The ADP-ribose-1″-monophosphatase domains of severe acute respiratory syndrome coronavirus and human coronavirus 229E mediate resistance to antiviral interferon responses

Several plus-strand RNA viruses encode proteins containing macrodomains. These domains possess ADP-ribose-1″-phosphatase (ADRP) activity and/or bind poly(ADP-ribose), poly(A) or poly(G). The relevance of these activities in the viral life cycle has not yet been resolved. Here, we report that genetically engineered mutants of severe acute respiratory syndrome coronavirus (SARS-CoV) and human coronavirus 229E (HCoV-229E) expressing ADRP-deficient macrodomains displayed an increased sensitivity to the antiviral effect of alpha interferon compared with their wild-type counterparts. The data suggest that macrodomain-associated ADRP activities may have a role in viral escape from the innate immune responses of the host.

Download Full-text

Deubiquitinase Activity and Regulation of Antiviral Innate Immune Responses by Papain-like Proteases of Human Coronavirus NL63*

PROGRESS IN BIOCHEMISTRY AND BIOPHYSICS ◽

10.3724/sp.j.1206.2010.00111 ◽

2010 ◽

Vol 37 (8) ◽

pp. 871-880 ◽

Cited By ~ 5

Author(s):

Li SUN ◽

Yu-Dong YANG ◽

Dian-Bo LIU ◽

Ya-Ling XING ◽

Xiao-Juan CHEN ◽

...

Keyword(s):

Immune Responses ◽

Innate Immune ◽

Innate Immune Responses ◽

Human Coronavirus

Download Full-text

Structure of interferon-stimulated gene product 15 (ISG15) from the bat species Myotis davidii and the impact of interdomain ISG15 interactions on viral protein engagement

Acta Crystallographica Section D Structural Biology ◽

10.1107/s2059798318015322 ◽

2019 ◽

Vol 75 (1) ◽

pp. 21-31 ◽

Cited By ~ 6

Author(s):

Caroline Langley ◽

Octavia Goodwin ◽

John V. Dzimianski ◽

Courtney M. Daczkowski ◽

Scott D. Pegan

Keyword(s):

Gene Product ◽

Species Differences ◽

Viral Proteins ◽

Innate Immune ◽

Type I ◽

Innate Immune Responses ◽

Host Proteins ◽

Post Translational Modifications ◽

Interferon Responses ◽

The Impact

Bats have long been observed to be the hosts and the origin of numerous human diseases. Bats, like all mammals, rely on a number of innate immune mechanisms to combat invading pathogens, including the interferon type I, II and III responses. Ubiquitin-like interferon-stimulated gene product 15 (ISG15) is a key modulator of these interferon responses. Within these pathways, ISG15 can serve to stabilize host proteins modulating innate immune responses and act as a cytokine. Post-translational modifications of viral proteins introduced by ISG15 have also been observed to directly affect the function of numerous viral proteins. Unlike ubiquitin, which is virtually identical across all animals, comparison of ISG15s across species reveals that they are relatively divergent, with sequence identity dropping to as low as ∼58% among mammals. In addition to serving as an obstacle to the zoonotic transmission of influenza, these ISG15 species–species differences have also long been shown to have an impact on the function of viral deISGylases. Recently, the structure of the first nonhuman ISG15, originating from mouse, suggested that the structures of human ISG15 may not be reflective of other species. Here, the structure of ISG15 from the bat species Myotis davidii solved to 1.37 Å resolution is reported. Comparison of this ISG15 structure with those from human and mouse not only underscores the structural impact of ISG15 species–species differences, but also highlights a conserved hydrophobic motif formed between the two domains of ISG15. Using the papain-like deISGylase from Severe acute respiratory syndrome coronavirus as a probe, the biochemical importance of this motif in ISG15–protein engagements was illuminated.

