Peroxisomal very long-chain fatty acid transport is targeted by herpesviruses and the antiviral host response
Open accessAbstract
Very long-chain fatty acids (VLCFA) are critical for human cytomegalovirus replication and accumulate upon infection. Here, we used Epstein-Barr virus (EBV) infection of human B cells to elucidate how herpesviruses target VLCFA metabolism. Gene expression profiling revealed that, despite a general induction of peroxisome-related genes, EBV early infection decreased expression of the peroxisomal VLCFA transporters ABCD1 and ABCD2, thus impairing VLCFA degradation. The mechanism underlying ABCD1 and ABCD2 repression involved RNA interference by the EBV-induced microRNAs miR-9-5p and miR-155, respectively, causing significantly increased VLCFA levels. Treatment with 25-hydroxycholesterol, an antiviral innate immune modulator produced by macrophages, restored ABCD1 expression and reduced VLCFA accumulation in EBV-infected B-lymphocytes, and, upon lytic reactivation, reduced virus production in control but not ABCD1-deficient cells. Finally, also other herpesviruses and coronaviruses target ABCD1 expression. Because viral infection might trigger neuroinflammation in X-linked adrenoleukodystrophy (X-ALD, inherited ABCD1 deficiency), we explored a possible link between EBV infection and cerebral X-ALD. However, neither immunohistochemistry of post-mortem brains nor analysis of EBV seropositivity in 35 X-ALD children supported involvement of EBV in the onset of neuroinflammation. Collectively, our findings indicate a previously unrecognized, pivotal role of ABCD1 in viral infection and host defence, prompting consideration of other viral triggers in cerebral X-ALD.
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Written from the paper’s full text.
TL;DR
EBV infection of human B cells drives VLCFA accumulation by inducing miR-9-5p and miR-155, which repress the peroxisomal VLCFA transporters ABCD1 and ABCD2. The antiviral metabolite 25-hydroxycholesterol restores ABCD1, lowers VLCFAs, and reduces EBV production in an ABCD1-dependent manner, while EBV seropositivity was not elevated in children with cerebral X-ALD.
Key findings
- EBV infection/transformation significantly increased saturated VLCFA levels, including C24:0 and C26:0, in human B cells; C26:0 was further increased in EBV-transformed X-ALD B lymphocytes compared with controls.
- Despite general induction of peroxisome-related genes, EBV early infection reduced ABCD1 and ABCD2 mRNA by about 80% and 50%, respectively, at 1–2 days post infection, and impaired peroxisomal C26:0 β-oxidation.
- ABCD1 and ABCD2 were validated as direct targets of EBV-induced miR-9-5p and miR-155, respectively, via 3′-UTR luciferase reporter assays and mutagenesis.
- 25-hydroxycholesterol restored ABCD1 expression, reduced C26:0/C24:0 levels, and decreased EBV release after lytic reactivation in control B lymphocytes but not in ABCD1-deficient X-ALD cells.
- EBV seropositivity was similar in children with MRI-confirmed cerebral X-ALD (63%, n = 35) and age-matched controls (70%, n = 285), and EBV LMP1/EBER was not detected in post-mortem CALD brain tissue (n = 4).
- ABCD1 downregulation was shared across several herpesviruses and coronaviruses, whereas ABCD1 was upregulated in PBMCs from COVID-19 patients.
Methods
- Primary human B cells from healthy controls and X-ALD patients were infected with EBV in vitro or immortalized; EBV replication was induced with PMA/sodium butyrate, and virus release was measured by qPCR for BALF5.
- Fatty acids were quantified by GC-MS and ESI-MS; peroxisomal β-oxidation was measured with ¹⁴C-labeled C26:0 and C16:0; gene expression used RT-qPCR, RNA-Seq reanalysis, Western blotting, and luciferase reporter assays with miRNA mimics and mutated 3′-UTRs.
- Clinical association was tested by EBV serology in 35 children with CALD and 285 age-matched controls, plus immunohistochemistry and EBER in situ hybridization on post-mortem CALD brain tissue; public transcriptomic datasets were mined for ABCD1 expression upon herpes- and coronavirus infection.
Limitations
- The paper states that mechanisms underlying 25-HC antiviral properties remain incompletely understood and that future research is needed to explain how ABCD1 deficiency interferes with 25-HC’s ability to prevent EBV replication.
- The paper states that the CALD cohort findings do not support EBV as a trigger in the investigated children, but call for consideration of other herpesviruses or enveloped viruses as candidate environmental factors.
- Evident from the text: several public dataset analyses relied on small numbers of biological replicates, and the CALD serology/immunohistochemistry analyses were retrospective and limited to the studied cohorts.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
17 of 33 cited sources checked · 13 supported · 0 flagged · accuracy not yet measured
- Findingcitation
RNA-Seq data indicate a time-dependent early increase in VLCFA synthesis around 2-3 days post EBV infection, indicated by transient robust induction of ELOVL1.
“the RNA-Seq data22 also pointed to a time-dependent early increase in VLCFA synthesis around 2–3 dpi, as indicated by a transient but robust induction of ELOVL1 (Fig. 2f).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [22] Mrozek-Gorska, P. et al. Epstein-Barr virus reprograms human B lymphocytes immediately in the prelatent phase of infection. Proc. Natl Acad. Sci. USA 116, 16046–16055 (2019). source
The Results section on gene-expression clusters reports time-resolved RNA-seq findings, including a cellular-metabolism cluster that peaks on day 3 after EBV infection. It does not identify VLCFA synthesis or report transient, robust induction of ELOVL1; searches for ELOVL1, VLCFA, and fatty-acid synthesis found no supporting passage in our copy. (LLM, conf=0.77)
Experimental — accuracy not yet measured
- Premisenone given
Very long-chain fatty acids are critical for human cytomegalovirus replication.
“Very long-chain fatty acids (VLCFA) are critical for human cytomegalovirus replication and accumulate upon infection.”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [5] Koyuncu, E., Purdy, J. G., Rabinowitz, J. D. & Shenk, T. Saturated very long chain fatty acids are required for the production of infectious human cytomegalovirus progeny. PLoS Pathog. 9, e1003333 (2013). source
- cites [6] Purdy, J. G., Shenk, T. & Rabinowitz, J. D. Fatty acid elongase 7 catalyzes lipidome remodeling essential for human cytomegalovirus replication. Cell Rep. 10, 1375–1385 (2015). source
- Premisecitation
VLCFAs accumulate upon human cytomegalovirus infection.
