylogenetically related to plant virus, the evolutionary history of negevirus-host and its relationship with plant virus remain largely unknown. In this study, we used endogenous nege-like viral elements (ENVEs) as the molecular fossil records to investigate the history of nege-like viral infection in arthropod hosts and the evolution of two related plant virus families (<i>Virgaviridae</i> and <i>Kitaviridae</i>). Our results showed the infection of nege-like viruses for over 60 My during the arthropod evolution. ENVEs highly homologous to viral sequences in <i>Virgaviridae</i> and <i>Kitaviridae</i> were present in a wide range of arthropod genomes but were absent in plant genomes, indicating that plant viruses in these two families possibly evolved from the nege-like virus ancestor through cross-species horizontal virus transmission. Our findings provide a new perspective on the virus-host coevolution and the origins of plant viruses.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142108811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Three-dimensional chromatin control of eukaryotic transcription is pivotal for regulating gene expression. This additional layer of epigenetic regulation is also utilized by DNA viruses, including herpesviruses. Dynamic, spatial genomic organization often involves looping of chromatin anchored by host-encoded CCCTC-binding factor (CTCF) and other factors, which control crosstalk between promoters and enhancers. Herein, we review the contribution of CTCF-mediated looping in regulating transcription during herpesvirus infection, with a specific focus on the betaherpesvirus, human cytomegalovirus (HCMV).
真核生物转录的三维染色质控制是调节基因表达的关键。包括疱疹病毒在内的 DNA 病毒也利用了这一额外的表观遗传调控层。动态的空间基因组组织通常涉及由宿主编码的 CCCTC 结合因子(CTCF)和其他因子锚定的染色质循环,这些因子控制着启动子和增强子之间的串扰。在此,我们回顾了 CTCF 介导的环状结构在疱疹病毒感染过程中调节转录的作用,并特别关注β疱疹病毒--人类巨细胞病毒(HCMV)。
{"title":"Loopy virus or controlled contortionist? 3D regulation of HCMV gene expression by CTCF-driven chromatin interactions.","authors":"Ian J Groves, Christine M O'Connor","doi":"10.1128/jvi.01148-24","DOIUrl":"https://doi.org/10.1128/jvi.01148-24","url":null,"abstract":"<p><p>Three-dimensional chromatin control of eukaryotic transcription is pivotal for regulating gene expression. This additional layer of epigenetic regulation is also utilized by DNA viruses, including herpesviruses. Dynamic, spatial genomic organization often involves looping of chromatin anchored by host-encoded CCCTC-binding factor (CTCF) and other factors, which control crosstalk between promoters and enhancers. Herein, we review the contribution of CTCF-mediated looping in regulating transcription during herpesvirus infection, with a specific focus on the betaherpesvirus, human cytomegalovirus (HCMV).</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142108813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
RNA helicases are integral in RNA metabolism, performing important roles in cellular homeostasis and stress responses. In particular, the DExD/H-box (DDX) helicase family possesses a conserved catalytic core that binds structural features rather than specific sequences in RNA targets. DDXs have critical roles in all aspects of RNA metabolism including ribosome biogenesis, translation, RNA export, and RNA stability. Importantly, functional specialization within this family arises from divergent N and C termini and is driven at least in part by gene duplications with 18 of the 42 human helicases having paralogs. In addition to their key roles in the homeostatic control of cellular RNA, these factors have critical roles in RNA virus infection. The canonical RIG-I-like receptors (RLRs) play pivotal roles in cytoplasmic sensing of viral RNA structures, inducing antiviral gene expression. Additional RNA helicases function as viral sensors or regulators, further diversifying the innate immune defense arsenal. Moreover, some of these helicases have been coopted by viruses to facilitate their replication. Altogether, DDX helicases exhibit functional specificity, playing intricate roles in RNA metabolism and host defense. This review will discuss the mechanisms by which these RNA helicases recognize diverse RNA structures in cellular and viral RNAs, and how this impacts RNA processing and innate immune responses.
