Abstract:
UNLABELLED:Middle East respiratory syndrome coronavirus (MERS-CoV) is the first highly pathogenic human coronavirus to emerge since severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002. Like many coronaviruses, MERS-CoV carries genes that encode multiple accessory proteins that are not required for replication of the genome but are likely involved in pathogenesis. Evasion of host innate immunity through interferon (IFN) antagonism is a critical component of viral pathogenesis. The IFN-inducible oligoadenylate synthetase (OAS)-RNase L pathway activates upon sensing of viral double-stranded RNA (dsRNA). Activated RNase L cleaves viral and host single-stranded RNA (ssRNA), which leads to translational arrest and subsequent cell death, preventing viral replication and spread. Here we report that MERS-CoV, a lineage CBetacoronavirus, and related bat CoV NS4b accessory proteins have phosphodiesterase (PDE) activity and antagonize OAS-RNase L by enzymatically degrading 2',5'-oligoadenylate (2-5A), activators of RNase L. This is a novel function for NS4b, which has previously been reported to antagonize IFN signaling. NS4b proteins are distinct from lineage ABetacoronavirusPDEs and rotavirus gene-encoded PDEs, in having an amino-terminal nuclear localization signal (NLS) and are localized mostly to the nucleus. However, the expression level of cytoplasmic MERS-CoV NS4b protein is sufficient to prevent activation of RNase L. Finally, this is the first report of an RNase L antagonist expressed by a human or bat coronavirus and provides a specific mechanism by which this occurs. Our findings provide a potential mechanism for evasion of innate immunity by MERS-CoV while also identifying a potential target for therapeutic intervention. IMPORTANCE:Middle East respiratory syndrome coronavirus (MERS-CoV) is the first highly pathogenic human coronavirus to emerge since severe acute respiratory syndrome coronavirus (SARS-CoV). MERS-CoV, like other coronaviruses, carries genes that encode accessory proteins that antagonize the host antiviral response, often the type I interferon response, and contribute to virulence. We found that MERS-CoV NS4b and homologs from related lineage C bat betacoronaviruses BtCoV-SC2013 (SC2013) and BtCoV-HKU5 (HKU5) are members of the 2H-phosphoesterase (2H-PE) enzyme family with phosphodiesterase (PDE) activity. Like murine coronavirus NS2, a previously characterized PDE, MERS NS4b, can antagonize activation of the OAS-RNase L pathway, an interferon-induced potent antiviral activity. Furthermore, MERS-CoV mutants with deletion of genes encoding accessory proteins NS3 to NS5 or NS4b alone or inactivation of the PDE can activate RNase L during infection of Calu-3 cells. Our report may offer a potential target for therapeutic intervention if NS4b proves to be critical to pathogenesis inin vivomodels of MERS-CoV infection.
journal_name
mBiojournal_title
mBioauthors
Thornbrough JM,Jha BK,Yount B,Goldstein SA,Li Y,Elliott R,Sims AC,Baric RS,Silverman RH,Weiss SRdoi
10.1128/mBio.00258-16subject
Has Abstractpub_date
2016-03-29 00:00:00pages
e00258issue
2issn
2150-7511pii
mBio.00258-16journal_volume
7pub_type
杂志文章相关文献
mBio文献大全abstract::Tuberculosis (TB), caused by Mycobacterium tuberculosis infection, remains a major cause of mortality and morbidity worldwide. One-third of the world population is infected with M. tuberculosis, and about 15 million people with latent tuberculosis infection (LTBI) reside in the United States. An estimated 10% of indiv...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.02771-18
更新日期:2019-04-16 00:00:00
abstract:UNLABELLED:Kaposi's sarcoma (KS), caused by KS-associated herpesvirus (KSHV), is the most common cancer among HIV-infected patients in Malawi and in the United States today. In Malawi, KSHV is endemic. We conducted a cross-sectional study of patients with HIV infection and KS with no history of chemo- or antiretroviral...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.01633-14
更新日期:2014-09-23 00:00:00
abstract:UNLABELLED:Pneumococcal pili have been shown to influence pneumococcal colonization, disease development, and the inflammatory response in mice. The role of the pilus-associated RrgA adhesin in pneumococcal interactions with murine and human macrophages was investigated. Expression of pili with RrgA enhanced the uptake...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.00535-12
更新日期:2012-12-26 00:00:00
abstract::Protein lysine acetylation, a prevalent posttranslational modification, regulates numerous crucial biological processes in cells. Nevertheless, how lysine acetylation interacts with other types of regulation to coordinate metabolism remains largely unknown owing to the complexity of the process. Here, using a represen...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.00650-20
更新日期:2020-08-18 00:00:00
abstract::The facultative intracellular pathogen Listeria monocytogenes, like many related Firmicutes, uses the nucleotide second messenger cyclic di-AMP (c-di-AMP) to adapt to changes in nutrient availability, osmotic stress, and the presence of cell wall-acting antibiotics. In rich medium, c-di-AMP is essential; however, muta...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.01625-20
