scholarly journals Activation of the Chicken Type I Interferon Response by Infectious Bronchitis Coronavirus

2014 ◽  
Vol 89 (2) ◽  
pp. 1156-1167 ◽  
Author(s):  
Joeri Kint ◽  
Marcela Fernandez-Gutierrez ◽  
Helena J. Maier ◽  
Paul Britton ◽  
Martijn A. Langereis ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Cell Types ◽  
Interferon Response ◽  
Type I ◽  
Content Type ◽  
Infectious Bronchitis ◽  
Tracheal Epithelial Cells ◽  
Chicken Cell ◽  
Host Virus Interactions ◽  
Virus Interactions

ABSTRACTCoronaviruses from both theAlphacoronavirusandBetacoronavirusgenera interfere with the type I interferon (IFN) response in various ways, ensuring the limited activation of the IFN response in most cell types. Of the gammacoronaviruses that mainly infect birds, little is known about the activation of the host immune response. We show that the prototypicalGammacoronavirus, infectious bronchitis virus (IBV), induces a delayed activation of the IFN response in primary renal cells, tracheal epithelial cells, and a chicken cell line. In fact,Ifnβexpression is delayed with respect to the peak of viral replication and the accompanying accumulation of double-stranded RNA (dsRNA). In addition, we demonstrate that MDA5 is the primary sensor forGammacoronavirusinfections in chicken cells. Furthermore, we provide evidence that accessory proteins 3a and 3b of IBV modulate the response at the transcriptional and translational levels. Finally, we show that, despite the lack of activation of the IFN response during the early phase of IBV infection, the signaling of nonself dsRNA through both MDA5 and TLR3 remains intact in IBV-infected cells. Taken together, this study provides the first comprehensive analysis of host-virus interactions of aGammacoronaviruswith avian innate immune responses.IMPORTANCEOur results demonstrate that IBV has evolved multiple strategies to avoid the activation of the type I interferon response. Taken together, the present study closes a gap in the understanding of host-IBV interaction and paves the way for further characterization of the mechanisms underlying immune evasion strategies as well as the pathogenesis of gammacoronaviruses.

scholarly journals Nicastrin haploinsufficiency alters expression of type-I interferon-stimulated genes in two immortalized human cell lines

2018 ◽  
Author(s):  
Li Cao ◽  
David J. Morales-Heil ◽  
Elisha D. O. Roberson
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Rare Variants ◽  
Type I Interferon ◽  
Human Keratinocytes ◽  
Cell Types ◽  
Interferon Response ◽  
Luciferase Reporter ◽  
Type I ◽  
Loss Of Function

A.AbstractBackgroundHidradenitis suppurativa (HS) is a chronic skin disease. The symptoms can be severe, and include intensely painful nodules and abscesses in apocrine-gland rich inverse skin, such as the buttocks, under the arms, and the groin. Autosomal dominant forms of HS exist, but are rare. Some of these kindred have heterozygous loss-of-function rare variants in the γ-secretase complex component nicastrin (NCSTN).ObjectivesWe wanted to know what effect NCSTN haploinsufficiency has on human keratinocytes to assess potential mechanisms for lesion development.MethodsWe knocked down nicastrin using an shRNA construct in both a keratinocyte cell line (HEK001) and an embryonic kidney cell line (HEK293). We assessed differential gene expression using RNA microarray. We also generated a NCSTN heterozygous deletion in the HEK293 line using CRISPR/Cas9 genome-editing and assessed NFKB activity in this line using a luciferase reporter.ResultsThe keratinocyte NCSTN knockdown cell line demonstrated significantly increased expression of genes related to the type-I interferon response pathway when compared to controls. Both HEK001 and HEK293 knockdowns demonstrated evidence for altered growth. We observed a small, but significant increase in NFKB signaling in response to TNF treatment a HEK293 line genome-edited for reduced NCSTN.ConclusionsOur data suggest a role for increased keratinocyte inflammatory responsiveness in familial HS. Confirming this phenotype, and characterizing additional effects in different cell types, will require study beyond cell lines in primary cells and tissues.

