Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2022.09.26.508302

Antiretroviral Therapy Does Not Restore Brain Lipids During SIV Infection: Regional Analysis of Metabolic Homeostasis and Depletion

White, C. J.·Gausepohl, A. M.·Seneviratne, H. K.·Bumpus, N. N.·Williams, D. W.
View original source ↗Export metadata ↓

Abstract

Human immunodeficiency virus (HIV) infection continues to promote neurocognitive impairment, mood disorders, and brain atrophy even in the modern era of viral suppression. Brain lipids are vulnerable to HIV-associated energetic strain and contribute to HIV-associated neurologic dysfunction due to alterations in lipid breakdown and structural lipid composition. HIV neuropathology is region dependent, yet there has not been comprehensive characterization of the spatial heterogeneity of brain lipids during infection that may impact neurologic function. To address this gap, we evaluated the spatial lipid distribution using matrix laser desorption/ionization imaging mass spectrometry (MALDI-IMS) across four brain regions (parietal cortex, midbrain, thalamus, and temporal cortex), as well as kidney for a peripheral tissue control, in a virally suppressed simian immunodeficiency virus (SIV)-infected rhesus macaque. We assessed lipids indicative of fat breakdown [acylcarnitines (CARs)] and critical structural lipids [phosphatidylcholines (PCs) and phosphatidylethanolamines (PEs)] across fatty acid chain lengths and degrees of unsaturation. CARs with very long-chain, polyunsaturated fatty acids (PUFAs) were more abundant across all brain regions than shorter chain, saturated or monounsaturated species. We observed distinct brain lipid distribution patterns for CARs and PCs. However, no clear expression patterns emerged for PEs. Surprisingly, kidney was nearly devoid of ions corresponding to PUFAs common in brain. PEs and PCs with PUFAs had little intensity and less density than other species and, only one CAR species was observed in kidney at high intensity. Overall, our study provides substantial evidence for persistent bioenergetic changes to the brain despite viral suppression, including region-dependent mobilization of CARs for oxidation and disparities in the presence of key phospholipids necessary for maintaining proper brain structure and function. These data indicate that region-specific interventions to restore proper lipid metabolism are essential for treating HIV neurologic disease in the era of antiretroviral therapy. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/508302v3_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@598d53org.highwire.dtl.DTLVardef@14d5cf1org.highwire.dtl.DTLVardef@10f6c9org.highwire.dtl.DTLVardef@1ba1aab_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG

Source connections

Explore related subjects

pathologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

White, C. J., Gausepohl, A. M., Seneviratne, H. K., Bumpus, N. N., Williams, D. W.. 2022-09-27. Antiretroviral Therapy Does Not Restore Brain Lipids During SIV Infection: Regional Analysis of Metabolic Homeostasis and Depletion. https://doi.org/10.1101/2022.09.26.508302

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

NAE1-Dependent Protein Neddylation Preserves Endothelial Identity and Vascular Integrity

Background: Endothelial dysfunction is a central driver of cardiovascular and inflammatory diseases, yet the post-translational mechanisms that preserve endothelial homeostasis remain incompletely understood. Protein neddylation, the covalent conjugation of a ubiquitin-like modifier, regulates diverse cellular processes, yet its physiological role in the vascular endothelium remains unknown. This study investigated whether protein neddylation is required to preserve endothelial identity and vascular homeostasis. Methods: We generated tamoxifen-inducible endothelial-specific Nae1 knockout mice to inhibit neddylation and combined bulk RNA sequencing, single-cell and single-nucleus transcriptomics, quantitative proteomics, biochemical analyses, and gain- and loss-of-function approaches to define the role of endothelial neddylation in vascular homeostasis and inflammatory injury. Results: Endothelial-specific Nae1 deletion caused rapid mortality associated with vascular leakage, platelet accumulation, inflammation, and multi-organ injury. Multi-omics analyses demonstrated profound loss of endothelial identity, characterized by suppression of core endothelial programs and activation of inflammatory, procoagulant, and pyroptotic pathways. Single-cell analyses revealed progressive endothelial dysfunction culminating in depletion of the endothelial population and remodeling of the vascular niche. Mechanistically, endothelial neddylation deficiency activated gasdermin D (GSDMD)- and gasdermin E (GSDME)-dependent pyroptosis, whereas dual inhibition of GSDMD and GSDME markedly attenuated inflammatory transcriptomic remodeling, vascular injury, hepatocyte death, immune cell infiltration, and platelet accumulation. Translational analyses demonstrated reduced endothelial neddylation in experimental endotoxemia and decreased expression of neddylation pathway components in human atherosclerosis and COVID-19 datasets. Conversely, restoration of endothelial neddylation partially reversed inflammatory endothelial transcriptomic reprogramming in vivo. Conclusions: NAE1-dependent protein neddylation is an essential regulator of endothelial identity and vascular integrity. Loss of endothelial neddylation promotes gasdermin-dependent pyroptosis and thrombo-inflammatory vascular injury, whereas restoration of the neddylation pathway mitigates inflammatory endothelial dysfunction. These findings identify endothelial neddylation as a fundamental mechanism maintaining vascular homeostasis and a potential therapeutic target for cardiovascular and inflammatory diseases.