更新日期:2020-08-25 00:00:00
abstract::Type II polyketides are a group of secondary metabolites with various biological activities. In nature, biosynthesis of type II polyketides involves multiple enzymatic steps whereby key enzymes, including ketoacyl-synthase (KSα), chain length factor (KSβ), and acyl carrier protein (ACP), are utilized to elongate the p...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.01334-20
更新日期:2020-09-15 00:00:00
abstract:UNLABELLED:Mycobacterium tuberculosis depends on aerobic respiration for growth and utilizes an aa3-type cytochrome c oxidase for terminal electron transfer. Cytochrome c maturation in bacteria requires covalent attachment of heme to apocytochrome c, which occurs outside the cytoplasmic membrane. We demonstrate that in...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.00475-13
更新日期:2013-09-17 00:00:00
abstract:UNLABELLED:The initiating events in autoimmune disease remain to be completely understood, but it is thought that genetic predisposition synergizes with "environmental" factors, including viral infection, leading to disease. One elegant animal model used to study the pathogenesis of multiple sclerosis that perfectly bl...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.01175-15
更新日期:2015-08-04 00:00:00
abstract::Japanese encephalitis virus (JEV) remains a leading cause of viral encephalitis worldwide. Although JEV-specific antibodies have been described, an assessment of their ability to neutralize multiple genotypes of JEV has been limited. Here, we describe the development of a panel of mouse and human neutralizing monoclon...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.00008-18
更新日期:2018-02-27 00:00:00
abstract::Nuclear factor Y (NF-Y) is a heterotrimeric transcription factor composed of three subunits, namely, NF-YA, NF-YB, and NF-YC, which are conserved throughout evolution. In higher eukaryotes, NF-Y plays important roles in several cellular processes (development, cell cycle regulation, apoptosis, and response to growth, ...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.00737-19
更新日期:2019-06-18 00:00:00
abstract:UNLABELLED:The promoter most strongly induced upon activation of the Cpx two-component envelope stress response is the cpxP promoter. The 3' untranscribed region (UTR) of the cpxP transcript is shown to produce a small RNA (sRNA), CpxQ. We investigated the role of CpxQ in combating envelope stress. Remarkably, the two ...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.00312-16
更新日期:2016-04-05 00:00:00
abstract::Helicobacter pylori colonizes about half of humans worldwide, and its presence in the gastric mucosa is associated with an increased risk of gastric adenocarcinoma, gastric lymphoma, and peptic ulcer disease. H. pylori strains carrying the cag pathogenicity island (cagPAI) are associated with increased risk of disease...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.00849-19
更新日期:2019-05-14 00:00:00
abstract::Escherichia coli sequence type 131 (ST131), a pandemic clone responsible for the high incidence of extraintestinal pathogenic E. coli (ExPEC) infections, has been known widely for its contribution to the worldwide dissemination of multidrug resistance. Although other ExPEC-associated and extended-spectrum-β-lactamase ...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.01596-17
更新日期:2017-10-24 00:00:00
abstract::During 2015 to 2016, Brazil reported more Zika virus (ZIKV) cases than any other country, yet population exposure remains unknown. Serological studies of ZIKV are hampered by cross-reactive immune responses against heterologous viruses. We conducted serosurveys for ZIKV, dengue virus (DENV), and Chikungunya virus (CHI...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.01390-17
更新日期:2017-11-14 00:00:00
abstract:UNLABELLED:Promiscuous plasmids replicate in a wide range of bacteria and therefore play a key role in the dissemination of various host-beneficial traits, including antibiotic resistance. Despite the medical relevance, little is known about the evolutionary dynamics through which drug resistance plasmids adapt to new ...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.00077-12
更新日期:2012-07-03 00:00:00
abstract::Typhoid fever, caused by Salmonella enterica serovar Typhi, is a global public health concern due to increasing antimicrobial resistance (AMR). Characterization of S Typhi genomes for AMR and the evolution of different lineages, especially in countries where typhoid fever is endemic such as Bangladesh, will help publi...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.02112-18
更新日期:2018-11-13 00:00:00
abstract::Chlamydiales species are obligate intracellular bacteria lacking a classical peptidoglycan sacculus but relying on peptidoglycan synthesis for cytokinesis. While septal peptidoglycan biosynthesis seems to be regulated by MreB actin and its membrane anchor RodZ rather than FtsZ tubulin in Chlamydiales, the mechanism of...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.01128-19
更新日期:2019-07-16 00:00:00