“Infection with HCMV results in markedly elevated cellular levels of saturated very long-chain fatty acids (VLCFAs, ≥ C22), with C26:0 as the most abundant VLCFA of the viral envelope5,6.”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [5] Koyuncu, E., Purdy, J. G., Rabinowitz, J. D. & Shenk, T. Saturated very long chain fatty acids are required for the production of infectious human cytomegalovirus progeny. PLoS Pathog. 9, e1003333 (2013). source
- cites [6] Purdy, J. G., Shenk, T. & Rabinowitz, J. D. Fatty acid elongase 7 catalyzes lipidome remodeling essential for human cytomegalovirus replication. Cell Rep. 10, 1375–1385 (2015). source
- Premisecitation
25-HC is effective in vitro against a wide range of viruses including SARS-CoV-2.
“25-HC is effective in vitro against a wide range of viruses including SARS-CoV-242”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [42] Zang, R. et al. Cholesterol 25-hydroxylase suppresses SARS-CoV-2 replication by blocking membrane fusion. Proc. Natl Acad. Sci. USA 117, 32105–32113 (2020). source
- Findingown data
25-hydroxycholesterol represses ELOVL1 mRNA levels.
“Conversely, 25-HC repressed ELOVL1 mRNA levels (Fig. 5c), confirming a previous observation in human fibroblasts44.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [44] Jang, J., Lee, J. W., Song, J., Kim, D. W. & Min, K. H. Exogenous addition of 25-hydroxycholesterol reduces level of very long-chain fatty acids in X-linked adrenoleukodystrophy. ChemistryOpen 8, 188–191 (2019). source
- Findingcitation
Peroxisomal beta-oxidation enzymes ACOX1, HSD17B4 and ACAA1 are upregulated upon EBV infection.
“the expression of genes encoding enzymes participating in the peroxisomal β-oxidation of VLCFAs (acyl-CoA oxidase 1, ACOX1; hydroxysteroid 17-beta dehydrogenase 4, HSD17B4 and acetyl-CoA acyltransferase 1, ACAA1/thiolase) were upregulated (Fig. 2e).”
Quote in the paperSubstantial claim - Findingown data
ABCD1 protein levels are markedly decreased at 2 and 5 days post EBV infection by Western blot.
“we validated the markedly decreased ABCD1 protein levels at 2 and 5 dpi by Western blot analysis (Supplementary Fig. 3b).”
Quote in the paperSubstantial claim - Findingown data
EBV seropositivity is not elevated in children with inflammatory cerebral X-ALD.
“neither immunohistochemistry of post-mortem brains nor analysis of EBV seropositivity in 35 X-ALD children supported involvement of EBV in the onset of neuroinflammation.”
Quote in the paperSubstantial claim - Findingown data
miR-155 is strongly upregulated upon EBV infection and immortalization of primary human B cells.
“We observed both miR-9-5p and miR-155 (cellular miRNAs) being strongly upregulated upon EBV infection and immortalization of primary human B cells (Fig. 3b, f), thus confirming previous reports26,27.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [26] Dai, X. et al. Expression pattern of hsa-miR-9 and its association with BCL6 in EBV-positive and EBV-negative Burkitt lymphoma cell lines. Nan Fang Yi Ke Da Xue Xue Bao 33, 661–666 (2013).
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [27] Linnstaedt, S. D., Gottwein, E., Skalsky, R. L., Luftig, M. A. & Cullen, B. R. Virally induced cellular microRNA miR-155 plays a key role in B-cell immortalization by Epstein-Barr virus. J. Virol. 84, 11670–11678 (2010). source
- Findingown data
At 1 and 2 days post EBV infection, ABCD1 mRNA levels are reduced by about 80%.
“Already at both 1 and 2 dpi, we observed reductions of ABCD1 and ABCD2 mRNA levels by about 80 and 50%, respectively (Fig. 2d)”
Quote in the paperSubstantial claim - Findingown data
At 5 days post EBV infection, VLCFA species including C26:0 are markedly increased.
“At 5 days post infection (dpi), we found markedly increased VLCFA species, including C26:0 (Fig. 1c).”
Quote in the paperSubstantial claim - Findingown data
Upon lytic reactivation, 25-hydroxycholesterol reduces virus production in control but not ABCD1-deficient cells.
“upon lytic reactivation, reduced virus production in control but not ABCD1-deficient cells”
Quote in the paperSubstantial claim - Findingown data
EBV infection and transformation reduce ABCD2 mRNA levels in B cells.
“We found markedly reduced mRNA levels for both ABCD1 and ABCD2 in EBV-immortalized B lymphocytes when compared to non-infected primary B cells (Fig. 2a).”
Quote in the paperSubstantial claim - Findingown data
Co-transfection of ABCD1 3'UTR reporter with miR-9-5p mimic significantly decreases luciferase activity compared to negative control.
“Co-transfection of the ABCD1- or ABCD2-3′-UTR reporter constructs with either miR-9-5p or miR-155 mimics, respectively, resulted in significantly decreased luciferase activity when compared to non-targeting miRNA negative controls.”
Quote in the paperSubstantial claim - Findingown data
25-hydroxycholesterol reduces VLCFA accumulation in EBV-infected B-lymphocytes.
“Treatment with 25-hydroxycholesterol, an antiviral innate immune modulator produced by macrophages, restored ABCD1 expression and reduced VLCFA accumulation in EBV-infected B-lymphocytes”
Quote in the paperSubstantial claim - Findingown data
Mutations in the second target site of ABCD1 3'UTR are sufficient to ablate the effect of miR-9-5p mimic on the reporter construct.
“mutations in the second target site (M-TS2) of the ABCD1-3′-UTR were sufficient to ablate the effect of the miR-9-5p mimic on the reporter construct (Fig. 3c, d)”
Quote in the paperSubstantial claim - Findingcitation
EBV infection profoundly changes expression of most peroxisome-related genes starting early at 1 day post infection with a peak around 3 days post infection.
“we found that EBV infection profoundly changed the expression of most genes related to peroxisomes starting early, at 1 dpi with a peak around 3 dpi (Fig. 2e).”
Quote in the paperSubstantial claim - Findingown data
Immunohistochemistry of post-mortem brains did not identify EBV positivity in CALD cases.
