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MERS-CoV 4b protein interferes with the NF-?B-dependent innate immune response during infection.

ABSTRACT: Middle East respiratory syndrome coronavirus (MERS-CoV) is a novel human coronavirus that emerged in 2012, causing severe pneumonia and acute respiratory distress syndrome (ARDS), with a case fatality rate of ~36%. When expressed in isolation, CoV accessory proteins have been shown to interfere with innate antiviral signaling pathways. However, there is limited information on the specific contribution of MERS-CoV accessory protein 4b to the repression of the innate antiviral response in the context of infection. We found that MERS-CoV 4b was required to prevent a robust NF-?B dependent response during infection. In wild-type virus infected cells, 4b localized to the nucleus, while NF-?B was retained in the cytoplasm. In contrast, in the absence of 4b or in the presence of cytoplasmic 4b mutants lacking a nuclear localization signal (NLS), NF-?B was translocated to the nucleus leading to the expression of pro-inflammatory cytokines. This indicates that NF-?B repression required the nuclear import of 4b mediated by a specific NLS. Interestingly, we also found that both in isolation and during infection, 4b interacted with ?-karyopherin proteins in an NLS-dependent manner. In particular, 4b had a strong preference for binding karyopherin-?4 (KPNA4), which is known to translocate the NF-?B protein complex into the nucleus. Binding of 4b to KPNA4 during infection inhibited its interaction with NF-?B-p65 subunit. Thereby we propose a model where 4b outcompetes NF-?B for KPNA4 binding and translocation into the nucleus as a mechanism of interference with the NF-?B-mediated innate immune response.

SUBMITTER: Canton J

PROVIDER: S-EPMC5800688 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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MERS-CoV 4b protein interferes with the NF-κB-dependent innate immune response during infection.

Canton Javier J Fehr Anthony R AR Fernandez-Delgado Raúl R Gutierrez-Alvarez Francisco J FJ Sanchez-Aparicio Maria T MT García-Sastre Adolfo A Perlman Stanley S Enjuanes Luis L Sola Isabel I

PLoS pathogens 20180125 1

Middle East respiratory syndrome coronavirus (MERS-CoV) is a novel human coronavirus that emerged in 2012, causing severe pneumonia and acute respiratory distress syndrome (ARDS), with a case fatality rate of ~36%. When expressed in isolation, CoV accessory proteins have been shown to interfere with innate antiviral signaling pathways. However, there is limited information on the specific contribution of MERS-CoV accessory protein 4b to the repression of the innate antiviral response in the cont ...[more]

PMID: 29370303

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Project description:The common fruit fly, Drosophila melanogaster, is an outstanding model to study the molecular basis of anti-pathogen immunity. The parasitic nematode Heterorhabditis gerrardi, together with its mutualistic bacteria Photorhabdus asymbiotica, infects a wide range of insects, including D. melanogaster. Recently, we have shown that transforming growth factor-β (TGF-ß) signaling in D. melanogaster is regulated in response to parasitic nematode infection. In the current study, we investigated the contribution of two TGF-ß signaling branches, the activin and the bone morphogenetic protein (BMP), to D. melanogaster immune function against H. gerrardi. We used D. melanogaster larvae carrying mutations in the genes coding for the TGF-ß extracellular ligands daw and dpp. We have demonstrated that the number of circulating hemocytes in uninfected daw and dpp mutants decreases twofold compared to background controls, yet no significant changes in hemocyte numbers and survival of the TGF-ß mutants are observed upon nematode infection. However, we have shown that nematode-infected daw mutants express Dual oxidase at higher levels and phenoloxidase activity at lower levels compared to their background controls. To elucidate the contribution of TGF-ß signaling in the metabolic response of D. melanogaster to parasitic nematodes, we estimated lipid and carbohydrate levels in daw and dpp mutant larvae infected with H. gerrardi. We have found that both nematode-infected mutants contain lipid droplets of larger size, with daw mutant larvae also containing elevated glycogen levels. Overall, our findings indicate that the regulation of activin and BMP branches of TGF-ß signaling can alter the immune and metabolic processes in D. melanogaster during response to parasitic nematode infection. Results from this study shed light on the molecular signaling pathways insects activate to regulate mechanisms for fighting potent nematode parasites, which could lead to the identification of novel management strategies for the control of damaging pests.

Project description:Compared to adults, neonates are at increased risk of infection. There is a growing recognition that dynamic qualitative and quantitative differences in immunity over development contribute to these observations. The liver plays a key role as an immunologic organ, but whether its contribution to the acute innate immune response changes over lifetime is unknown. We hypothesized that the liver would activate a developmentally-regulated acute innate immune response to intraperitoneal lipopolysaccharide (LPS). We first assessed the hepatic expression and activity of the NF-κB, a key regulator of the innate immune response, at different developmental ages (p0, p3, p7, p35, and adult). Ontogeny of the NF-κB subunits (p65/p50) revealed a reduction in Rela (p65) and Nfkb1 (p105, precursor to p50) gene expression (p0) and p65 subunit protein levels (p0 and p3) vs. older ages. The acute hepatic innate immune response to LPS was associated by the degradation of the NF-κB inhibitory proteins (IκBα and IκBβ), and nuclear translocation of the NF-κB subunit p50 in all ages, whereas nuclear translocation of the NF-κB subunit p65 was only observed in the p35 and adult mouse. Consistent with these findings, we detected NF-κB subunit p65 nuclear staining exclusively in the LPS-exposed adult liver compared with p7 mouse. We next interrogated the LPS-induced hepatic expression of pro-inflammatory genes (Tnf, Icam1, Ccl3, and Traf1), and observed a gradually increase in gene expression starting from p0. Confirming our results, hepatic NF-κB subunit p65 nuclear translocation was associated with up-regulation of the Icam1 gene in the adult, and was not detected in the p7 mouse. Thus, an inflammatory challenge induces an NF-κB-mediated hepatic innate immune response activation across all developmental ages, but nuclear translocation of the NF-κB subunit p65 and associated induction of pro-inflammatory genes occurred only after the first month of life. Our results demonstrate that the LPS-induced hepatic innate immune response is developmentally regulated by the NF-κB subunit p65 in the mouse.

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MERS-CoV 4b protein interferes with the NF-?B-dependent innate immune response during infection.

Publications

MERS-CoV 4b protein interferes with the NF-κB-dependent innate immune response during infection.

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