scholarly journals The Andes Orthohantavirus NSs Protein Antagonizes the Type I Interferon Response by Inhibiting MAVS Signaling

2020 ◽  
Vol 94 (13) ◽  
Author(s):  
Jorge Vera-Otarola ◽  
Loretto Solis ◽  
Fernando Lowy ◽  
Valeria Olguín ◽  
Jenniffer Angulo ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Type I Interferon ◽  
Innate Immune ◽  
Interferon Response ◽  
Type I ◽  
Free System ◽  
Content Type ◽  
N Protein ◽  
The Andes ◽  
Cellular Antiviral Response

ABSTRACT The small messenger RNA (SmRNA) of the Andes orthohantavirus (ANDV), a rodent-borne member of the Hantaviridae family of viruses of the Bunyavirales order, encodes a multifunctional nucleocapsid (N) protein and for a nonstructural (NSs) protein of unknown function. We have previously shown the expression of the ANDV-NSs, but only in infected cell cultures. In this study, we extend our early findings by confirming the expression of the ANDV-NSs protein in the lungs of experimentally infected golden Syrian hamsters. Next, we show, using a virus-free system, that the ANDV-NSs protein antagonizes the type I interferon (IFN) induction pathway by suppressing signals downstream of the melanoma differentiation-associated protein 5 (MDA5) and the retinoic acid-inducible gene 1 (RIG-I) and upstream of TBK1. Consistent with this observation, the ANDV-NSs protein antagonized mitochondrial antiviral-signaling protein (MAVS)-induced IFN-β, NF-κB, IFN-regulatory factor 3 (IRF3), and IFN-sensitive response element (ISRE) promoter activity. Results demonstrate that ANDV-NSs binds to MAVS in cells without disrupting the MAVS-TBK-1 interaction. However, in the presence of the ANDV-NSs ubiquitination of MAVS is reduced. In summary, this study provides evidence showing that the ANDV-NSs protein acts as an antagonist of the cellular innate immune system by suppressing MAVS downstream signaling by a yet not fully understand mechanism. Our findings reveal new insights into the molecular regulation of the hosts’ innate immune response by the Andes orthohantavirus. IMPORTANCE Andes orthohantavirus (ANDV) is endemic in Argentina and Chile and is the primary etiological agent of hantavirus cardiopulmonary syndrome (HCPS) in South America. ANDV is distinguished from other hantaviruses by its unique ability to spread from person to person. In a previous report, we identified a novel ANDV protein, ANDV-NSs. Until now, ANDV-NSs had no known function. In this new study, we established that ANDV-NSs acts as an antagonist of cellular innate immunity, the first line of defense against invading pathogens, hindering the cellular antiviral response during infection. This study provides novel insights into the mechanisms used by ANDV to establish its infection.

scholarly journals The Human P-Glycoprotein Transporter Enhances the Type I Interferon Response to Listeria monocytogenes Infection

2015 ◽  
Vol 83 (6) ◽  
pp. 2358-2368 ◽  
Author(s):  
Nadejda Sigal ◽  
Millie Kaplan Zeevi ◽  
Shiri Weinstein ◽  
Dan Peer ◽  
Anat A. Herskovits
Keyword(s):  
Listeria Monocytogenes ◽  
Type I Interferon ◽  
Bacterial Pathogen ◽  
Type I Interferons ◽  
Interferon Response ◽  
Type I ◽  
Monocytic Cell ◽  
Monocytic Cell Line ◽  
Content Type ◽  
P Glycoprotein