“we were unable to identify EBV positivity in post-mortem brain tissue of four CALD cases”
Quote in the paperSubstantial claim - Findingown data
Co-transfection of ABCD2 3'UTR reporter with miR-155 mimic significantly decreases luciferase activity compared to negative control.
“Co-transfection of the ABCD1- or ABCD2-3′-UTR reporter constructs with either miR-9-5p or miR-155 mimics, respectively, resulted in significantly decreased luciferase activity when compared to non-targeting miRNA negative controls.”
Quote in the paperSubstantial claim - Findingcitation
Own results and Caliskan data show sustained repression of ABCD1 in EBV-infected and immortalized B lymphocytes.
“This contrasts with our results and for ABCD1 with the data retrieved from Caliskan et al.21 (Supplementary Fig. 1) showing sustained repression in EBV-infected and immortalized B lymphocytes.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [21] Caliskan, M., Cusanovich, D. A., Ober, C. & Gilad, Y. The effects of EBV transformation on gene expression levels and methylation profiles. Hum. Mol. Genet. 20, 1643–1652 (2011). source
- Findingcitation
In Mrozek-Gorska data, ABCD1 and ABCD2 mRNA levels are downregulated early upon EBV infection.
“the mRNA levels of the peroxisomal VLCFA transporters ABCD1 and ABCD2 were downregulated early upon infection, thus confirming our own results (Fig. 2e).”
Quote in the paperSubstantial claim - Findingown data
C16:0 degradation rate is not significantly different upon EBV infection and transformation.
“the rate of C26:0 degradation was significantly reduced upon EBV infection and transformation, whereas no significant difference was found for C16:0 degradation (Fig. 2c).”
Quote in the paperNot a substantial claim - Findingown data
C26:0 relative amount is further increased upon EBV transformation in X-ALD B lymphocytes compared to controls.
“the relative amount of C26:0 was further increased upon EBV transformation in X-ALD B lymphocytes, either as ratio to C22:0, as used in X-ALD diagnostics, or to C16:0 as standard reference fatty acid (Fig. 1a, b).”
Quote in the paperSubstantial claim - Findingown data
C26:0 degradation rate is significantly reduced upon EBV infection and transformation.
“the rate of C26:0 degradation was significantly reduced upon EBV infection and transformation, whereas no significant difference was found for C16:0 degradation (Fig. 2c).”
Quote in the paperSubstantial claim - Findingown data
C26:0 levels are significantly elevated upon EBV transformation of B cells.
“The levels of both C24:0 and C26:0 were significantly elevated upon EBV transformation of B cells (Fig. 1a, b).”
Quote in the paperSubstantial claim - Findingown data
EBV infection increases cellular levels of saturated VLCFAs.
“EBV infection increases the cellular levels of saturated VLCFAs”
Quote in the paperSubstantial claim - Findingown data
25-hydroxycholesterol restores ABCD1 expression in EBV-infected B-lymphocytes.
“Treatment with 25-hydroxycholesterol, an antiviral innate immune modulator produced by macrophages, restored ABCD1 expression and reduced VLCFA accumulation in EBV-infected B-lymphocytes”
Quote in the paperSubstantial claim - Findingown data
A non-related beta-actin 3'UTR sequence is not affected by miR-9-5p or miR-155 mimics.
“a non-related 3′-UTR sequence of the β-actin gene was not affected by these mimics.”
Quote in the paperSubstantial claim - Findingown data
Two putative miR-9-5p binding sites are present in the 3'UTR of ABCD1.
“We identified two putative miR-9-5p binding sites in the 3′-UTR of ABCD1 and three putative miR-155 binding sites in the 3′-UTR of ABCD2 (Fig. 3a, e and Supplementary Tables 1, 2).”
Quote in the paperSubstantial claim - Findingown data
Total plasmalogen levels are not significantly altered at 5 days post EBV infection.
“we did not observe significant alterations in total plasmalogen levels 5 dpi.”
Quote in the paperNot a substantial claim - Findingown data
EBV early infection decreases expression of the peroxisomal VLCFA transporters ABCD1 and ABCD2.
“EBV early infection decreased expression of the peroxisomal VLCFA transporters ABCD1 and ABCD2, thus impairing VLCFA degradation.”
Quote in the paperSubstantial claim - Findingown data
Plasmalogen synthesis enzymes FAR1, GNPAT and AGPS are transiently upregulated with a peak at 3 days post EBV infection.
“also mRNAs encoding enzymes involved in the peroxisomal steps of plasmalogen synthesis (fatty acyl-CoA reductase 1, FAR1; glyceronephosphate O-acetyltransferase, GNPAT and alkylglycerone phosphate synthase, AGPS) were transiently upregulated with a peak at 3 dpi (Fig. 2e).”
Quote in the paperNot a substantial claim - Findingown data
Mutations in all three miR-155 binding sites in ABCD2 3'UTR or their deletion reduce the effect size of miR-155 mimics to about 10%.
“the concomitant introduction of mutations into all three miR-155 binding sites in the ABCD2-3′-UTR (M-TS1/TS2/TS3) or their deletion reduced the effect size of the miR-155 mimics to about 10% (Fig. 3g, h).”
Quote in the paperSubstantial claim - Findingown data
At 1 and 2 days post EBV infection, ABCD2 mRNA levels are reduced by about 50%.
“Already at both 1 and 2 dpi, we observed reductions of ABCD1 and ABCD2 mRNA levels by about 80 and 50%, respectively (Fig. 2d)”
Quote in the paperSubstantial claim - Findingown data
C24:0 levels are significantly elevated upon EBV transformation of B cells.
“The levels of both C24:0 and C26:0 were significantly elevated upon EBV transformation of B cells (Fig. 1a, b).”
Quote in the paperSubstantial claim - Findingown data
EBV infection and transformation do not significantly alter ELOVL7 mRNA levels.
“we observed no significant alterations in mRNA levels of elongases catalyzing saturated LCFA and VLCFA synthesis such as ELOVL1 and ELOVL7 and even downregulated expression of ELOVL3 (Fig. 2b).”
Quote in the paperNot a substantial claim - Findingown data
EBV infection and transformation downregulate ELOVL3 expression.
“we observed no significant alterations in mRNA levels of elongases catalyzing saturated LCFA and VLCFA synthesis such as ELOVL1 and ELOVL7 and even downregulated expression of ELOVL3 (Fig. 2b).”
