Interferon lambda inhibits dengue virus replication in epithelial cells

Palma-Ocampo, Helen K.; Flores-Alonso, Juan Carlos; Vallejo-Ruíz, Verónica; Reyes‐Leyva, Julio; Flores-Mendoza, Lilián; Herrera‐Camacho, Irma; Rosas-Murrieta, Nora Hilda; Santos‐López, Gerardo

doi:10.1186/s12985-015-0383-4

Cited by 52 publications

(52 citation statements)

References 39 publications

(52 reference statements)

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“…Among the four members of human IFN-L, IFN-L1 and IFN-L3 are studied most and show some differences in their antiviral activities (Dellgren et al, 2009;Lazear et al, 2015;review). Previous studies have shown that human IFN-L3 has the highest antiviral activity in an in vitro model of encephalomyocarditis viral infection (Palma-Ocampo et al, 2015). This finding is consistent with our results comparing the anti-PEDV activity of rpIFN-L1 and L3, as we found that rpIFN-L3 exhibited more anti-PEDV activity at lower concentrations (from 100 ng/ml to 10 ng/ml) than rpIFN-L1 in IPEC-J2 cells (Figs.…”

Section: Discussionsupporting

confidence: 93%

IFN-lambda preferably inhibits PEDV infection of porcine intestinal epithelial cells compared with IFN-alpha

Xue

et al. 2017

Antiviral Research

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In contrast to type I interferons that target various types of cells and organs, interferon lambda (IFN-L) primarily acts on mucosal epithelial cells and exhibits robust antiviral activity within the mucosal surface. Porcine epidemic diarrhea virus (PEDV), which causes high morbidity and mortality in piglets, is an enteropathogenic coronavirus with economic importance. Here, we demonstrated that both recombinant porcine IFN-L1 (rpIFN-L1) and rpIFN-L3 have powerful antiviral activity against PEDV infection of both Vero E6 cells and the intestinal porcine epithelial cell line J2 (IPEC-J2). Both forms of rpIFN-L inhibited two genotypes of PEDV (strain CV777 of genotype 1 and strain LNCT2 of genotype 2). rpIFN-L1 primarily controlled viral infection in the early stage and had less antiviral activity in IPEC-J2 than in rpIFN-L3 cells infected with PEDV. In addition, rpIFN-L1 exhibited greater antiviral activity against PEDV infection of IPEC-J2 cells than that of porcine IFN-alpha. Consistent with this finding, rpIFN-L1 triggered higher levels of certain antiviral IFN-stimulated genes (ISGs) (ISG15, OASL, and MxA) in IPEC-J2 cells than porcine IFN-alpha. Although IPEC-J2 cells responded to both IFN-alpha and lambda, transcriptional profiling of ISGs (specifically ISG15, OASL, MxA, and IFITMs) differed when induced by either IFN-alpha or rpIFN-L. Therefore, our data provide the experimental evidence that porcine IFN-L suppresses PEDV infection of IPEC-J2 cells, which may offer a promising therapeutic for combating PED in piglets.

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Section: Discussionsupporting

confidence: 93%

IFN-lambda preferably inhibits PEDV infection of porcine intestinal epithelial cells compared with IFN-alpha

Xue

et al. 2017

Antiviral Research

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“…In our study, IFN-3 restricts PEDV infection more efficiently than does IFN-1 (Fig. 2), which is consistent with the previously reported finding that IFN-3 exhibits more potent antiviral activity than does IFN-1 (44,46). The potent antiviral activities of type III IFNs indicate therapeutic applications of these cytokines to enteric viral infections.…”

Section: Discussionsupporting

confidence: 92%

Type III Interferon Restriction by Porcine Epidemic Diarrhea Virus and the Role of Viral Protein nsp1 in IRF1 Signaling