Human multidrug efflux transporters are known for their ability to extrude antibiotics and toxic compounds out of cells, yet accumulating data indicate they have additional functions in diverse physiological processes not related to drug efflux. Here, we show that the human multidrug transporter P-glycoprotein (P-gp) (also named MDR1 and ABCB1) is transcriptionally induced in the monocytic cell line THP-1 upon infection with the human intracellular bacterial pathogenListeria monocytogenes. Notably, we found that P-gp is important for full activation of the type I interferon response elicited againstL. monocytogenesbacteria. Both inhibition of P-gp function by verapamil and inhibition of its transcription using mRNA silencing led to a reduction in the magnitude of the type I response in infected cells. This function of P-gp was specific to type I interferon cytokines elicited against cytosolic replicating bacteria and was not observed in response to cyclic di-AMP (c-di-AMP), a molecule that was shown to be secreted byL. monocytogenesduring infection and to trigger type I interferons. Moreover, P-gp was not involved in activation of other proinflammatory cytokines, such as those triggered by vacuolar-restrictedL. monocytogenesor lipopolysaccharide (LPS). Taken together, these findings demonstrate a role for P-gp in proper development of an innate immune response against intracellular pathogens, highlighting the complexity in employing therapeutic strategies that involve inhibition of multidrug resistance (MDR) efflux pumps.

scholarly journals Mycobacterium tuberculosis MmsA (Rv0753c) Interacts with STING and Blunts the Type I Interferon Response

mBio ◽  
2020 ◽  
Vol 11 (6) ◽  
Author(s):  
Yifan Sun ◽  
Wei Zhang ◽  
Chunsheng Dong ◽  
Sidong Xiong
Keyword(s):  
Mass Spectrometry ◽  
Mycobacterium Tuberculosis ◽  
Proteomic Analysis ◽  
Type I Interferon ◽  
Interferon Response ◽  
Type I ◽  
Type I Ifn ◽  
Content Type ◽  
C Terminus ◽  
Autophagic Degradation

ABSTRACT Type I interferon (IFN) plays an important role in Mycobacterium tuberculosis persistence and disease pathogenesis. M. tuberculosis has evolved a number of mechanisms to evade host immune surveillance. However, it is unclear how the type I IFN response is tightly regulated by the M. tuberculosis determinants. Stimulator of interferon genes (STING) is an essential adaptor for type I IFN production triggered by M. tuberculosis genomic DNA or cyclic dinucleotides upon infection. To investigate how the type I IFN response is regulated by M. tuberculosis determinants, immunoprecipitation-mass spectrometry-based (IP-MS) proteomic analysis was performed to screen proteins interacting with STING in the context of M. tuberculosis infection. Among the many predicted candidates interacting with STING, the M. tuberculosis coding protein Rv0753c (MmsA) was identified. We confirmed that MmsA binds and colocalizes with STING, and the N-terminal regions of MmsA (amino acids [aa] 1 to 251) and STING (aa 1 TO 190) are responsible for MmsA-STING interaction. Type I IFN production was impaired with exogenous expression of MmsA in RAW264.7 cells. MmsA inhibited the STING-TBK1-IRF3 pathway, as evidenced by reduced STING levelS and subsequent IRF3 activation. Furthermore, MmsA facilitated p62-mediated STING autophagic degradation by binding p62 with its C terminus (aa 252 to 455), which may account for the negative regulation of M. tuberculosis MmsA in STING-mediated type I IFN production. Additionally, the M. tuberculosis mmsA R138W mutation, detected in a hypervirulent clinical isolate, enhanced the degradation of STING, implying the important relevance of MmsA in disease outcome. Together, we report a novel mechanism where M. tuberculosis MmsA serves as an antagonist of type I IFN response by targeting STING with p62-mediated autophagic degradation. IMPORTANCE It is unclear how the type I IFN response is regulated by mycobacterial determinants. Here, we characterized the previously unreported role of M. tuberculosis MmsA in immunological regulation of type I IFN response by targeting the central adaptor STING in the DNA sensing pathway. We identified STING-interacting MmsA by coimmunoprecipitation-mass spectrometry-based (IP-MS) proteomic analysis and showed MmsA interacting with STING and autophagy receptor p62 via its N terminus and C terminus, respectively. We also showed that MmsA downregulated type I IFN by promoting p62-mediated STING degradation. Moreover, the MmsA mutant R138W is potentially associated with the virulence of M. tuberculosis clinical strains owing to the modulation of STING protein. Our results provide novel insights into the regulatory mechanism of type I IFN response manipulated by mycobacterial MmsA and the additional cross talk between autophagy and STING in M. tuberculosis infection, wherein a protein from microbial pathogens induces autophagic degradation of host innate immune molecules.

