Induction of an Antiviral State and Attenuated Coxsackievirus Replication in Type III Interferon-Treated Primary Human Pancreatic Islets

Lind, Katharina; Richardson, Sarah J.; Leete, Pia; Morgan, Noel G.; Korsgren, Olle; Flodström‐Tullberg, Malin

doi:10.1128/jvi.03431-12

Cited by 36 publications

(62 citation statements)

References 42 publications

(81 reference statements)

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“…Previous studies have shown that enteroviruses such as the coxsackie B viruses (CVBs) block type I IFN production (Feng et al, 2014a;Mukherjee et al, 2011). Recently, we reported that type III IFNs attenuate the replication of coxsackievirus B3 (CVB3) in primary human pancreatic endocrine cells (Lind et al, 2013) and hepatocytes (Lind et al, 2014). Previous reports have indicated that some viruses may also inhibit the production of type III IFNs (Ding et al, 2012;Wang et al, 2011Wang et al, , 2014.…”

Section: Introductionmentioning

confidence: 99%

“…Type III IFNs bind to a specific receptor, the IFNlreceptor (IFNlR) consisting of two subunits, IFNLR1 and IL10R2. While the type I IFN receptor (IFNAR) is expressed on all nucleated cells, the IFNlR is only expressed on some immune cells and cells of an epithelial origin such as hepatocytes and pancreatic islet cells (de Weerd & Nguyen, 2012;Li et al, 2009;Lind et al, 2013). Similar to type I IFNs, the type III IFNs interfere with the replication of several viruses including hepatitis B, hepatitis C, rhinovirus and human immunodeficiency virus (Egli et al, 2014;Hermant & Michiels, 2014;Lazear et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…Considering the emerging data supporting an important function of type III IFNs in the host immune response to coxsackieviruses (Lind et al, 2013(Lind et al, , 2014, we hypothesized that coxsackieviruses have evolved mechanisms to evade the type III IFN response. In the present study, we tested this hypothesis and, to our knowledge, we show for the first time that CVB3 inhibits the induction of type III IFNs.…”

Section: Introductionmentioning

confidence: 99%

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Coxsackievirus counters the host innate immune response by blocking type III interferon expression

Lind

Svedin

Domsgen

et al. 2016

Journal of General Virology

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Type I IFNs play an important role in the immune response to enterovirus infections. Their importance is underscored by observations showing that many enteroviruses including coxsackie B viruses (CVBs) have developed strategies to block type I IFN production. Recent studies have highlighted a role for the type III IFNs (also called IFNls) in reducing permissiveness to infections with enteric viruses including coxsackievirus. However, whether or not CVBs have measures to evade the effects of type III IFNs remains unknown. By combining virus infection studies and different modes of administrating the dsRNA mimic poly I : C, we discovered that CVBs target both Toll-like receptor 3-and MDA5/RIG-I-mediated type III IFN expression. Consistent with this, the cellular protein expression levels of the signal transduction proteins TRIF and IPS1 were reduced and no hyperphosphorylation of interferon regulatory factor 3 was observed following infection with the virus. Notably, decreased expression of full-length TRIF and IPS1 and the appearance of cleavage products was observed upon both CVB3 infection and in cellular protein extracts incubated with recombinant 2A pro , indicating an important role for the viral protease in subverting the cellular immune system. Collectively, our study reveals that CVBs block the expression of type III IFNs, and that this is achieved by a similar mechanism as the virus uses to block type I IFN production. We also demonstrate that the virus blocks several intracellular viral recognition pathways of importance for both type I and III IFN production. The simultaneous targeting of numerous arms of the host immune response may be required for successful viral replication and dissemination.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Coxsackievirus counters the host innate immune response by blocking type III interferon expression

Lind

Svedin

Domsgen

et al. 2016

Journal of General Virology

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“…Neutralisation of the IFNα/β receptor (IFNAR1) with monoclonal antibodies prevents diabetes in NOD mice [13,19] and self-reactive antibodies targeting type I IFNs-particularly IFNα-are associated with protection against type 1 diabetes in patients with mutations in the thymus transcription factor autoimmune regulator (AIRE) [20]. It is surprising that very few studies have investigated the direct effects of this cytokine in pancreatic beta cells [21][22][23].…”

