👤 Jessica G Avalos

Chronic neuroinflammation is associated with comorbidities in people with HIV (PWH) on antiretroviral therapy (ART). While cannabis use is associated with reduced neuroinflammation and neurocognitive impairment (NCI) in PWH, the underlying mechanisms are unknown. To address this gap in knowledge, we analyzed monocyte-derived macrophages (MDMs) from a cohort of 50 PWH and 33 people without HIV (mean age: 61.9 years), categorized by frequency of cannabis use (naïve/low, moderate, daily). We performed immunocytochemistry, RNA sequencing, and qPCR on MDMs and quantified related biomarkers in donor plasma. In this cohort study, daily cannabis use in PWH was associated with less global neurocognitive deficits, and with an anti-inflammatory immunometabolic-phenotype in MDMs characterized by (1) a metabolic shift from glycolysis to oxidative phosphorylation, (2) higher mitochondrial numbers, (3) altered cytokine profiles (pro-inflammatory downregulation, anti-inflammatory upregulation), and (4) higher brain-derived neurotrophic factor (BDNF) expression. These cellular changes were corroborated by a plasma biomarker profile in PWH including (1) lower levels of growth differentiation factor 15 and soluble triggering receptor expressed on myeloid cells 2, and (2) higher mature BDNF/precursor BDNF ratios that correlated with better cognition. Thus, cannabis use may mitigate NCI in PWH by immunometabolically reprogramming MDM function towards an anti-inflammatory and neuroprotective state. Show less

Animals in nature potentially experience multiple stressors, and those of anthropogenic origin are likely to be repeated or chronic. However, stress hormone levels are highly context-dependent and are not consistent predictors of chronic stress in wildlife. Profiling the downstream consequences of repeated stress responses, such as changes in metabolism or gene expression, may be more informative for predicting their individual-level health consequences and population-level impacts, which are key objectives for wildlife conservation. We previously found that in free-ranging juvenile elephant seals, the blubber transcriptome and proteome, but not cortisol levels, could distinguish between responses to single versus repeated stress axis stimulation. However, the blubber proteome response to stress was limited and mainly involved extra-cellular matrix proteins. In this study, we examined the plasma proteome response of four of the same animals to the repeated stress experiment, since multiple organs secrete proteins into the circulation, providing a readout of their activity and integration. We isolated plasma proteins, identified and quantified them using liquid chromatography and tandem mass spectrometry (LC-MS/MS) and compared their abundance between sampling times. We identified >200 proteins in plasma, of which 42 were altered in abundance, revealing complex protein dynamics in response to repeated stress challenges. These changes were delayed but sustained, suggesting that the plasma proteome may reflect longer term integration of multi-organ responses to recent, rather than immediate, challenges. Differentially abundant proteins included components of the osmoregulatory system, acute phase and complement proteins, organokines, apolipoproteins and hormone transport proteins, which coordinate physiological processes with significant implications for marine mammal health and may explain several aspects of marine mammal stress physiology, such as insulin resistance and high aldosterone levels. We identified several potentially novel biomarkers, such as AGT, HPX, TTR and APOA4, that may be useful for detecting recent and repeated stress exposure in marine mammals. Show less