Quote in the paperNot a substantial claim - Findingown data
EBV early infection impairs VLCFA degradation.
“EBV early infection decreased expression of the peroxisomal VLCFA transporters ABCD1 and ABCD2, thus impairing VLCFA degradation.”
Quote in the paperSubstantial claim - Findingown data
EBV infection and transformation do not significantly alter ELOVL1 mRNA levels.
“we observed no significant alterations in mRNA levels of elongases catalyzing saturated LCFA and VLCFA synthesis such as ELOVL1 and ELOVL7 and even downregulated expression of ELOVL3 (Fig. 2b).”
Quote in the paperNot a substantial claim - Findingown data
miR-9-5p is strongly upregulated upon EBV infection and immortalization of primary human B cells.
“We observed both miR-9-5p and miR-155 (cellular miRNAs) being strongly upregulated upon EBV infection and immortalization of primary human B cells (Fig. 3b, f), thus confirming previous reports26,27.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [26] Dai, X. et al. Expression pattern of hsa-miR-9 and its association with BCL6 in EBV-positive and EBV-negative Burkitt lymphoma cell lines. Nan Fang Yi Ke Da Xue Xue Bao 33, 661–666 (2013).
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [27] Linnstaedt, S. D., Gottwein, E., Skalsky, R. L., Luftig, M. A. & Cullen, B. R. Virally induced cellular microRNA miR-155 plays a key role in B-cell immortalization by Epstein-Barr virus. J. Virol. 84, 11670–11678 (2010). source
- Findingown data
EBV infection and transformation reduce ABCD1 mRNA levels in B cells.
“We found markedly reduced mRNA levels for both ABCD1 and ABCD2 in EBV-immortalized B lymphocytes when compared to non-infected primary B cells (Fig. 2a).”
Quote in the paperSubstantial claim - Findingcitation
Mrozek-Gorska data revealed only a transient decrease in ABCD1 and ABCD2 expression with normalized levels by 4 days post infection.
“the data from Mrozek-Gorska et al. revealed only a transient decrease in ABCD1 and ABCD2 expression with normalized levels by 4 dpi.”
Quote in the paperNot a substantial claim - Findingown data
No substantial change in saturated long-chain fatty acids C12-C20 such as C16:0, C18:0 or C20:0 occurs at 5 days post EBV infection.
“In contrast, no substantial change was observed for saturated long-chain fatty acids (C12–C20) such as C16:0, C18:0 or C20:0.”
Quote in the paperNot a substantial claim - Findingown data
Three putative miR-155 binding sites are present in the 3'UTR of ABCD2.
“We identified two putative miR-9-5p binding sites in the 3′-UTR of ABCD1 and three putative miR-155 binding sites in the 3′-UTR of ABCD2 (Fig. 3a, e and Supplementary Tables 1, 2).”
Quote in the paperSubstantial claim - Findingown data
Valpromide shares the ability of 25-HC to stimulate ABCD1 expression.
“the ability of 25-HC to stimulate ABCD1 expression was shared by the EBV lytic cycle inhibitor valpromide”
Quote in the paperSubstantial claim - Findingown data
In healthy control B lymphocytes, decreased VLCFA levels after 3 weeks of 25-hydroxycholesterol treatment correlate with reduced capacity of EBV for lytic reactivation, indicated by lower virus release.
“In healthy control B lymphocytes, the decreased VLCFA levels that we observed after 3 weeks of 25-HC treatment correlated with a reduced capacity of EBV for lytic reactivation, as indicated by significantly lower virus release upon pharmacological induction (Fig. 5e).”
Quote in the paperSubstantial claim - Findingown data
Valpromide significantly upregulates ABCD1 mRNA levels in EBV-immortalized B lymphocytes.
“Our data revealed that similar to 25-HC, valpromide significantly upregulated ABCD1 mRNA levels and additionally stimulated ABCD2 expression in EBV-immortalized B lymphocytes.”
Quote in the paperSubstantial claim - Findingown data
Downregulated ABCD1 expression is a feature shared by different members of the herpes- and coronavirus families.
“we found that downregulated expression of ABCD1 was a feature shared by different members of the herpes- and coronavirus families (Fig. 4a–i and Supplementary Fig. 5).”
Quote in the paperSubstantial claim - Findingown data
ABCD1 expression is significantly upregulated in PBMCs of COVID-19 patients.
“a significant upregulation of ABCD1 expression in peripheral blood mononuclear cells (PBMCs) of COVID-19 patients was observed (Fig. 4j)”
Quote in the paperSubstantial claim - Findingown data
25-hydroxycholesterol induces ABCD1 expression in all tested EBV-immortalized B cell lines.
“we analyzed ABCD1 mRNA and protein levels after 24 and 48 h of treatment, respectively, of the EBV-immortalized B lymphocytes and observed induced ABCD1 expression in all tested cell lines (Fig. 5c, d).”
Quote in the paperSubstantial claim - Findingown data
A mirTar database screen revealed 61 putative interactions of virus miRNAs with ABCD1 and 12 with ABCD2.
“revealed 61 putative interactions of virus miRNAs with ABCD1 and 12 with ABCD2”
Quote in the paperNot a substantial claim - Findingown data
EBV LMP1 and EBER are not detected in post-mortem brain tissue of four CALD cases.
“by using immunohistochemistry for detection of EBV latent membrane protein 1 (LMP1) and in situ hybridization for the EBV-associated small non-coding RNA EBER, we were unable to identify EBV positivity in post-mortem brain tissue of four CALD cases (Supplementary Fig. 4e, f).”
Quote in the paperSubstantial claim - Findingown data
25-hydroxycholesterol treatment for 3 weeks reduces C26:0 levels.
“with subsequent reduction of both C26:0 and C24:0 VLCFA levels upon 3 weeks of treatment (Fig. 5b).”
Quote in the paperSubstantial claim - Findingown data
25-hydroxycholesterol treatment does not significantly interfere with EBV reproduction in X-ALD-derived B lymphocytes lacking ABCD1.
“In contrast, 25-HC treatment did not significantly interfere with EBV reproduction in the X-ALD-derived B lymphocytes lacking ABCD1 (Fig. 5e).”
Quote in the paperSubstantial claim - Findingown data
EBV seropositivity incidence is similar in X-ALD (63%) and age-matched controls (70%).
