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Effects of Different Doses of Nucleocapsid Protein from Hantaan Virus A9 Strain on Regulation of Interferon Signaling.

ABSTRACT: Hantaan virus A9 strain (HTNV A9) is an etiologic agent of hemorrhagic fever with renal syndrome in China. The virulence of the pathogenic hantaviruses is determined by their ability to alter key signaling pathways of early interferon (IFN) induction within cells. The potential role of HTNV A9 structural proteins, such as nucleocapsid (N) and envelope glycoproteins (Gn and Gc), in regulating human's innate antiviral immune response has not yet been clarified. In this study, we investigated the effect of HTNV A9?N protein on the regulation of the IFN pathway. We found that A9?N protein can influence the host innate immune response by regulating the activation of IFN?. The A9?N protein stimulates IFN response in low doses, whereas significantly inhibits IFN? production at high doses. Furthermore, A9?N protein constitutively inhibits nuclear factor kappa B activation. A high dose of A9?N protein could inhibit either Poly IC-induced IFN? or vesicular stomatitis virus-induced IFN? and interferon-stimulated gene production. Our results indicate that HTNV A9?N protein helps virus establish successful infection by downregulating the IFN response and shed new light to the understanding of the interaction between the host innate immunity and virus during Hantaan virus infection.

SUBMITTER: Pan W

PROVIDER: S-EPMC4599133 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Effects of Different Doses of Nucleocapsid Protein from Hantaan Virus A9 Strain on Regulation of Interferon Signaling.

Pan Wen W Bian Gang G Wang Kezhen K Feng Tingting T Dai Jianfeng J

Viral immunology 20150721 8

Hantaan virus A9 strain (HTNV A9) is an etiologic agent of hemorrhagic fever with renal syndrome in China. The virulence of the pathogenic hantaviruses is determined by their ability to alter key signaling pathways of early interferon (IFN) induction within cells. The potential role of HTNV A9 structural proteins, such as nucleocapsid (N) and envelope glycoproteins (Gn and Gc), in regulating human's innate antiviral immune response has not yet been clarified. In this study, we investigated the e ...[more]

PMID: 26196448

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Project description:Andes virus (ANDV) causes hantavirus pulmonary syndrome (HPS) and is the only hantavirus shown to spread person to person and cause a highly lethal HPS-like disease in Syrian hamsters. The unique ability of ANDV N protein to inhibit beta interferon (IFNβ) induction may contribute to its virulence and spread. Here we analyzed IFNβ regulation by ANDV N protein substituted with divergent residues from the nearly identical Maporal virus (MAPV) N protein. We found that MAPV N fails to inhibit IFNβ signaling and that replacing ANDV residues 252 to 296 with a hypervariable domain (HVD) from MAPV N prevents IFNβ regulation. In addition, changing ANDV residue S386 to the histidine present in MAPV N or the alanine present in other hantaviruses prevented ANDV N from regulating IFNβ induction. In contrast, replacing serine with phosphoserine-mimetic aspartic acid (S386D) in ANDV N robustly inhibited interferon regulatory factor 3 (IRF3) phosphorylation and IFNβ induction. Additionally, the MAPV N protein gained the ability to inhibit IRF3 phosphorylation and IFNβ induction when ANDV HVD and H386D replaced MAPV residues. Mass spectroscopy analysis of N protein from ANDV-infected cells revealed that S386 is phosphorylated, newly classifying ANDV N as a phosphoprotein and phosphorylated S386 as a unique determinant of IFN regulation. In this context, the finding that the ANDV HVD is required for IFN regulation by S386 but dispensable for IFN regulation by D386 suggests a role for HVD in kinase recruitment and S386 phosphorylation. These findings delineate elements within the ANDV N protein that can be targeted to attenuate ANDV and suggest targeting cellular kinases as potential ANDV therapeutics.IMPORTANCE ANDV contains virulence determinants that uniquely permit it to spread person to person and cause highly lethal HPS in immunocompetent hamsters. We discovered that ANDV S386 and an ANDV-specific hypervariable domain permit ANDV N to inhibit IFN induction and that IFN regulation is directed by phosphomimetic S386D substitutions in ANDV N. In addition, MAPV N proteins containing D386 and ANDV HVD gained the ability to inhibit IFN induction. Validating these findings, mass spectroscopy analysis revealed that S386 of ANDV N protein is uniquely phosphorylated during ANDV infection. Collectively, these findings reveal new paradigms for ANDV N protein as a phosphoprotein and IFN pathway regulator and suggest new mechanisms for hantavirus regulation of cellular kinases and signaling pathways. Our findings define novel IFN-regulating virulence determinants of ANDV, identify residues that can be modified to attenuate ANDV for vaccine development, and suggest the potential for kinase inhibitors to therapeutically restrict ANDV replication.

Dataset Information

Effects of Different Doses of Nucleocapsid Protein from Hantaan Virus A9 Strain on Regulation of Interferon Signaling.

Publications

Effects of Different Doses of Nucleocapsid Protein from Hantaan Virus A9 Strain on Regulation of Interferon Signaling.

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