Zhang

Blikslager

et al. 2018

J Virol

119

161

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Type III interferons (IFNs) play a vital role in maintaining the antiviral state of the mucosal epithelial surface in the gut, and in turn, enteric viruses may have evolved to evade the type III IFN responses during infection. To study the possible immune evasion of the type III IFN response by porcine epidemic diarrhea virus (PEDV), a line of porcine intestinal epithelial cells was developed as a cell model for PEDV replication. IFN-λ1 and IFN-λ3 inhibited PEDV replication, indicating the anti-PEDV activity of type III IFNs. Of the 21 PEDV proteins, nsp1, nsp3, nsp5, nsp8, nsp14, nsp15, nsp16, open reading frame 3 (ORF3), E, M, and N were found to suppress type III IFN activities, and IRF1 (interferon regulatory factor 1) signaling mediated the suppression. PEDV specifically inhibited IRF1 nuclear translocation. The peroxisome is the innate antiviral signaling platform for the activation of IRF1-mediated IFN-λ production, and the numbers of peroxisomes were found to be decreased in PEDV-infected cells. PEDV nsp1 blocked the nuclear translocation of IRF1 and reduced the number of peroxisomes to suppress IRF1-mediated type III IFNs. Mutational studies showed that the conserved residues of nsp1 were crucial for IRF1-mediated IFN-λ suppression. Our study for the first time provides evidence that the porcine enteric virus PEDV downregulates and evades IRF1-mediated type III IFN responses by reducing the number of peroxisomes. Porcine epidemic diarrhea virus (PEDV) is a highly contagious enteric coronavirus that emerged in swine in the United States and has caused severe economic losses. PEDV targets intestinal epithelial cells in the gut, and intestinal epithelial cells selectively induce and respond to the production of type III interferons (IFNs). However, little is known about the modulation of the type III IFN response by PEDV in intestinal epithelial cells. In this study, we established a porcine intestinal epithelial cell model for PEDV replication. We found that PEDV inhibited IRF1-mediated type III IFN production by decreasing the number of peroxisomes in porcine intestinal epithelial cells. We also demonstrated that the conserved residues in the PEDV nsp1 protein were crucial for IFN suppression. This study for the first time shows PEDV evasion of the type III IFN response in intestinal epithelial cells, and it provides valuable information on host cell-virus interactions not only for PEDV but also for other enteric viral infections in swine.

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“…Type-III IFNs have been shown to control a range of clinically important infections such as flu (21, 59), respiratory syncytial virus (60), norovirus (19, 20), rotavirus (61), Zika virus (62), West Nile virus (63) and Dengue (64). Expression of type-III IFNs in cells of epithelial origin was also induced by clinically relevant bacterial pathogens such as S. aureus and L. monocytogenes as well as M. tuberculosis (65).…”

Section: Discussionmentioning

confidence: 99%

IFN-λ4 Attenuates Antiviral Responses by Enhancing Negative Regulation of IFN Signaling

Obajemu

Rao

Dilley

et al. 2017

The Journal of Immunology

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Type-III interferons (IFNs) are important mediators of antiviral immunity. IFN-λ4 is a unique type-III IFN because it is produced only in individuals who carry a dG allele of a genetic variant rs368234815-dG/TT. Counterintuitively, those individuals who can produce IFN-λ4, an antiviral cytokine, are also less likely to clear HCV infection. Here, we searched for unique functional properties of IFN-λ4 that might explain its negative effect on HCV clearance. We used fresh primary human hepatocytes (PHH) treated with recombinant type-III IFNs or infected with Sendai virus (SeV) to model acute viral infection, and subsequently validated our findings in HepG2 cell line models. Endogenous IFN-λ4 protein was detectable only in SeV-infected PHH from individuals with the dG allele, where it was poorly secreted but highly functional even at concentrations below 50 pg/ml. IFN-λ4 acted faster than other type-III IFNs in inducing antiviral genes as well as negative regulators of IFN response, such as USP18 and SOCS1. Transient treatment of PHH with IFN-λ4 but not IFN-λ3 caused a strong and sustained induction of SOCS1, and refractoriness to further stimulation with IFN-λ3. Our results suggest unique functional properties of IFN-λ4 that can be important in viral clearance and other clinical conditions.

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Interferon lambda inhibits dengue virus replication in epithelial cells

Cited by 52 publications

References 39 publications

IFN-lambda preferably inhibits PEDV infection of porcine intestinal epithelial cells compared with IFN-alpha

IFN-lambda preferably inhibits PEDV infection of porcine intestinal epithelial cells compared with IFN-alpha

Type III Interferon Restriction by Porcine Epidemic Diarrhea Virus and the Role of Viral Protein nsp1 in IRF1 Signaling

IFN-λ4 Attenuates Antiviral Responses by Enhancing Negative Regulation of IFN Signaling

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