Download Full-text

Innate Immune Responses of Bat and Human Cells to Filoviruses: Commonalities and Distinctions

Journal of Virology ◽

10.1128/jvi.02471-16 ◽

2017 ◽

Vol 91 (8) ◽

Cited By ~ 22

Author(s):

Ivan V. Kuzmin ◽

Toni M. Schwarz ◽

Philipp A. Ilinykh ◽

Ingo Jordan ◽

Thomas G. Ksiazek ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Innate Immune Response ◽

Antiviral Effect ◽

Human Cells ◽

Innate Immune ◽

Innate Immune Responses ◽

Symptomatic Disease ◽

Ifn Γ

ABSTRACT Marburg (MARV) and Ebola (EBOV) viruses are zoonotic pathogens that cause severe hemorrhagic fever in humans. The natural reservoir of MARV is the Egyptian rousette bat (Rousettus aegyptiacus); that of EBOV is unknown but believed to be another bat species. The Egyptian rousette develops subclinical productive infection with MARV but is refractory to EBOV. Interaction of filoviruses with hosts is greatly affected by the viral interferon (IFN)-inhibiting domains (IID). Our study was aimed at characterization of innate immune responses to filoviruses and the role of filovirus IID in bat and human cells. The study demonstrated that EBOV and MARV replicate to similar levels in all tested cell lines, indicating that permissiveness for EBOV at cell and organism levels do not necessarily correlate. Filoviruses, particularly MARV, induced a potent innate immune response in rousette cells, which was generally stronger than that in human cells. Both EBOV VP35 and VP24 IID were found to suppress the innate immune response in rousette cells, but only VP35 IID appeared to promote virus replication. Along with IFN-α and IFN-β, IFN-γ was demonstrated to control filovirus infection in bat cells but not in human cells, suggesting host species specificity of the antiviral effect. The antiviral effects of bat IFNs appeared not to correlate with induction of IFN-stimulated genes 54 and 56, which were detected in human cells ectopically expressing bat IFN-α and IFN-β. As bat IFN-γ induced the type I IFN pathway, its antiviral effect is likely to be partially induced via cross talk. IMPORTANCE Bats serve as reservoirs for multiple emerging viruses, including filoviruses, henipaviruses, lyssaviruses, and zoonotic coronaviruses. Although there is no evidence for symptomatic disease caused by either Marburg or Ebola viruses in bats, spillover of these viruses into human populations causes deadly outbreaks. The reason for the lack of symptomatic disease in bats infected with filoviruses remains unknown. The outcome of a virus-host interaction depends on the ability of the host immune system to suppress viral replication and the ability of a virus to counteract the host defenses. Our study is a comparative analysis of the host innate immune response to either MARV or EBOV infection in bat and human cells and the role of viral interferon-inhibiting domains in the host innate immune responses. The data are useful for understanding the interactions of filoviruses with natural and accidental hosts and for identification of factors that influence filovirus evolution.

Download Full-text

Rotavirus susceptibility of antibiotic-treated mice ascribed to diminished expression of interleukin-22

PLoS ONE ◽

10.1371/journal.pone.0247738 ◽

2021 ◽

Vol 16 (8) ◽

pp. e0247738

Author(s):

Daniel Schnepf ◽

Pedro Hernandez ◽

Tanel Mahlakõiv ◽

Stefania Crotta ◽

Meagan E. Sullender ◽

...

Keyword(s):

Antiviral Effect ◽

Innate Immune ◽

Fine Tuning ◽

Type I ◽

Innate Immune Responses ◽

Wild Type ◽

Interleukin 22 ◽

Commensal Microbiota ◽

Type Iii Interferon ◽

Deficient Mice

The commensal microbiota regulates susceptibility to enteric pathogens by fine-tuning mucosal innate immune responses, but how susceptibility to enteric viruses is shaped by the microbiota remains incompletely understood. Past reports have indicated that commensal bacteria may either promote or repress rotavirus replication in the small intestine of mice. We now report that rotavirus replicated more efficiently in the intestines of germ-free and antibiotic-treated mice compared to animals with an unmodified microbiota. Antibiotic treatment also facilitated rotavirus replication in type I and type III interferon (IFN) receptor-deficient mice, revealing IFN-independent proviral effects. Expression of interleukin-22 (IL-22) was strongly diminished in the intestine of antibiotic-treated mice. Treatment with exogenous IL-22 blocked rotavirus replication in microbiota-depleted wild-type and Stat1-/- mice, demonstrating that the antiviral effect of IL-22 in animals with altered microbiome is not dependent on IFN signaling. In antibiotic-treated animals, IL-22-induced a specific set of genes including Fut2, encoding fucosyl-transferase 2 that participates in the biosynthesis of fucosylated glycans which can mediate rotavirus binding. Interestingly, IL-22 also blocked rotavirus replication in antibiotic-treated Fut2-/- mice. Furthermore, IL-22 inhibited rotavirus replication in antibiotic-treated mice lacking key molecules of the necroptosis or pyroptosis pathways of programmed cell death. Taken together, our results demonstrate that IL-22 determines rotavirus susceptibility of antibiotic-treated mice, yet the IL-22-induced effector molecules conferring rotavirus resistance remain elusive.