“Our analysis revealed similar incidences in the X-ALD (63%) and the age-matched control groups (70%) consisting of 285 children”
Quote in the paperSubstantial claim - Findingown data
Valpromide has no significant effect on ELOVL1 transcription.
“However, in contrast to 25-HC, valpromide had no significant effect on ELOVL1 transcription (Supplementary Fig. 7).”
Quote in the paperNot a substantial claim - Findingown data
25-hydroxycholesterol does not affect genes involved in plasmalogen synthesis.
“In contrast, expression of ABCD2 and genes involved in plasmalogen synthesis were unaffected by 25-HC (Supplementary Fig. 6).”
Quote in the paperNot a substantial claim - Findingown data
No higher prevalence of EBV seropositivity was detected in childhood CALD patients than in controls of similar age with conditions unrelated to X-ALD.
“we did not detect a higher prevalence of EBV seropositivity in childhood CALD patients than in controls of similar age with conditions unrelated to X-ALD.”
Quote in the paperSubstantial claim- Rests on an assumption: Controls of similar age with conditions unrelated to X-ALD are appropriate for comparing EBV seroprevalence with childhood CALD patients.
- Findingown data
Valpromide stimulates ABCD2 expression in EBV-immortalized B lymphocytes.
“Our data revealed that similar to 25-HC, valpromide significantly upregulated ABCD1 mRNA levels and additionally stimulated ABCD2 expression in EBV-immortalized B lymphocytes.”
Quote in the paperNot a substantial claim - Findingown data
EBV induces host-derived miRNAs including miR-9-5p and miR-155.
“we discovered that EBV induces host-derived miRNAs including miR-9-5p and miR-155”
Quote in the paperSubstantial claim - Findingown data
25-hydroxycholesterol does not affect ABCD2 expression.
“In contrast, expression of ABCD2 and genes involved in plasmalogen synthesis were unaffected by 25-HC (Supplementary Fig. 6).”
Quote in the paperNot a substantial claim - Findingown data
miR-9-5p and miR-155 repress ABCD1 and ABCD2.
“that repress ABCD1 and ABCD2, two related peroxisomal fatty acid transporters with overlapping substrate specificity but distinct expression profiles.”
Quote in the paperSubstantial claim - Findingown data
No association was revealed between recent EBV infections and onset of neuroinflammation in the investigated cohort of CALD patients.
“we could not reveal an association between recent EBV infections and onset of neuroinflammation in the investigated cohort of CALD patients.”
Quote in the paperSubstantial claim - Findingown data
25-hydroxycholesterol treatment for 3 weeks reduces C24:0 levels.
“with subsequent reduction of both C26:0 and C24:0 VLCFA levels upon 3 weeks of treatment (Fig. 5b).”
Quote in the paperSubstantial claim - Findingown data
No support links a change in ABCD1 protein levels to induction of EBV lytic replication.
“we found no support linking a change in ABCD1 protein levels to induction of EBV lytic replication.”
Quote in the paperNot a substantial claim - Findingown data
Predicted binding sites for the EBV miRNAs ebv-miR-BART10-5p and ebv-miR-BART1-5p exist in the ABCD1 and ABCD2 mRNAs, respectively.
“including predicted binding sites for the EBV miRNAs ebv-miR-BART10-5p and ebv-miR-BART1-5p in the ABCD1 and ABCD2 mRNAs, respectively.”
Quote in the paperNot a substantial claim - Findingown data
25-hydroxycholesterol treatment for 48 h significantly elevates peroxisomal beta-oxidation of C26:0 in EBV-immortalized healthy control B lymphocytes.
“After 48 h we found significantly elevated peroxisomal β-oxidation of C26:0 (Fig. 5a)”
Quote in the paperSubstantial claim - Findingown data
No association of recent EBV infection with onset of neuroinflammation in EBV-positive CALD patients.
“indicated no association of a recent EBV infection with onset of neuroinflammation in EBV-positive CALD patients (Supplementary Fig. 4d).”
Quote in the paperSubstantial claim - Findingown data
Several herpesviruses, including EBV and HCMV, and coronaviruses target ABCD1.
“we here complement this knowledge by showing that several herpesviruses, including EBV and HCMV, and coronaviruses target ABCD1, the main transporter mediating peroxisomal degradation of saturated VLCFAs.”
Quote in the paperSubstantial claim- Rests on an assumption: ABCD1 is the main transporter mediating peroxisomal degradation of saturated VLCFAs.
- Interpretationown data
ABCD1 has a pivotal role in viral infection and host defence.
“our findings indicate a previously unrecognized, pivotal role of ABCD1 in viral infection and host defence”
Quote in the paperSubstantial claim - Interpretationown data
Repression of ABCD1 and ABCD2 by miR-9-5p and miR-155 causes significantly increased VLCFA levels.
“The mechanism underlying ABCD1 and ABCD2 repression involved RNA interference by the EBV-induced microRNAs miR-9-5p and miR-155, respectively, causing significantly increased VLCFA levels.”
Quote in the paperSubstantial claim - Interpretationown data
In the investigated cohort of CALD patients, onset of neuroinflammation could not be correlated to previous or acute EBV infection.
“we conclude that in the investigated cohort of CALD patients, the onset of neuroinflammation could not be correlated to a previous or acute EBV infection.”
Quote in the paperSubstantial claim - Interpretationown data
ABCD2 is a direct functional target of EBV-induced miR-155.
“Collectively, these results further validate ABCD1 and ABCD2 as direct functional targets of EBV-induced miR-9-5p and miR-155”
Quote in the paperSubstantial claim - Interpretationown data
ABCD1 is a direct functional target of EBV-induced miR-9-5p.
“Collectively, these results further validate ABCD1 and ABCD2 as direct functional targets of EBV-induced miR-9-5p and miR-155”
Quote in the paperSubstantial claim - Interpretationreasoning
The targeting and molecular mechanism of ABCD1 repression involving miRNAs might be conserved between different viruses.
“both the targeting of as well as the molecular mechanism of ABCD1 repression involving miRNAs might be conserved between different viruses.”
Quote in the paperSubstantial claim - Interpretationown data
Instructing host cells to accumulate VLCFAs is a common strategy adopted by HCMV, EBV, and possibly other herpesviruses to support their propagation.
“Our present study revealed that instructing host cells to accumulate VLCFAs apparently is a common strategy, adopted not only by HCMV but also by EBV and possibly other herpesviruses to support their propagation.”