{"title":"DDX RNA helicases: key players in cellular homeostasis and innate antiviral immunity.","authors":"Iulia Tapescu, Sara Cherry","doi":"10.1128/jvi.00040-24","DOIUrl":"https://doi.org/10.1128/jvi.00040-24","url":null,"abstract":"<p><p>RNA helicases are integral in RNA metabolism, performing important roles in cellular homeostasis and stress responses. In particular, the DExD/H-box (DDX) helicase family possesses a conserved catalytic core that binds structural features rather than specific sequences in RNA targets. DDXs have critical roles in all aspects of RNA metabolism including ribosome biogenesis, translation, RNA export, and RNA stability. Importantly, functional specialization within this family arises from divergent N and C termini and is driven at least in part by gene duplications with 18 of the 42 human helicases having paralogs. In addition to their key roles in the homeostatic control of cellular RNA, these factors have critical roles in RNA virus infection. The canonical RIG-I-like receptors (RLRs) play pivotal roles in cytoplasmic sensing of viral RNA structures, inducing antiviral gene expression. Additional RNA helicases function as viral sensors or regulators, further diversifying the innate immune defense arsenal. Moreover, some of these helicases have been coopted by viruses to facilitate their replication. Altogether, DDX helicases exhibit functional specificity, playing intricate roles in RNA metabolism and host defense. This review will discuss the mechanisms by which these RNA helicases recognize diverse RNA structures in cellular and viral RNAs, and how this impacts RNA processing and innate immune responses.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142108808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Reassortant Eurasian avian-like H1N1 (rEA H1N1) viruses carrying the internal genes of H1N1/2009 virus have been circulating in pigs for more than 10 years and have caused sporadic human infections. The enhanced virulence phenotype of the rEA H1N1 viruses highlights potential risks to public health. However, the molecular mechanism underlying the viral pathogenicity of the currently circulating rEA H1N1 viruses remains unclear. In this study, we found that two naturally isolated rEA H1N1 swine influenza viruses, A/swine/Liaoning/FX38/2017 (FX38) and A/swine/Liaoning/SY72/2018 (SY72), possessed similar genetic characteristics but exhibited significantly different pathogenicity in a mouse model. Using reverse genetics, we demonstrated that amino acid mutations at positions 100 and 122 in the polymerase acidic (PA) protein had individual and synergistic effects on the polymerase activity and viral replication capacity in vitro, as well as the viral pathogenicity in mice. Furthermore, we revealed that amino acid residue 100 in PA influenced the transcription of viral RNA (vRNA) by altering the endonuclease activity, and amino acid residue 122 affected the synthesis of complementary RNA and messenger RNA by altering the RNA-binding ability and endonuclease activity of the PA protein. Taken together, we identified that two naturally occurring amino acid mutations in PA derived from H1N1/2009 virus are crucial determinants of the virulence of rEA H1N1 viruses and revealed the differential mechanism by which these two mutations affect the transcription and replication of vRNA. These findings will extend our understanding of the roles of PA in the virulence of influenza A viruses.IMPORTANCEMultiple genetic determinants are involved in the virulence of influenza A viruses. In this study, we identified two naturally occurring amino acid mutations, located at residues 100 and 122 in the polymerase acidic (PA) protein, which are associated with viral polymerase activity, replication competence, and pathogenicity in mice. In particular, we clarified the specific mechanism by which the two residues play an important role in viral transcription and replication. These findings will help to improve understanding the functions of amino acid residues in the N-terminal region of the PA protein involved in the pathogenicity of influenza A viruses.