Section: Introductionmentioning

confidence: 99%

Interferon-α mediates human beta cell HLA class I overexpression, endoplasmic reticulum stress and apoptosis, three hallmarks of early human type 1 diabetes

et al. 2017

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Aims/hypothesis Three hallmarks of the pancreatic islets in early human type 1 diabetes are overexpression of HLA class I, endoplasmic reticulum (ER) stress and beta cell apoptosis. The mediators of these phenomena remain to be defined. The type I interferon IFNα is expressed in human islets from type 1 diabetes patients and mediates HLA class I overexpression. We presently evaluated the mechanisms involved in IFNα-induced HLA class I expression in human beta cells and determined whether this cytokine contributes to ER stress and apoptosis. Methods IFNα-induced inflammation, ER stress and apoptosis were evaluated by RT-PCR, western blot, immunofluorescence and nuclear dyes, and proteins involved in type I interferon signalling were inhibited by small interfering RNAs. All experiments were performed in human islets or human EndoC-βH1 cells.Results IFNα upregulates HLA class I, inflammation and ER stress markers in human beta cells via activation of the candidate gene TYK2, and the transcription factors signal transducer and activator of transcription 2 and IFN regulatory factor 9. Furthermore, it acts synergistically with IL-1β to induce beta cell apoptosis. Conclusions/interpretation The innate immune effects induced by IFNα may induce and amplify the adaptive immune response against human beta cells, indicating that IFNα has a central role in the early phases of diabetes.

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“…ISGs constitute a group of genes that are upregulated in response to IFN and put the surrounding cells in an antiviral state, protecting them from being infected. Being induced by virus infection (7), signs of their expression have been interpreted as "viral footprints," but, importantly, many of these genes are also overexpressed under other conditions, in the absence of viral infection (8,9).…”

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Expression of Interferon-Stimulated Genes in Insulitic Pancreatic Islets of Patients Recently Diagnosed With Type 1 Diabetes

et al. 2016

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A primary insult to the pancreatic islets of Langerhans, leading to the activation of innate immunity, has been suggested as an important step in the inflammatory process in type 1 diabetes (T1D). The aim of this study was to examine whether interferon (IFN)-stimulated genes (ISGs) are overexpressed in human T1D islets affected with insulitis. By using laser capture microdissection and a quantitative PCR array, 23 of 84 examined ISGs were found to be overexpressed by at least fivefold in insulitic islets from living patients with recent-onset T1D, participating in the Diabetes Virus Detection (DiViD) study, compared with islets from organ donors without diabetes. Most of the overexpressed ISGs, including GBP1, TLR3, OAS1, EIF2AK2, HLA-E, IFI6, and STAT1, showed higher expression in the islet core compared with the peri-islet area containing the surrounding immune cells. In contrast, the T-cell attractant chemokine CXCL10 showed an almost 10-fold higher expression in the peri-islet area than in the islet, possibly partly explaining the localization of T cells mainly to this region. In conclusion, insulitic islets from recent-onset T1D subjects show overexpression of ISGs, with an expression pattern similar to that seen in islets infected with virus or exposed to IFN-γ/interleukin-1β or IFN-α.

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Induction of an Antiviral State and Attenuated Coxsackievirus Replication in Type III Interferon-Treated Primary Human Pancreatic Islets

Abstract: Type III interferons (IFNs), also called lambda interferons (IFN-), comprise three isoforms, IFN-1 (interleukin-29 [IL-29]), IFN-2 (IL-28A), and IFN-3 (IL-28B

Cited by 36 publications

References 42 publications

Coxsackievirus counters the host innate immune response by blocking type III interferon expression

Coxsackievirus counters the host innate immune response by blocking type III interferon expression

Interferon-α mediates human beta cell HLA class I overexpression, endoplasmic reticulum stress and apoptosis, three hallmarks of early human type 1 diabetes

Expression of Interferon-Stimulated Genes in Insulitic Pancreatic Islets of Patients Recently Diagnosed With Type 1 Diabetes

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