Download Full-text

To “Z” or not to “Z”: Z-RNA, self-recognition, and the MDA5 helicase

PLoS Genetics ◽

10.1371/journal.pgen.1009513 ◽

2021 ◽

Vol 17 (5) ◽

pp. e1009513

Author(s):

Alan Herbert

Keyword(s):

Immune Responses ◽

Innate Immune ◽

Type I ◽

Innate Immune Responses ◽

Genetic Elements ◽

Self Recognition ◽

Risc Complex ◽

A Site ◽

Interferon Responses ◽

Rna Formation

Double-stranded RNA (dsRNA) is produced both by virus and host. Its recognition by the melanoma differentiation–associated gene 5 (MDA5) initiates type I interferon responses. How can a host distinguish self-transcripts from nonself to ensure that responses are targeted correctly? Here, I discuss a role for MDA5 helicase in inducing Z-RNA formation by Alu inverted repeat (AIR) elements. These retroelements have highly conserved sequences that favor Z-formation, creating a site for the dsRNA-specific deaminase enzyme ADAR1 to dock. The subsequent editing destabilizes the dsRNA, ending further interaction with MDA5 and terminating innate immune responses directed against self. By enabling self-recognition, Alu retrotransposons, once invaders, now are genetic elements that keep immune responses in check. I also discuss the possible but less characterized roles of the other helicases in modulating innate immune responses, focusing on DExH-box helicase 9 (DHX9) and Mov10 RISC complex RNA helicase (MOV10). DHX9 and MOV10 function differently from MDA5, but still use nucleic acid structure, rather than nucleotide sequence, to define self. Those genetic elements encoding the alternative conformations involved, referred to as flipons, enable helicases to dynamically shape a cell’s repertoire of responses. In the case of MDA5, Alu flipons switch off the dsRNA-dependent responses against self. I suggest a number of genetic systems in which to study interactions between flipons and helicases further.

Download Full-text

Rotavirus susceptibility of antibiotic-treated mice ascribed to diminished expression of interleukin-22

10.1101/2021.02.18.431818 ◽

2021 ◽

Cited By ~ 1

Author(s):

Daniel Schnepf ◽

Pedro Hernandez ◽

Tanel Mahlakõiv ◽

Stefania Crotta ◽

Meagan E. Sullender ◽

...

Keyword(s):

Antiviral Effect ◽

Innate Immune ◽

Fine Tuning ◽

Type I ◽

Innate Immune Responses ◽

Glycosylation Pattern ◽

Interleukin 22 ◽

Commensal Microbiota ◽

Type Iii Interferon ◽

Deficient Mice

AbstractThe commensal microbiota regulates susceptibility to enteric pathogens by fine-tuning mucosal innate immune responses, but how susceptibility to enteric viruses is shaped by the microbiota remains incompletely understood. Past reports have indicated that commensal bacteria may either promote or repress rotavirus replication in the small intestine of mice. We now report that rotavirus replicated more efficiently in the intestines of germ-free and antibiotic-treated mice compared to animals with an unmodified microbiota. Antibiotic treatment also facilitated rotavirus replication in type I and type III interferon (IFN) receptor-deficient mice, revealing IFN-independent proviral effects. Expression of interleukin-22 (IL-22) was strongly diminished in the intestine of antibiotic-treated mice. Treatment with exogenous IL-22 blocked rotavirus replication in microbiota-depleted wild-type and Stat1−/− mice, demonstrating that the antiviral effect of IL-22 in animals with altered microbiome is not dependent on IFN signaling. In antibiotic-treated animals, IL-22-induced a specific set of genes including Fut2, encoding fucosyl-transferase 2 that modifies the O-glycosylation pattern of rotavirus entry mediators. Interestingly, IL-22 also blocked rotavirus replication in antibiotic-treated Fut2−/− mice. Furthermore, IL-22 inhibited rotavirus replication in antibiotic-treated mice lacking key molecules of the necroptosis or pyroptosis pathways of programmed cell death. Taken together, our results demonstrate that IL-22 determines rotavirus susceptibility of antibiotic-treated mice, yet the IL-22-induced effector molecules conferring rotavirus resistance remain elusive.