Quote in the paperSubstantial claim- The authors state this as an assumption: EBV infection of B cells is a valid paradigm for herpesvirus infection.
- Premisecitation
C26:0 has similar hydrophobicity and dissociation rate from membranes as cholesterol.
“the VLCFA C26:0 has similar hydrophobicity and dissociation rate from membranes as cholesterol51,52”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [51] Hamilton, J. A. Fast flip-flop of cholesterol and fatty acids in membranes: Implications for membrane transport proteins. Curr. Opin. Lipido. 14, 263–271 (2003). source
- cites [52] Pillai, B. K., Jasuja, R., Simard, J. R. & Hamilton, J. A. Fast diffusion of very long chain saturated fatty acids across a bilayer membrane and their rapid extraction by cyclodextrins: implications for adrenoleukodystrophy. J. Biol. Chem. 284, 33296–33304 (2009). source
- Interpretationown data
These findings do not support the hypothesis of EBV being a trigger of cerebral involvement in these children.
“Together, these findings do not support the hypothesis of EBV being a trigger of cerebral involvement in these children.”
Quote in the paperSubstantial claim - Interpretationreasoning
Impaired peroxisomal degradation of VLCFAs and concurrent upregulation of VLCFA synthesis via ELOVL1 leads to increased cellular VLCFA levels.
“The impaired peroxisomal degradation of VLCFAs but concurrent upregulation of VLCFA synthesis via the fatty acid elongase ELOVL1 leads to increased cellular VLCFA levels”
Quote in the paperSubstantial claim - Interpretationown data
ABCD1 and VLCFAs are targeted by both viral and antiviral host-cell strategies.
“our data revealing that the peroxisomal VLCFA transporter ABCD1, a protein associated with X-linked adrenoleukodystrophy, and VLCFAs are targeted by both viral and antiviral host-cell strategies”
Quote in the paperSubstantial claim - Premisecitation
miR-9-5p is part of the HCMV host-virus crosstalk.
“With miR-9-5p also being part of the HCMV host-virus crosstalk”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [45] Kim, S. et al. Temporal landscape of MicroRNA-mediated host-virus crosstalk during productive human cytomegalovirus infection. Cell Host Microbe 17, 838–851 (2015). source
- Interpretationown data
EBV infection of B cells results in rapid miRNA-mediated downregulation of ABCD1 and ABCD2.
“EBV infection of B cells results in rapid miRNA-mediated downregulation of the peroxisomal VLCFA importers ABCD1 and ABCD2.”
Quote in the paperSubstantial claim - Premisecitation
ABCD1 is targeted by the HCMV miRNA hcmv-miR-US29-3p.
“ABCD1 also being targeted by the HCMV miRNA hcmv-miR-US29-3p45”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [45] Kim, S. et al. Temporal landscape of MicroRNA-mediated host-virus crosstalk during productive human cytomegalovirus infection. Cell Host Microbe 17, 838–851 (2015). source
- Study design and conductown data
The accumulation of saturated VLCFAs in the blood of X-ALD patients was confirmed by GC-MS measurement of C26:0, C24:0, C22:0 and C16:0.
“The accumulation of saturated VLCFAs in the blood of X-ALD patients was confirmed by measurement of the total amount of the fatty acids C26:0, C24:0, C22:0 and, for normalization, C16:0 by using gas chromatography–mass spectrometry (GC–MS).”
Quote in the paperSubstantial claim
- May combine two claims. 9
- Classified as probably not a substantial claim. 15
May combine two claims.
FindingcitationProteomic data confirm general upregulation of proteins involved in beta-oxidation, plasmalogen and VLCFA synthesis (ELOVL1) with concurrent downregulation of ABCD1.
“data retrieved and reanalyzed from a temporal proteomic data set, obtained during EBV infection of primary human B cells by Wang and colleagues23, confirmed the general upregulation of proteins involved in β-oxidation, plasmalogen and VLCFA synthesis (ELOVL1) with concurrent downregulation of ABCD1 (Supplementary Fig. 3a).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [23] Wang, L. W. et al. Epstein-Barr-virus-induced one-carbon metabolism drives B cell transformation. Cell Metab. 30, 539–555.e511 (2019). source
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation25-hydroxycholesterol confers broad antiviral activity by blocking entry, replication and production of infectious viruses of diverse enveloped viruses.
“Previous reports have demonstrated that the natural cholesterol metabolite 25-hydroxycholesterol (25-HC), an immune modulator secreted by macrophages during the host response, confers broad antiviral activity by blocking entry, replication and production of infectious viruses of diverse enveloped viruses39–42”
Quote in the paperNot a substantial claim3 of 4 sources checked- cites [39] Liu, S. Y. et al. Interferon-inducible cholesterol-25-hydroxylase broadly inhibits viral entry by production of 25-hydroxycholesterol. Immunity 38, 92–105 (2013). source
- cites [40] Yuan, Y. et al. Cholesterol 25-hydroxylase suppresses rabies virus infection by inhibiting viral entry. Arch. Virol. 164, 2963–2974 (2019). source
- cites [41] Shrivastava-Ranjan, P. et al. 25-Hydroxycholesterol inhibition of Lassa virus infection through aberrant GP1 glycosylation. mBio https://doi.org/10.1128/mBio.01808-16 (2016). source
- cites [42] Zang, R. et al. Cholesterol 25-hydroxylase suppresses SARS-CoV-2 replication by blocking membrane fusion. Proc. Natl Acad. Sci. USA 117, 32105–32113 (2020). source
The paper reports that 25HC has broad activity against enveloped viruses and shows that it inhibits SARS-CoV-2 entry and replication (Abstract, page not provided). It does not establish that 25HC blocks production of infectious virus: the authors say that effects on viral maturation, release, or progeny infectivity warrant further investigation (Abstract, page not provided). (LLM, conf=0.88)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim.
PremisecitationVLCFAs influence membrane properties such as curvature and permeability.
“VLCFAs are thought to influence membrane properties such as curvature and permeability46,47.”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [46] Schneiter, R. et al. Identification and biophysical characterization of a very-long-chain-fatty-acid-substituted phosphatidylinositol in yeast subcellular membranes. Biochem. J. 381, 941–949 (2004). source
- cites [47] Ho, J. K., Moser, H., Kishimoto, Y. & Hamilton, J. A. Interactions of a very long chain fatty acid with model membranes and serum albumin. Implications for the pathogenesis of adrenoleukodystrophy. J. Clin. Invest. 96, 1455–1463 (1995). source
The Discussion reports that excess VLCFAs can profoundly affect membrane structure and describes altered phospholipid packing in model membranes. It does not establish effects on membrane curvature or permeability, the specific properties named in the citing sentence. (LLM, conf=0.85)
Experimental — accuracy not yet measured
May combine two claims.
