Myxoma virus subdues type 1 interferon responses through a host range determinant
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA806155 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17988660_1.fastq.gz | Fastqsanger.gz | |||
| SRR17988660_2.fastq.gz | Fastqsanger.gz | |||
| SRR17988661_1.fastq.gz | Fastqsanger.gz | |||
| SRR17988661_2.fastq.gz | Fastqsanger.gz | |||
| SRR17988662_1.fastq.gz | Fastqsanger.gz |
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Project description:Evolutionarily successful poxviruses presented effective and diverse strategies to circumvent or overcome host defense mechanisms. Poxviruses encode many immunoregulatory proteins to evade host immunity for a productive infection and unique means of inhibiting DNA-sensing dependent type 1 interferon (IFN-I) responses is anticipated due to the biology of its dsDNA genome in nature and an exclusive cytoplasmic life cycle. We found the key DNA sensing inhibition by poxvirus infection was dominant during the early stage of poxvirus infection independent from DNA replication. In an effort of identifying poxvirus novel means to subdue antiviral proinflammatory responses e.g., IFN-I response, we focused on the function of one early gene that is the known host range determinant from the highly conserved poxvirus host range C7L superfamily, myxoma virus (MYXV) M062. Host range factors are unique features of poxviruses that determine the species and cell type tropism. Almost all sequenced mammalian poxviruses retain at least one homologue of the poxvirus host range C7L superfamily. In MYXV, a rabbit specific poxvirus, the dominant and broad-spectrum host range determinant of the C7L superfamily is the M062R gene. M062R gene product is essential for MYXV infection in almost all cells tested from different mammalian species and specifically inhibits the function of host Sterile α Motif Domain-containing 9 (SAMD9), as M062R-null (ΔM062R) MYXV causes abortive infection in a SAMD9-dependend manner. In this study we investigated the immunostimulatory property of the ΔM062R. We found that the replication-defective ΔM062R infection activated host DNA sensing pathway in the cGAS dependent fashion and knocking down SAMD9 expression attenuated proinflammatory responses. Moreover, transcriptomic analyses showed a unique feature of host gene expression landscape that is different from dsDNA stimulated inflammatory state. This study built a link between the anti-neoplastic SAMD9 and the regulation of the innate immune responses.
2022-02-14 | GSE196608 | GEO
Project description:A century ago, influenza A virus (IAV) infection caused the 1918 flu pandemic and killed an estimated 20-40 million people. Pandemic IAV outbreaks occur when strains from animal reservoirs acquire the ability to infect and spread among humans. The molecular details of this species barrier are incompletely understood. We combined metabolic pulse labeling and quantitative shotgun proteomics to globally monitor protein synthesis upon infection of human cells with a human- and a bird-adapted IAV strain. While production of host proteins was remarkably similar, we observed striking differences in the kinetics of viral protein synthesis over the course of infection. Most importantly, the matrix protein M1 was inefficiently produced by the bird-adapted strain at later stages. We show that impaired production of M1 from bird-adapted strains is caused by increased splicing of the M segment RNA to alternative isoforms. Experiments with reporter constructs and recombinant influenza viruses revealed that strain-specific M segment splicing is controlled by the 3’ splice site and functionally important for permissive infection. Independent in silico and biochemical evidence shows that avian-adapted M segments have evolved different conserved RNA structure features than human-adapted sequences. Thus, our data identifies M segment RNA splicing as a viral determinant of host range.
2019-11-11 | PXD015475 | Pride
Project description:A century ago, influenza A virus (IAV) infection caused the 1918 flu pandemic and killed an estimated 20-40 million people. Pandemic IAV outbreaks occur when strains from animal reservoirs acquire the ability to infect and spread among humans. The molecular details of this species barrier are incompletely understood. We combined metabolic pulse labeling and quantitative shotgun proteomics to globally monitor protein synthesis upon infection of human cells with a human- and a bird-adapted IAV strain. While production of host proteins was remarkably similar, we observed striking differences in the kinetics of viral protein synthesis over the course of infection. Most importantly, the matrix protein M1 was inefficiently produced by the bird-adapted strain at later stages. We show that impaired production of M1 from bird-adapted strains is caused by increased splicing of the M segment RNA to alternative isoforms. Experiments with reporter constructs and recombinant influenza viruses revealed that strain-specific M segment splicing is controlled by the 3’ splice site and functionally important for permissive infection. Independent in silico and biochemical evidence shows that avian-adapted M segments have evolved different conserved RNA structure features than human-adapted sequences. Thus, our data identifies M segment RNA splicing as a viral determinant of host range.