Download Full-text

Influenza A virus antagonizes type I and type II interferon responses via SOCS1-dependent ubiquitination and degradation of JAK1

10.21203/rs.2.22023/v2 ◽

2020 ◽

Author(s):

Yinping Du ◽

Fan Yang ◽

Qiuxia Wang ◽

Nuo Xu ◽

Yizhang Xie ◽

...

Keyword(s):

Influenza A Virus ◽

Influenza A ◽

Innate Immune ◽

Cytokine Signaling ◽

Type I ◽

Type Ii ◽

Innate Immune Responses ◽

Suppressor Of Cytokine Signaling ◽

Interferon Responses ◽

Socs Protein

Abstract BACKGROUND Although influenza A virus (IAV) employs diverse strategies to evade IFN responses by inhibiting the synthesis of IFN, how IAV regulates signaling downstream of IFN is incompletely understood. METHODS In this study, we used Western blot-based protein analysis coupled with RT-qPCR, overexpression and RNA interference to investigate the regulation of JAK1 by IAV infection. RESULTS The results indicated that JAK1 was ubiquitinated and degraded, resulting in inhibition of type I and type II IFN responses, demonstrating that IAV antagonizes the IFN-activated JAK/STAT signaling pathway by inducing the degradation of JAK1. Furthermore. IAV infection upregulated the suppressor of cytokine signaling (SOCS) protein SOCS1, and SOCS1 mediated the ubiquitination and degradation of JAK1. CONCLUSION: Collectively, our findings suggest that IAV infection induced SOCS1 expression promotes JAK1 degradation, which in turn inhibits host innate immune responses.

Download Full-text

Severe Acute Respiratory Syndrome Coronavirus Fails To Activate Cytokine-Mediated Innate Immune Responses in Cultured Human Monocyte-Derived Dendritic Cells

Journal of Virology ◽

10.1128/jvi.79.21.13800-13805.2005 ◽

2005 ◽

Vol 79 (21) ◽

pp. 13800-13805 ◽

Cited By ~ 57

Author(s):

Thedi Ziegler ◽

Sampsa Matikainen ◽

Esa Rönkkö ◽

Pamela Österlund ◽

Maarit Sillanpää ◽

...

Keyword(s):

Dendritic Cells ◽

Severe Acute Respiratory Syndrome ◽

Immune Responses ◽

A549 Cells ◽

Human Monocyte ◽

Innate Immune ◽

Lung Epithelial Cells ◽

Cytokine Gene Expression ◽

Innate Immune Responses ◽

Necrosis Factor Alpha

ABSTRACT Activation of host innate immune responses was studied in severe acute respiratory syndrome coronavirus (SCV)-infected human A549 lung epithelial cells, macrophages, and dendritic cells (DCs). In all cell types, SCV-specific subgenomic mRNAs were seen, whereas no expression of SCV proteins was found. No induction of cytokine genes (alpha interferon [IFN-α], IFN-β, interleukin-28A/B [IL-28A/B], IL-29, tumor necrosis factor alpha, CCL5, or CXCL10) or IFN-α/β-induced MxA gene was seen in SCV-infected A549 cells, macrophages, or DCs. SCV also failed to induce DC maturation (CD86 expression) or enhance major histocompatibility complex class II expression. Our data strongly suggest that SCV fails to activate host cell cytokine gene expression in human macrophages and DCs.

Download Full-text