Premisecitation25-HC is effective against de novo EBV infection by suppressing key viral genes and interfering with viral induced proliferation.
“also against de novo EBV infection by suppressing key viral genes and interfering with viral induced proliferation43”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [43] Serquina, A. K. P., Tagawa, T., Oh, D., Mahesh, G. & Ziegelbauer, J. M. 25-Hydroxycholesterol inhibits Kaposi’s sarcoma Herpesvirus and Epstein-Barr virus infections and activates inflammatory cytokine responses. mBio https://doi.org/10.1128/mBio.02907-21 (2021). source
Classified as probably not a substantial claim.
Premisecitation25-hydroxycholesterol blocks de novo EBV infection of B cells.
“and, as recently described, including also de novo EBV infection of B cells43.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [43] Serquina, A. K. P., Tagawa, T., Oh, D., Mahesh, G. & Ziegelbauer, J. M. 25-Hydroxycholesterol inhibits Kaposi’s sarcoma Herpesvirus and Epstein-Barr virus infections and activates inflammatory cytokine responses. mBio https://doi.org/10.1128/mBio.02907-21 (2021). source
The Results section ('25HC inhibited EBV infection'; page not provided) shows that 25HC impaired outcomes of de novo EBV infection in B-cell-enriched samples, particularly proliferation and transformation. It does not show that 25HC blocks infection itself: GFP-positive infected cells remained after treatment. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
FindingcitationThe determined prevalence of EBV infection in control children aged 4-15 years was comparable to rates previously observed for children within this age group in Berlin/Germany.
“the determined prevalence of EBV infection in our cohort of control children aged 4–15 years was comparable to rates previously observed for children within this age group in Berlin/Germany54”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [54] Abrahamyan, S. et al. Complete Epstein-Barr virus seropositivity in a large cohort of patients with early multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 91, 681–686 (2020). source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationVLCFAs are enriched upon HCMV infection by targeting the fatty acid elongation process.
“Whereas previous reports demonstrated that VLCFAs are enriched upon HCMV infection by targeting the fatty acid elongation process5,6”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [5] Koyuncu, E., Purdy, J. G., Rabinowitz, J. D. & Shenk, T. Saturated very long chain fatty acids are required for the production of infectious human cytomegalovirus progeny. PLoS Pathog. 9, e1003333 (2013). source
- cites [6] Purdy, J. G., Shenk, T. & Rabinowitz, J. D. Fatty acid elongase 7 catalyzes lipidome remodeling essential for human cytomegalovirus replication. Cell Rep. 10, 1375–1385 (2015). source
Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Findingnone givenOther herpesviruses and coronaviruses target ABCD1 expression.
“Finally, also other herpesviruses and coronaviruses target ABCD1 expression.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataEBV infection of B cells induces peroxisome-related genes but interferes with the β-oxidation of VLCFAs by preventing their peroxisomal import.
“our observations show that despite a general induction of peroxisome-related genes, viral infection simultaneously interferes with the β-oxidation of VLCFAs by preventing their peroxisomal import (Fig. 5f).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data25-HC promotes cellular VLCFA degradation by positive modulation of ABCD1 expression with simultaneous downregulation of ELOVL1 to curb VLCFA synthesis.
“Our finding that the antiviral cholesterol metabolite 25-HC promotes cellular VLCFA degradation by positive modulation of ABCD1 expression with simultaneous downregulation of ELOVL1 to curb VLCFA synthesis”
Quote in the paperSubstantial claim- Rests on an assumption: ABCD1 is the main transporter mediating peroxisomal degradation of saturated VLCFAs.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMagnaporthe oryzae depends on VLCFAs for pathogenicity.
“not only viruses but also the rice blast fungus Magnaporthe oryzae seem to depend on VLCFAs for pathogenicity48.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [48] He, M. et al. Discovery of broad-spectrum fungicides that block septin-dependent infection processes of pathogenic fungi. Nat. Microbiol. 5, 1565–1575 (2020). source
May combine two claims.
Interpretationown data25-hydroxycholesterol interferes with EBV reproduction by opposite regulation of ABCD1 (up) and ELOVL1 (down), resulting in net VLCFA catabolism and preventing cellular accumulation of VLCFAs.
“the antiviral metabolite 25-hydroxycholesterol interferes with EBV reproduction, among other, by opposite regulation of ABCD1 (up) and ELOVL1 (down), thus resulting in net VLCFA catabolism and preventing cellular accumulation of VLCFAs.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataLuciferase reporter assays were carried out in triplicates.
“in triplicates using Lipofectamine® 2000 (Invitrogen) according to the manufacturer’s protocol.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation25-HC lacks the membrane-ordering and packing capacities of cholesterol, altering membrane fluidity upon incorporation.
“25-HC lacks the membrane-ordering and packing capacities of cholesterol, thus membrane fluidity is altered upon its incorporation49,50.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [49] Gomes, B., Goncalves, S., Disalvo, A., Hollmann, A. & Santos, N. C. Effect of 25-hydroxycholesterol in viral membrane fusion: Insights on HIV inhibition. Biochim. Biophys. Acta Biomembr. 1860, 1171–1178 (2018). source
- cites [50] Lange, Y. Cholesterol movement from plasma membrane to rough endoplasmic reticulum. Inhibition by progesterone. J. Biol. Chem. 269, 3411–3414 (1994). source
May combine two claims.
Interpretationown data25-hydroxycholesterol restores ABCD1 expression in B lymphocytes, resulting in reduced VLCFA levels and an ABCD1-dependent decrease in EBV production.
“Collectively, these data show that the antiviral mediator 25-HC restores ABCD1 expression in B lymphocytes, resulting in reduced VLCFA levels and an ABCD1-dependent decrease in EBV production (Fig. 5f).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe fungus uses VLCFAs to recruit filament-forming septins to curved plasma membranes, promoting formation of a penetration peg required for host infection.