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Project description:The evolutionarily successful poxviruses possess effective and diverse strategies to circumvent or overcome host defense mechanisms. Poxviruses encode many immunoregulatory proteins to evade host immunity to establish a productive infection and have unique means of inhibiting DNA sensing-dependent type 1 interferon (IFN-I) responses, a necessity given their dsDNA genome and exclusively cytoplasmic life cycle. We found that the key DNA sensing inhibition by poxvirus infection was dominant during the early stage of poxvirus infection before DNA replication. In an effort to identify the poxvirus gene products which subdue the antiviral proinflammatory responses (e.g., IFN-I response), we investigated the function of one early gene that is the known host range determinant from the highly conserved poxvirus host range C7L superfamily, myxoma virus (MYXV) M062. Host range factors are unique features of poxviruses that determine the species and cell type tropism. Almost all sequenced mammalian poxviruses retain at least one homologue of the poxvirus host range C7L superfamily. In MYXV, a rabbit-specific poxvirus, the dominant and broad-spectrum host range determinant of the C7L superfamily is the M062R gene. The M062R gene product is essential for MYXV infection in almost all cells tested from different mammalian species and specifically inhibits the function of host Sterile α Motif Domain-containing 9 (SAMD9), as M062R-null (ΔM062R) MYXV causes abortive infection in a SAMD9-dependent manner. In this study we investigated the immunostimulatory property of the ΔM062R. We found that the replication-defective ΔM062R activated host DNA sensing pathway during infection in a cGAS-dependent fashion and that knocking down SAMD9 expression attenuated proinflammatory responses. Moreover, transcriptomic analyses showed a unique feature of the host gene expression landscape that is different from the dsDNA alone-stimulated inflammatory state. This study establishes a link between the anti-neoplastic function of SAMD9 and the regulation of innate immune responses.
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Project description:The cornerstone of mammalian intrinsic and innate immune defense against pathogens is the production of interferons (IFN), cytokines that stimulate anti-pathogen signaling pathways through the simultaneous expression of hundreds of interferon-stimulated genes (ISG). We compared the effects of IFN classes on the cellular proteome and relative restriction of virus progeny production across multiple physiologically relevant cell types and viruses. We integrated global proteome analyses with targeted mass spectrometry (MS), thermal proximity coaggregation-MS (TPCA-MS), and molecular virology assays to determine how ISGs differentially contribute to host antiviral capacities between immune-modulatory cell types. In differentiated macrophage-like monocytic cells, we classified sets of both shared and distinct ISG proteins responsive to each IFN class. We orthogonally confirmed the relative protein alterations using parallel reaction monitoring (PRM) by developing a proteotypic peptide library for ISG markers induced by each IFN class. Additional comparison to stimulation with pro-inflammatory LPS helped to contextualize the observed IFN signatures. We further assessed ISG protein interactions upon IFN types I and II stimulation, observing maintenance of key ISG protein complexes across treatments. Subsequent comparison of macrophage-like monocytic cells to primary keratinocytes enabled us to identify relative ISG abundances, cytokine induction, and antiviral capacities of both cell types across infections with several ubiquitous human viruses. Infections with herpes simplex virus-1 (HSV-1), adenovirus (AdV), and human cytomegalovirus (HCMV) revealed cell type-dependent differences in virus progeny production.
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Project description:Pandemic influenza A virus (IAV) outbreaks occur when strains from animal reservoirs acquire the ability to infect and spread among humans. The molecular basis of this species barrier is incompletely understood. Here we combine metabolic pulse labeling and quantitative proteomics to monitor protein synthesis upon infection of human cells with a human- and a bird-adapted IAV strain and observe striking differences in viral protein synthesis. Most importantly, the matrix protein M1 is inefficiently produced by the bird-adapted strain. We show that impaired production of M1 from bird-adapted strains is caused by increased splicing of the M segment RNA to alternative isoforms. Strain-specific M segment splicing is controlled by the 3' splice site and functionally important for permissive infection. In silico and biochemical evidence shows that avian-adapted M segments have evolved different conserved RNA structure features than human-adapted sequences. Thus, we identify M segment RNA splicing as a viral host range determinant.
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Project description:In humans, deleterious mutations in the sterile α motif domain protein 9 (SAMD9) gene are associated with cancer, inflammation, weakening of the immune response, and developmental arrest. However, the biological function of SAMD9 and its sequence-structure relationships remain to be characterized. Previously, we found that an essential host range factor, M062 protein from myxoma virus (MYXV), antagonized the function of human SAMD9. In this study, we examine the interaction between M062 and human SAMD9 to identify regions that are critical to SAMD9 function. We also characterize the in vitro kinetics of the interaction. In an infection assay, exogenous expression of SAMD9 N-terminus leads to a potent inhibition of wild-type MYXV infection. We reason that this effect is due to the sequestration of viral M062 by the exogenously expressed N-terminal SAMD9 region. Our studies reveal the first molecular insight into viral M062-dependent mechanisms that suppress human SAMD9-associated antiviral function.
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Project description:Airway epithelial cells and macrophages differ markedly in their responses to influenza A virus (IAV) infection. To investigate transcriptional responses underlying these differences, purified subsets of type II airway epithelial cells (ATII) and alveolar macrophages (AM) recovered from the lungs of mock- or IAV-infected mice were subjected to RNA sequencing. In the absence of infection, AM predominantly expressed genes related to immunity whereas ATII expressed genes consistent with their physiological roles in the lung. Following IAV infection, AM almost exclusively activated cell-intrinsic antiviral pathways that were dependent on interferon regulatory factor (IRF)3/7 and/or type I interferon (IFN) signaling. In contrast, IAV-infected ATII activated a broader range of physiological responses, including cell-intrinsic antiviral pathways, which were both independent and dependent on IRF3/7 and/or type I IFN. These data suggest that transcriptional profiles hardwired during development could be a major determinant underlying the different responses of ATII and AM to IAV infection.
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