scholarly journals Infectious Bronchitis Coronavirus Limits Interferon Production by Inducing a Host Shutoff That Requires Accessory Protein 5b

2016 ◽  
Vol 90 (16) ◽  
pp. 7519-7528 ◽  
Author(s):  
Joeri Kint ◽  
Martijn A. Langereis ◽  
Helena J. Maier ◽  
Paul Britton ◽  
Frank J. van Kuppeveld ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Infectious Bronchitis Virus ◽  
Type I Interferon ◽  
Antiviral Response ◽  
Accessory Protein ◽  
Type I ◽  
Host Proteins ◽  
Content Type ◽  
Infectious Bronchitis ◽  
Host Shutoff

ABSTRACTDuring infection of their host cells, viruses often inhibit the production of host proteins, a process that is referred to as host shutoff. By doing this, viruses limit the production of antiviral proteins and increase production capacity for viral proteins. Coronaviruses from the generaAlphacoronavirusandBetacoronavirus, such as severe acute respiratory syndrome coronavirus (SARS-CoV), establish host shutoff via their nonstructural protein 1 (nsp1). TheGammacoronavirusandDeltacoronavirusgenomes, however, do not encode nsp1, and it has been suggested that these viruses do not induce host shutoff. Here, we show that theGammacoronavirusinfectious bronchitis virus (IBV) does induce host shutoff, and we find that its accessory protein 5b is indispensable for this function. Importantly, we found that 5b-null viruses, unlike wild-type viruses, induce production of high concentrations of type I interferon proteinin vitro, indicating that host shutoff by IBV plays an important role in antagonizing the host's innate immune response. Altogether, we demonstrate that 5b is a functional equivalent of nsp1, thereby answering the longstanding question of whether lack of nsp1 in gammacoronaviruses is compensated for by another viral protein. As such, our study is a significant step forward in the understanding of coronavirus biology and closes a gap in the understanding of some IBV virulence strategies.IMPORTANCEMany viruses inhibit protein synthesis by their host cell to enhance virus replication and to antagonize antiviral defense mechanisms. This process is referred to as host shutoff. We studied gene expression and protein synthesis in chicken cells infected with the important poultry pathogen infectious bronchitis virus (IBV). We show that IBV inhibits synthesis of host proteins, including that of type I interferon, a key component of the antiviral response. The IBV-induced host shutoff, however, does not require degradation of host RNA. Furthermore, we demonstrate that accessory protein 5b of IBV plays a crucial role in the onset of host shutoff. Our findings suggest that inhibition of host protein synthesis is a common feature of coronaviruses and primarily serves to inhibit the antiviral response of the host.

scholarly journals Cyclic di-AMP Released from Staphylococcus aureus Biofilm Induces a Macrophage Type I Interferon Response

2016 ◽  
Vol 84 (12) ◽  
pp. 3564-3574 ◽  
Author(s):  
Casey M. Gries ◽  
Eric L. Bruger ◽  
Derek E. Moormeier ◽  
Tyler D. Scherr ◽  
Christopher M. Waters ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Biofilm Formation ◽  
Bacterial Infections ◽  
Type I Interferon ◽  
Interferon Response ◽  
Type I ◽  
Type I Ifn ◽  
Biofilm Growth ◽  
Content Type ◽  
Anti Inflammatory