“He and co-workers show that the fungus uses VLCFAs to recruit filament-forming septins to curved plasma membranes, thereby promoting the formation of a penetration peg required for host infection.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [48] He, M. et al. Discovery of broad-spectrum fungicides that block septin-dependent infection processes of pathogenic fungi. Nat. Microbiol. 5, 1565–1575 (2020). source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenqPCR was performed for each cDNA sample in technical duplicates.
“qPCR was performed with the CFX96™ Real-Time PCR Detection System (BioRad) for each cDNA sample in technical duplicates.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataThe purity of isolated primary B cells was determined using flow cytometry.
“The purity of isolated primary B cells was determined using a mouse anti-human CD19 monoclonal antibody, PE conjugated (clone LT19, # 130-091-247, Miltenyi) and the PE-conjugated monoclonal antibody isotype control (#120-002-723, Miltenyi) by flow cytometry.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe Berlin/Germany rate was higher than the incidence reported in a U.S. study.
“which was higher than the incidence reported in a U.S. study55.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [55] Balfour, H. H. Jr. et al. Age-specific prevalence of Epstein-Barr virus infection among individuals aged 6-19 years in the United States and factors affecting its acquisition. J. Infect. Dis. 208, 1286–1293 (2013). source
Classified as probably not a substantial claim. May combine two claims.
Study design and conductnone givenStatistical analysis used one-sided Fisher's exact test, two-tailed unpaired or paired, and nested Student's t-test, with Bonferroni adjustment to correct for multiple testing, and P-values below 0.05 were regarded as significant.
“For statistical analysis, one-sided Fisher´s exact test, two-tailed unpaired or paired, as well as nested Student’s t-test, were used with Bonferroni adjustment to correct for multiple testing. P-values below 0.05 were regarded to indicate statistical significance.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenParallel determination of VCA IgG, EBNA IgG and EBV IgM levels enabled discrimination among different phases of EBV infection.
“Parallel determination of VCA IgG, EBNA IgG and EBV IgM levels enabled the discrimination among different phases of the EBV infection.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataBioinformatic analysis used a significance level cut-off of 0.05 and Benjamin Hochberg correction for false discovery rate.
“significance level cut-off 0.05; Benjamin Hochberg correction for false discovery rate”
Quote in the paperNot a substantial claim
The paper relies on this without support.
Viruses exploit host lipid metabolism to promote their replication.
“Viruses have developed highly sophisticated strategies to exploit the host lipid metabolism to promote their replication.”
The paper relies on this without support.
ABCD1 is the main transporter mediating peroxisomal degradation of saturated VLCFAs.
“ABCD1, the main transporter mediating peroxisomal degradation of saturated VLCFAs”
The authors state this as an assumption.
EBV infection of B cells is a valid paradigm for herpesvirus infection.
“Using EBV infection of B cells as a paradigm for herpesvirus infection”
The paper relies on this without support.
Controls of similar age with conditions unrelated to X-ALD are appropriate for comparing EBV seroprevalence with childhood CALD patients.
“controls of similar age with conditions unrelated to X-ALD”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
A recent study in rodent B lymphocytes showed that peroxisomal VLCFA transport is targeted by herpes viruses and antiviral host response.
“A recent study in rodent B lymphocytes showed that peroxisomal VLCFA transport is targeted by herpes viruses and antiviral host response [391].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [391]
The Discussion states that herpesviruses and antiviral host-cell strategies target the peroxisomal VLCFA transporter ABCD1. But the Results section on EBV-induced VLCFA accumulation identifies the B lymphocytes studied as human, not rodent; the claimed species is unsupported. Our copy provides section labels but no page numbers. (LLM, conf=0.94)
Experimental — accuracy not yet measuredABCD1 mutations might play a pivotal role in viral infection and host defenses, prompting consideration of viral triggers in cALD.
“ABCD1 mutations might thus play a pivotal role of in viral infection and host defenses, prompting consideration of viral triggers in cALD and suggesting new candidate disease mechanisms [391].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [391]
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Self-citation25-Hydroxycholesterol Inhibition of Lassa Virus Infection through Aberrant GP1 Glycosylation
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Flagged first, then by citations
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Cited by
Sorted by citations
Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy
Bougnères, P., & Le Stunff, C. (2025) · Genes · doi:10.3390/genes16050590 · Cited by 11 · see citing works
- Authors
- Weinhofer, I., Buda, A., Kunze, M., Palfi, Z., Traunfellner, M., Hesse, S., Villoria-Gonzalez, A., Hofmann, J., Hametner, S., Regelsberger, G., Moser, A. B., Eichler, F., Kemp, S., Bauer, J., Kühl, J.-S., Forss-Petter, S., & Berger, J.
- Affiliations
- Medical University of Vienna (AT)
- Charité - Universitätsmedizin Berlin (DE)
- Kennedy Krieger Institute (US)
- Harvard University (US)
- Amsterdam Neuroscience (NL)
- University Hospital Leipzig (DE)
- Corresponding author
- Weinhofer, Isabelle
- Berger, Johannes
- ORCID
- Venue
- Communications Biology
- Published
- 2022-09-09
- Volume
- 5
- Issue
- 1
- Pages
- 944-944
- ISSN
- 2399-3642 (ISSN-L)
- PMC
- PMC9462615
- OpenAlex
- W4295047885
- Cited by
- 20
- References
- 61
- Citations by year
- 2026: 8 · 2025: 4 · 2024: 3 · 2023: 4 · 2022: 1
- FWCI
- 1.83
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Communications Biology (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, cc-by)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
- PubMed Central (submittedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Austrian Science Fund (KLI 837-B, DOC 33-B27)
- Topics
- Health Sciences › Medicine › Epidemiology › Cytomegalovirus and herpesvirus research
- Health Sciences › Medicine › Epidemiology › Herpesvirus Infections and Treatments
- Health Sciences › Medicine › Oncology › Viral-associated cancers and disorders
- Keywords
- very long chain fatty acids, ABCD1, ABCD2, Epstein-Barr virus, herpesvirus infection, microRNA regulation, miR-9-5p, miR-155, 25-hydroxycholesterol, antiviral innate immunity, X-linked adrenoleukodystrophy, neuroinflammation, host-virus interaction
- MeSH terms
- Adrenoleukodystrophy, Antiviral Agents, Child, Herpesvirus 4, Human, Fatty Acids, Herpesviridae, Humans, Epstein-Barr Virus Infections
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-20.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-20.
Cited sources are checked by gpt-6-sol.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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