Peroxisomal very long-chain fatty acid transport is targeted by herpesviruses and the antiviral host response

Abstract

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.

Saturated very long-chain fatty acids regulate macrophage plasticity and invasiveness

“…Of note, the LPS-mediated upregulation of ABCD1, which is the rate-limiting factor in peroxisomal VLCFA degradation [ 50 ], was concurrent with repression of most peroxisomal genes including those involved in β-oxidation. This is the opposite pattern of that observed upon herpesvirus infection of B cells, where pathogen-induced downregulation of ABCD1 occurs despite general induction of peroxisomes [ 51 ]. This would allow both accumulation of VLCFAs, which are needed by the virus, and exploitation of other peroxisomal functions required for viral replication [ 51 ].…”

“…This is the opposite pattern of that observed upon herpesvirus infection of B cells, where pathogen-induced downregulation of ABCD1 occurs despite general induction of peroxisomes [ 51 ]. This would allow both accumulation of VLCFAs, which are needed by the virus, and exploitation of other peroxisomal functions required for viral replication [ 51 ]. Accordingly, ABCD1 could represent a dynamic regulatory switch point in immune cells either promoting or preventing VLCFA accumulation to modulate pro-inflammatory responses associated with the defence against pathogens.…”

Biomarker-based risk prediction for the onset of neuroinflammation in X-linked adrenoleukodystrophy

“… 1 , 5 What triggers CALD remains unclear; among others, traumatic brain injury 6 and viral infection have been proposed as causative agents. 7 Neuroinflammation in CALD is characterized by breakdown of the blood–brain barrier (BBB), infiltration of monocytes/macrophages, and, to a lower extent, T cells. 3 , 8 Hypertrophic astrocytes and activated microglial cells beyond the leading edge of brain lesions indicate both astrogliosis and microgliosis as early events, probably preceding demyelination and invasion of peripheral immune cells.…”

Neuroproteomic Analysis after SARS-CoV-2 Infection Reveals Overrepresented Neurodegeneration Pathways and Disrupted Metabolic Pathways

“…Another serum proteomic study in COVID-19 patients, both disease and recovery stage, showed disturbances in cholesterol metabolism [30], once again supporting our observation of disrupted cholesterol metabolism (Figure 4B). ELOVL1 (fatty acid elongase) has been associated with viral replication, as decreased ELOVL1 indicates disrupted viral replication [102]. The lack of replications of SARS-CoV-2 in the neurons is perhaps due to the decreased expression of ELOVL1 in infected neurons (Figure 2C) as a compensatory mechanism to evade the virus.…”