Staphylococcus aureus is a leading cause of community- and nosocomial-acquired infections, with a propensity for biofilm formation. S. aureus biofilms actively skew the host immune response toward an anti-inflammatory state; however, the biofilm effector molecules and the mechanism(s) of action responsible for this phenomenon remain to be fully defined. The essential bacterial second messenger cyclic diadenylate monophosphate (c-di-AMP) is an emerging pathogen-associated molecular pattern during intracellular bacterial infections, as c-di-AMP secretion into the infected host cytosol induces a robust type I interferon (IFN) response. Type I IFNs have the potential to exacerbate infectious outcomes by promoting anti-inflammatory effects; however, the type I IFN response to S. aureus biofilms is unknown. Additionally, while several intracellular proteins function as c-di-AMP receptors in S. aureus , it has yet to be determined if any extracellular role for c-di-AMP exists and its release during biofilm formation has not yet been demonstrated. This study examined the possibility that c-di-AMP released during S. aureus biofilm growth polarizes macrophages toward an anti-inflammatory phenotype via type I interferon signaling. DacA, the enzyme responsible for c-di-AMP synthesis in S. aureus , was highly expressed during biofilm growth, and 30 to 50% of total c-di-AMP produced from S. aureus biofilm was released extracellularly due to autolytic activity. S. aureus biofilm c-di-AMP release induced macrophage type I IFN expression via a STING-dependent pathway and promoted S. aureus intracellular survival in macrophages. These findings identify c-di-AMP as another mechanism for how S. aureus biofilms promote macrophage anti-inflammatory activity, which likely contributes to biofilm persistence.

Viral Invasion and Type I Interferon Response Characterize the Immunophenotypes during COVID-19 Infection

2020 ◽  
Author(s):  
Lai Wei ◽  
Siqi Ming ◽  
Bin Zou ◽  
Yongjian Wu ◽  
Zhongsi Hong ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Interferon Response ◽  
Type I

scholarly journals Positive natural selection in primate genes of the type I interferon response

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Elena N. Judd ◽  
Alison R. Gilchrist ◽  
Nicholas R. Meyerson ◽  
Sara L. Sawyer
Keyword(s):  
Natural Selection ◽  
Positive Selection ◽  
Type I Interferon ◽  
Interferon Response ◽  
Type I ◽  
Sequence Alignments ◽  
Multiple Sequence ◽  
Multiple Sequence Alignments ◽  
Interferon Stimulated Genes ◽  
Interferon Induction

Abstract Background The Type I interferon response is an important first-line defense against viruses. In turn, viruses antagonize (i.e., degrade, mis-localize, etc.) many proteins in interferon pathways. Thus, hosts and viruses are locked in an evolutionary arms race for dominance of the Type I interferon pathway. As a result, many genes in interferon pathways have experienced positive natural selection in favor of new allelic forms that can better recognize viruses or escape viral antagonists. Here, we performed a holistic analysis of selective pressures acting on genes in the Type I interferon family. We initially hypothesized that the genes responsible for inducing the production of interferon would be antagonized more heavily by viruses than genes that are turned on as a result of interferon. Our logic was that viruses would have greater effect if they worked upstream of the production of interferon molecules because, once interferon is produced, hundreds of interferon-stimulated proteins would activate and the virus would need to counteract them one-by-one. Results We curated multiple sequence alignments of primate orthologs for 131 genes active in interferon production and signaling (herein, “induction” genes), 100 interferon-stimulated genes, and 100 randomly chosen genes. We analyzed each multiple sequence alignment for the signatures of recurrent positive selection. Counter to our hypothesis, we found the interferon-stimulated genes, and not interferon induction genes, are evolving significantly more rapidly than a random set of genes. Interferon induction genes evolve in a way that is indistinguishable from a matched set of random genes (22% and 18% of genes bear signatures of positive selection, respectively). In contrast, interferon-stimulated genes evolve differently, with 33% of genes evolving under positive selection and containing a significantly higher fraction of codons that have experienced selection for recurrent replacement of the encoded amino acid. Conclusion Viruses may antagonize individual products of the interferon response more often than trying to neutralize the system altogether.

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