携带 H1N1/2009 病毒内部基因的欧亚禽流感样 H1N1(rEA H1N1)变种病毒已在猪群中流行了 10 多年,并引起了零星的人类感染。rEA H1N1 病毒毒力增强的表型凸显了其对公共卫生的潜在风险。然而,目前流行的 rEA H1N1 病毒致病性的分子机制仍不清楚。在这项研究中,我们发现两种自然分离的rEA H1N1猪流感病毒--A/swine/Liaoning/FX38/2017(FX38)和A/swine/Liaoning/SY72/2018(SY72)--具有相似的遗传特征,但在小鼠模型中表现出显著不同的致病性。我们利用反向遗传学方法证明,聚合酶酸性(PA)蛋白中第 100 位和第 122 位的氨基酸突变对聚合酶活性和体外病毒复制能力以及病毒在小鼠中的致病性具有单独和协同的影响。此外,我们还发现 PA 中的氨基酸残基 100 通过改变内切酶活性影响病毒 RNA(vRNA)的转录,而氨基酸残基 122 则通过改变 PA 蛋白的 RNA 结合能力和内切酶活性影响互补 RNA 和信使 RNA 的合成。综上所述,我们发现源自 H1N1/2009 病毒的 PA 蛋白中两个自然发生的氨基酸突变是决定 rEA H1N1 病毒毒力的关键因素,并揭示了这两个突变影响 vRNA 转录和复制的不同机制。这些发现将扩展我们对 PA 在甲型流感病毒毒力中作用的理解。在这项研究中,我们发现了位于聚合酶酸性蛋白(PA)残基 100 和 122 的两个天然氨基酸突变,它们与病毒聚合酶活性、复制能力和小鼠致病性有关。我们特别阐明了这两个残基在病毒转录和复制中发挥重要作用的具体机制。这些发现将有助于进一步了解 PA 蛋白 N 端区域的氨基酸残基与甲型流感病毒致病性有关的功能。
{"title":"Two amino acid residues in the N-terminal region of the polymerase acidic protein determine the virulence of Eurasian avian-like H1N1 swine influenza viruses in mice.","authors":"Yuying Yang, Chengzhi Xu, Naixin Zhang, Yunfei Wan, Yunpu Wu, Fei Meng, Yan Chen, Huanliang Yang, Liling Liu, Chuanling Qiao, Hualan Chen","doi":"10.1128/jvi.01293-24","DOIUrl":"https://doi.org/10.1128/jvi.01293-24","url":null,"abstract":"<p><p>Reassortant Eurasian avian-like H1N1 (rEA H1N1) viruses carrying the internal genes of H1N1/2009 virus have been circulating in pigs for more than 10 years and have caused sporadic human infections. The enhanced virulence phenotype of the rEA H1N1 viruses highlights potential risks to public health. However, the molecular mechanism underlying the viral pathogenicity of the currently circulating rEA H1N1 viruses remains unclear. In this study, we found that two naturally isolated rEA H1N1 swine influenza viruses, A/swine/Liaoning/FX38/2017 (FX38) and A/swine/Liaoning/SY72/2018 (SY72), possessed similar genetic characteristics but exhibited significantly different pathogenicity in a mouse model. Using reverse genetics, we demonstrated that amino acid mutations at positions 100 and 122 in the polymerase acidic (PA) protein had individual and synergistic effects on the polymerase activity and viral replication capacity <i>in vitro</i>, as well as the viral pathogenicity in mice. Furthermore, we revealed that amino acid residue 100 in PA influenced the transcription of viral RNA (vRNA) by altering the endonuclease activity, and amino acid residue 122 affected the synthesis of complementary RNA and messenger RNA by altering the RNA-binding ability and endonuclease activity of the PA protein. Taken together, we identified that two naturally occurring amino acid mutations in PA derived from H1N1/2009 virus are crucial determinants of the virulence of rEA H1N1 viruses and revealed the differential mechanism by which these two mutations affect the transcription and replication of vRNA. These findings will extend our understanding of the roles of PA in the virulence of influenza A viruses.IMPORTANCEMultiple genetic determinants are involved in the virulence of influenza A viruses. In this study, we identified two naturally occurring amino acid mutations, located at residues 100 and 122 in the polymerase acidic (PA) protein, which are associated with viral polymerase activity, replication competence, and pathogenicity in mice. In particular, we clarified the specific mechanism by which the two residues play an important role in viral transcription and replication. These findings will help to improve understanding the functions of amino acid residues in the N-terminal region of the PA protein involved in the pathogenicity of influenza A viruses.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142108817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pheonah Badu, Gabriele Baniulyte, Morgan A Sammons, Cara T Pager
Zika virus (ZIKV) is a re-emerging mosquito-borne flavivirus that can have devastating health consequences. The developmental and neurological effects of a ZIKV infection arise in part from the virus triggering cellular stress pathways and perturbing transcriptional programs. To date, the underlying mechanisms of transcriptional control directing viral restriction and virus-host interaction are understudied. Activating Transcription Factor 3 (ATF3) is a stress-induced transcriptional effector that modulates the expression of genes involved in a myriad of cellular processes, including inflammation and antiviral responses, to restore cellular homeostasis. While ATF3 is known to be upregulated during ZIKV infection, the mode by which ATF3 is activated, and the specific role of ATF3 during ZIKV infection is unknown. In this study, we show via inhibitor and RNA interference approaches that ZIKV infection initiates the integrated stress response pathway to activate ATF4 which in turn induces ATF3 expression. Additionally, by using CRISPR-Cas9 system to delete ATF3, we found that ATF3 acts to limit ZIKV gene expression in A549 cells. We also determined that ATF3 enhances the expression of antiviral genes such as STAT1 and other components in the innate immunity pathway to induce an ATF3-dependent anti-ZIKV response. Our study reveals crosstalk between the integrated stress response and innate immune response pathways and highlights an important role for ATF3 in establishing an antiviral effect during ZIKV infection.
