Host Defense against Viral Infection Involves Interferon Mediated Down-Regulation of Sterol Biosynthesis

Blanc, Mathieu; Hsieh, Wei Yuan; Robertson, Kevin A.; Watterson, Steven; Shui, Guanghou; Lacaze, Paul; Khondoker, Mizanur; Dickinson, Paul; Sing, Garwin K.; Rodríguez‐Martín, Sara; Phelan, Peter E.; Forster, Thorsten; Strobl, Birgit; Müller, Mathias; Riemersma, Rudolph A.; Osborne, Timothy F.; Wenk, Markus R.; Angulo, Ana; Ghazal, Peter

doi:10.1371/journal.pbio.1000598

Cited by 240 publications

(275 citation statements)

References 69 publications

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“…In contrast, incubation with LCL exosomes induced antiviral response-related pathways including sterol metabolic and biosynthetic processes in the DCs. Sterol-associated biochemistry was recently implicated in type I IFN-driven antiviral immunity induced by viral infection (26). In fact, type I IFN-stimulated genes (ISGs) were among the most strongly induced genes in DCs exposed to LCL exosomes.…”

Section: Resultsmentioning

confidence: 99%

Sensing of latent EBV infection through exosomal transfer of 5′pppRNA

Baglio¹,

Eijndhoven²,

Koppers-Lalić

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

141

145

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Complex interactions between DNA herpesviruses and host factors determine the establishment of a life-long asymptomatic latent infection. The lymphotropic Epstein-Barr virus (EBV) seems to avoid recognition by innate sensors despite massive transcription of immunostimulatory small RNAs (EBV-EBERs). Here we demonstrate that in latently infected B cells, EBER1 transcripts interact with the lupus antigen (La) ribonucleoprotein, avoiding cytoplasmic RNA sensors. However, in coculture experiments we observed that latent-infected cells trigger antiviral immunity in dendritic cells (DCs) through selective release and transfer of RNA via exosomes. In ex vivo tonsillar cultures, we observed that EBER1-loaded exosomes are preferentially captured and internalized by human plasmacytoid DCs (pDCs) that express the TIM1 phosphatidylserine receptor, a known viraland exosomal target. Using an EBER-deficient EBV strain, enzymatic removal of 5′ppp, in vitro transcripts, and coculture experiments, we established that 5′pppEBER1 transfer via exosomes drives antiviral immunity in nonpermissive DCs. Lupus erythematosus patients suffer from elevated EBV load and activated antiviral immunity, in particular in skin lesions that are infiltrated with pDCs. We detected high levels of EBER1 RNA in such skin lesions, as well as EBV-microRNAs, but no intact EBV-DNA, linking non-cell-autonomous EBER1 presence with skin inflammation in predisposed individuals. Collectively, our studies indicate that virus-modified exosomes have a physiological role in the host-pathogen stand-off and may promote inflammatory disease.exosomes | EBV-EBER1 | innate sensing | dendritic cells | skin inflammation

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Section: Resultsmentioning

confidence: 99%

Sensing of latent EBV infection through exosomal transfer of 5′pppRNA

Baglio¹,

Eijndhoven²,

Koppers-Lalić

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

141

145

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“…We investigated cholesterol profiles as a potential biomarker for IFN- therapy in MS based on a report that type 1 IFN treatment caused coordinated changes in the expression of genes involved in sterol synthesis (21). We found that each 10 mg/dl of greater baseline LDL cholesterol (LDL-C), total cholesterol (TC), and apoB was associated with a 7.4%, 5.9%, and 16% increase in the number of new T2 lesions over 2 years of IFN- treatment, respectively (22,23).…”

Section: Resultsmentioning

confidence: 99%

Serum lipid profile changes predict neurodegeneration in interferon-β1a-treated multiple sclerosis patients

Uher

Fellows

Horáková

et al. 2017

Journal of Lipid Research

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Interferon- (IFN-) treatment is one of the most widely used disease-modifying treatments for multiple sclerosis (MS). The efficacy of recombinant human IFN- for relapsing MS has been established by multiple double-blind placebo-controlled multi-center trials (1-3). IFN- can delay the conversion to clinically definite MS (CDMS) in patients with a first demyelinating event (4-6), which supports early intervention with IFN-.MRI atrophy measures of brain volume and gray matter, white matter, and lateral ventricle volumes provide quantitative measures of global and tissue-specific brain volumes (7-9). Brain atrophy is useful for evaluating disease progression and therapeutic efficacy in MS (7) because it is a predictor of physical disability, cognitive dysfunction, and quality of life (10). However, there is a lack of effective serum biomarkers capable of predicting atrophy in MS patients.There is considerable inter-individual variability of IFN1a effectiveness among MS patients. Phase III studies of IFN- indicate a 30-40% general clinical benefit, although the response varies significantly among MS patients. On MRI, approximately 40% of patients show complete suppression of new contrast-enhancing lesions (CELs), whereas 20% of patients have less than 70% suppression

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“…Newer laboratory evidence shows that the interferon response to viral infection of the innate immune immune system is coupled to the mevalonate-isoprenoid arm of the sterol pathway. These findings may explain the observation that the CMV and HCV viruses are sensitive to statin administration and that treatment with interferon decreases plasma cholesterol levels similar to treatment with statins (Blanc M et al, 2011). Several observational studies in patients with severe bacterial infections have reported improved survival in patients treated with statins (Bjoerkheim-Bergman et al, 2010).…”

Section: Statinsmentioning

confidence: 94%

Nontraditional Anti - Infectious Agents in Hemodialysis

Sedlacek¹

2011

Progress in Hemodialysis - From Emergent Biotechnology to Clinical Practice

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Host Defense against Viral Infection Involves Interferon Mediated Down-Regulation of Sterol Biosynthesis

Cited by 240 publications

References 69 publications

Sensing of latent EBV infection through exosomal transfer of 5′pppRNA

Sensing of latent EBV infection through exosomal transfer of 5′pppRNA

Serum lipid profile changes predict neurodegeneration in interferon-β1a-treated multiple sclerosis patients

Nontraditional Anti - Infectious Agents in Hemodialysis

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