pathology↗
bioRxiv2022

The effect of subconjunctival TNF-α inhibitors on retinal ganglion cell apoptosis and optic nerve degeneration after corneal surgery or trauma--of possible prophylactic value against secondary glaucoma.

AbstractO_ST_ABSBackground and PurposeC_ST_ABSLate secondary glaucoma is an often-severe complication after acute events like anterior segment surgery, trauma, infection, etc. TNF- is a major mediator that is rapidly upregulated, diffusing also to the retina and causes apoptosis of the ganglion cells and degeneration of their optic nerve axons (mediating steps to glaucomatous damage). Anti-TNF- antibodies are in animals very effective in protecting the retinal cells and the optic nerve--and might therefore be useful prophylactically against secondary glaucoma in future such patients.Here we evaluate 1) toxicity and 2) efficacy of two TNF- inhibitors (adalimumab and infliximab), in rabbits by subconjunctival administration. MethodsFor drug toxicity, animals with normal, unburned corneas were injected with adalimumab (0.4, 4, or 40 mg), or infliximab (1, 10, or 100 mg). For drug efficacy, other animals were subjected to alkali burn before such injection, or steroids (for control). The rabbits were evaluated clinically with slit lamp and photography, electroretinography, optical coherence tomography, and intraocular pressure manometry. A sub-set of eyes were stained ex vivo after 3 days for retinal cell apoptosis (TUNEL). In other experiments the optic nerves were evaluated by paraphenylenediamine staining after 50 or 90 days. Loss of retinal cells and optic nerve degeneration were quantified. ResultsSubconjunctival administration of 0.4 mg or 4.0 mg adalimumab were well tolerated, whereas 40.0 mg was toxic to the retina. 1, 10, or 100 mg infliximab were also well tolerated.Analysis of the optic nerve axons after 50 days confirmed the safety of 4.0 mg adalimumab and of 100 mg infliximab. For efficacy, 4.0 mg adalimumab subconjunctivally in 0.08 mL provided practically full protection against retinal cell apoptosis 3 days following alkali burn, and infliximab 100 mg only slightly less. At 90 days following burn injury, control optic nerves showed about 50% axon loss as compared to 8% in the adalimumab treatment group. ConclusionsSubconjunctival injection of 4.0 mg adalimumab in rabbits shows no eye toxicity and provides excellent neuroprotection, both short (3 days) and long-term (90 days). Ourtotal accumulated data from several of our studies, combined with the present paper, suggest that corneal injuries, including surgery, might benefit from routine administration of anti-TNF- biologics to reduce inflammation and future secondary glaucoma.

pathology↗
bioRxiv2022

Intracellular reactive oxygen species (intraROS)-aided localized cell death contributing to immune responses against wheat powdery mildew pathogen

Reactive oxygen species (ROS) and hypersensitive response (HR) mediated cell death have long been known to play critical roles in plant immunity to pathogens. Wheat powdery mildew caused by Blumeria graminis f. sp. tritici (Bgt) is a destructive wheat pathogen. Here, we report a quantitative analysis of the proportion of infected cells with local apoplastic ROS (apoROS) versus intracellular ROS (intraROS) accumulation in various wheat accessions that carry different disease resistance genes (R genes), at a series of time points post-infection. The proportion of apoROS accumulation was 70-80% of the infected wheat cells detected in both compatible and incompatible host-pathogen interactions. However, intensive intraROS accumulation followed by localized cell death responses were detected in 11-15% of the infected wheat cells, mainly in wheat lines that carried nucleotide-binding leucine-rich repeat (NLR) R genes (e.g. Pm3F, Pm41, TdPm60, MIIW72, Pm69). The lines that carry unconventional R genes, Pm24 (Wheat Tandem Kinase 3) and pm42 (a recessive R gene), showed very less intraROS responses, while 11% of Pm24 line infected epidermis cells still showed HR cell death, suggesting that different resistance pathways are activated there. Here, we also demonstrated that ROS could not act as a strong systemic signal for inducing high resistance to Bgt in wheat, although it induced the expression of pathogenesis-related (PR) genes. These results provide new insights on the contribution of intraROS and localized cell death to immune responses against wheat powdery mildew.

pathology↗