Importance: Zika virus (ZIKV) is a re-emerging mosquito-borne flavivirus that co-opts cellular mechanisms to support viral processes that can reprogram the host transcriptional profile. Such viral-directed transcriptional changes and the pro- or anti-viral outcomes remain understudied. We previously showed that ATF3, a stress-induced transcription factor, is significantly upregulated in ZIKV-infected mammalian cells, along with other cellular and immune response genes. We now define the intracellular pathway responsible for ATF3 activation and elucidate the impact of ATF3 expression on ZIKV infection. We show that during ZIKV infection, the integrated stress response pathway stimulates ATF3 which enhances the innate immune response to antagonize ZIKV infection. This study establishes a link between viral-induced stress response and transcriptional regulation of host defense pathways and thus expands our knowledge of virus-mediated transcriptional mechanisms and transcriptional control of interferon-stimulated genes during ZIKV infection.
{"title":"Activation of ATF3 via the integrated stress response pathway regulates innate immune response to restrict Zika virus.","authors":"Pheonah Badu, Gabriele Baniulyte, Morgan A Sammons, Cara T Pager","doi":"10.1128/jvi.01055-24","DOIUrl":"10.1128/jvi.01055-24","url":null,"abstract":"<p><p>Zika virus (ZIKV) is a re-emerging mosquito-borne flavivirus that can have devastating health consequences. The developmental and neurological effects of a ZIKV infection arise in part from the virus triggering cellular stress pathways and perturbing transcriptional programs. To date, the underlying mechanisms of transcriptional control directing viral restriction and virus-host interaction are understudied. Activating Transcription Factor 3 (ATF3) is a stress-induced transcriptional effector that modulates the expression of genes involved in a myriad of cellular processes, including inflammation and antiviral responses, to restore cellular homeostasis. While ATF3 is known to be upregulated during ZIKV infection, the mode by which ATF3 is activated, and the specific role of ATF3 during ZIKV infection is unknown. In this study, we show via inhibitor and RNA interference approaches that ZIKV infection initiates the integrated stress response pathway to activate ATF4 which in turn induces ATF3 expression. Additionally, by using CRISPR-Cas9 system to delete ATF3, we found that ATF3 acts to limit ZIKV gene expression in A549 cells. We also determined that ATF3 enhances the expression of antiviral genes such as STAT1 and other components in the innate immunity pathway to induce an ATF3-dependent anti-ZIKV response. Our study reveals crosstalk between the integrated stress response and innate immune response pathways and highlights an important role for ATF3 in establishing an antiviral effect during ZIKV infection.</p><p><strong>Importance: </strong>Zika virus (ZIKV) is a re-emerging mosquito-borne flavivirus that co-opts cellular mechanisms to support viral processes that can reprogram the host transcriptional profile. Such viral-directed transcriptional changes and the pro- or anti-viral outcomes remain understudied. We previously showed that ATF3, a stress-induced transcription factor, is significantly upregulated in ZIKV-infected mammalian cells, along with other cellular and immune response genes. We now define the intracellular pathway responsible for ATF3 activation and elucidate the impact of ATF3 expression on ZIKV infection. We show that during ZIKV infection, the integrated stress response pathway stimulates ATF3 which enhances the innate immune response to antagonize ZIKV infection. This study establishes a link between viral-induced stress response and transcriptional regulation of host defense pathways and thus expands our knowledge of virus-mediated transcriptional mechanisms and transcriptional control of interferon-stimulated genes during ZIKV infection.</p>","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142108804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chyan-Jang Lee, Hui-Ru Lin, Ching-Len Liao, Yi-Ling Lin
{"title":"Correction for Lee et al., \"Cholesterol Effectively Blocks Entry of Flavivirus\".","authors":"Chyan-Jang Lee, Hui-Ru Lin, Ching-Len Liao, Yi-Ling Lin","doi":"10.1128/jvi.01131-24","DOIUrl":"https://doi.org/10.1128/jvi.01131-24","url":null,"abstract":"","PeriodicalId":17583,"journal":{"name":"Journal of Virology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142108806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}