abstract::Nutritional immunity is an elegant host mechanism used to starve invading pathogens of necessary nutrient metals. Calprotectin, a metal-binding protein, is produced abundantly by neutrophils and is found in high concentrations within inflammatory sites during infection. Group B Streptococcus (GBS) colonizes the gastro...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.02302-20
更新日期:2020-11-10 00:00:00
abstract:UNLABELLED:Despite long-term investment, influenza continues to be a significant worldwide problem. The cornerstone of protection remains vaccination, and approved vaccines seek to elicit a hemagglutination inhibition (HAI) titer of ≥1:40 as the primary correlate of protection. However, recent poor vaccine performance ...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.00417-16
更新日期:2016-04-19 00:00:00
abstract:UNLABELLED:Candida albicans is a major life-threatening human fungal pathogen in the immunocompromised host. Host defense against systemic Candida infection relies heavily on the capacity of professional phagocytes of the innate immune system to ingest and destroy fungal cells. A number of pathogens, including C. albic...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.01874-14
更新日期:2014-12-02 00:00:00
abstract::Mannitol-1-phosphate dehydrogenase (M1PDH) is a key enzyme in Staphylococcus aureus mannitol metabolism, but its roles in pathophysiological settings have not been established. We performed comprehensive structure-function analysis of M1PDH from S. aureus USA300, a strain of community-associated methicillin-resistant ...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.02660-18
更新日期:2019-07-09 00:00:00
abstract:UNLABELLED:Antibiotics are a cost-effective tool for improving feed efficiency and preventing disease in agricultural animals, but the full scope of their collateral effects is not understood. Antibiotics have been shown to mediate gene transfer by inducing prophages in certain bacterial strains; therefore, one collate...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.00260-11
更新日期:2011-11-29 00:00:00
abstract::Our knowledge of cell cycle regulatory mechanisms in apicomplexan parasites is very limited. In this study, we describe a novel Toxoplasma gondii factor that has a vital role in chromosome replication and the regulation of cytoplasmic and nuclear mitotic structures, and we named this factor ECR1 for essential for chro...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.00579-17
更新日期:2017-08-22 00:00:00
abstract::Arthritogenic alphaviruses such as Ross River and Chikungunya viruses cause debilitating muscle and joint pain and pose significant challenges in the light of recent outbreaks. How host immune responses are orchestrated after alphaviral infections and lead to musculoskeletal inflammation remains poorly understood. Her...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.03353-19
更新日期:2020-03-03 00:00:00
abstract::Malaria parasite ookinetes must traverse the vector mosquito midgut epithelium to transform into sporozoite-producing oocysts. The Anopheles innate immune system is a key regulator of this process, thereby determining vector competence and disease transmission. The role of Anopheles innate immunity factors as agonists...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.01631-17
更新日期:2017-10-17 00:00:00
abstract:UNLABELLED:β-Lactam antibiotics are the drugs of choice to treat pneumococcal infections. The spread of β-lactam-resistant pneumococci is a major concern in choosing an effective therapy for patients. Systematically tracking β-lactam resistance could benefit disease surveillance. Here we developed a classification syst...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.00756-16
更新日期:2016-06-14 00:00:00
abstract::Most bacteria can generate ATP by respiratory metabolism, in which electrons are shuttled from reduced substrates to terminal electron acceptors, via quinone molecules like ubiquinone. Dioxygen (O2) is the terminal electron acceptor of aerobic respiration and serves as a co-substrate in the biosynthesis of ubiquinone....
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.01319-19
更新日期:2019-07-09 00:00:00
abstract::Host cytokine responses to Brucella abortus infection are elicited predominantly by the deployment of a type IV secretion system (T4SS). However, the mechanism by which the T4SS elicits inflammation remains unknown. Here we show that translocation of the T4SS substrate VceC into host cells induces proinflammatory resp...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.00418-12
更新日期:2013-02-19 00:00:00
abstract::SpxA is a unique transcriptional regulator highly conserved among members of the phylum Firmicutes that binds RNA polymerase and can act as an antiactivator. Why some Firmicutes members have two highly similar SpxA paralogs is not understood. Here, we show that the SpxA paralogs of the pathogen Streptococcus pyogenes,...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.00288-17
更新日期:2017-03-28 00:00:00
abstract:UNLABELLED:A mechanistic understanding of the determination and maintenance of the simplest bacterial cell shape, a sphere, remains elusive compared with that of more complex shapes. Cocci seem to lack a dedicated elongation machinery, and a spherical shape has been considered an evolutionary dead-end morphology, as a ...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.00908-16
更新日期:2016-09-06 00:00:00