Plasma metabolomics identifies lipid abnormalities linked to markers of inflammation, microbial translocation, and hepatic function in HIV patients receiving protease inhibitors

Cassol, Edana; Misra, Vikas; Holman, Alexander G.; Kamat, Anupa; Morgello, Susan; Gabuzda, Dana

doi:10.1186/1471-2334-13-203

Cited by 115 publications

(134 citation statements)

References 95 publications

(103 reference statements)

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“…Decreases observed in levels of -6 PUFAs and lysolipids from infected blood during 3 dpi suggests that both arms of AA production were disrupted. These results are consistent with other metabolomics studies of infection whose results have indicated the importance of eicosanoids and lysolipids during infection (45,50,63). However, it appears that decreases in levels of eicosanoids and lysolipids are not universal traits during bacterial infections.…”

Section: Discussionsupporting

confidence: 82%

Global Metabolomic Analysis of a Mammalian Host Infected with Bacillus anthracis

2015

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bWhereas DNA provides the information to design life and proteins provide the materials to construct it, the metabolome can be viewed as the physiology that powers it. As such, metabolomics, the field charged with the study of the dynamic small-molecule fluctuations that occur in response to changing biology, is now being used to study the basis of disease. Here, we describe a comprehensive metabolomic analysis of a systemic bacterial infection using Bacillus anthracis, the etiological agent of anthrax disease, as the model pathogen. An organ and blood analysis identified approximately 400 metabolites, including several key classes of lipids involved in inflammation, as being suppressed by B. anthracis. Metabolite changes were detected as early as 1 day postinfection, well before the onset of disease or the spread of bacteria to organs, which testifies to the sensitivity of this methodology. Functional studies using pharmacologic inhibition of host phospholipases support the idea of a role of these key enzymes and lipid mediators in host survival during anthrax disease. Finally, the results are integrated to provide a comprehensive picture of how B. anthracis alters host physiology. Collectively, the results of this study provide a blueprint for using metabolomics as a platform to identify and study novel host-pathogen interactions that shape the outcome of an infection. Metabolomics, a quickly emerging "omics" field in systems biology, is the global analysis of small molecules in a biological sample (1). Since the 1950s, the central dogma of biological information has been the transition from genes to transcript to protein (2). Only recently has the use of high-throughput systems biology been used to study the products of protein activity, the metabolites. The metabolome represents all endogenous and exogenous low-molecular-mass (Ͻ1-kDa) molecules present in a biological state, providing an instantaneous "snapshot" of the cell's metabolic and physiological activity (3). Applications of global metabolomic analysis fall into three broad categories: (i) disease diagnosis, (ii) biomarker and drug discovery, and (iii) study of metabolic pathways and their perturbations due to external factors (1). The analysis of altered metabolites has the potential for discovery of new biomarkers, thus providing the possibility of earlier intervention and insights into the mechanisms of diseases (4).The diagnosis of a bacterial infection encompasses an assessment of clinical symptoms, positive culture of an organism from tissues or blood, and/or reliance on often expensive, outsourced molecular methods (5). Metabolomics provides a unique perspective on bacterial infections as it is able to comprehensively characterize a vast number of metabolic changes in response to a biological perturbation within the host (2). In addition to the potential for biomarker discovery, the metabolic profiles obtained from this analysis can give insight into the identity and nature of molecules involved in the immune response, detect alterations in ho...

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Section: Discussionsupporting

confidence: 82%

Global Metabolomic Analysis of a Mammalian Host Infected with Bacillus anthracis

2015

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“…30 There is in vitro and clinical evidence that PIs can cause mitochondrial dysfunction through the generation of reactive oxygen species and by triggering pathways of mitophagy. 31,32 Importantly, PIs can also cause insulin resistance. FAO is perturbed in patients with insulin resistance, resulting in abnormal acylcarnitine levels 33 and excessive acylcarnitines may even play a role in the signaling pathways that lead to the development of insulin resistance.…”

Section: Discussionmentioning

confidence: 99%

Acylcarnitine Profiles in HIV-Exposed, Uninfected Neonates in the United States

Kirmse

Yao

Hofherr

et al. 2016

AIDS Research and Human Retroviruses

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We sought to determine the prevalence of abnormal acylcarnitine profiles (ACP) in HIV-exposed uninfected (HEU) newborns and to explore the association of abnormal ACP with clinical laboratory outcomes and antiretroviral drug exposures. Clinically, ACP are used to assess for fatty acid oxidation (FAO) dysfunction and normal FAO is necessary for optimal fetal/neonatal growth and development. We analyzed serum ACP in 522 HEU neonates enrolled in the Surveillance Monitoring for ART Toxicities (SMARTT) study of the Pediatric HIV/AIDS Cohort Study (PHACS) and evaluated the associations of abnormal ACP with in utero exposure to combination antiretroviral therapy (cART) in logistic regression models, adjusting for maternal demographic, disease, and behavioral characteristics. We evaluated the associations of abnormal ACP with laboratory parameters and measures of neurodevelopment and growth. Of 522 neonates, 89 (17%) had abnormal ACP. In adjusted analyses, in utero exposure to a protease inhibitor (PI) was associated with higher odds of having an abnormal ACP [adjusted odds ratio (aOR) = 2.35, 95% CI: 0.96, 5.76, p = 0.06] with marginal significance while exposure to a nonnucleoside reverse transcriptase inhibitor (NNRTI) was associated with lower odds (aOR = 0.23, 95% CI: 0.07, 0.80, p = 0.02). Mean ALT levels were slightly higher in those with abnormal ACP, but no differences in lactate, glucose, or CPK were observed. ACP status was not associated with neurodevelopment at 1 year or growth at 2 and 3 years of age. Abnormal ACP in HEU neonates are associated with exposure to PIcontaining as opposed to NNRTI-containing antiretroviral (ARV) regimens but are not associated with serious postnatal clinical problems. Further studies are needed to determine the long-term health implications of abnormal acylcarnitine metabolism at birth in HEU children.

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“…Metabolite extraction was performed as previously described (Evans et al, 2009). Metabolite extracts were subjected to three analyses: gas chromatography and mass spectrometry, ultra HPLC and tandem mass spectrometry optimized for basic metabolites, and ultra HPLC and tandem mass spectrometry optimized for acidic metabolites (Cassol et al, 2013). Relative abundance was determined for 194 identified (named) metabolites.…”

Section: Metabolite Profilingmentioning

confidence: 99%

Novel Roles for the Polyphenol Oxidase Enzyme in Secondary Metabolism and the Regulation of Cell Death in Walnut

et al. 2014

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The enzyme polyphenol oxidase (PPO) catalyzes the oxidation of phenolic compounds into highly reactive quinones. Polymerization of PPO-derived quinones causes the postharvest browning of cut or bruised fruit, but the native physiological functions of PPOs in undamaged, intact plant cells are not well understood. Walnut (Juglans regia) produces a rich array of phenolic compounds and possesses a single PPO enzyme, rendering it an ideal model to study PPO. We generated a series of PPO-silenced transgenic walnut lines that display less than 5% of wild-type PPO activity. Strikingly, the PPO-silenced plants developed spontaneous necrotic lesions on their leaves in the absence of pathogen challenge (i.e. a lesion mimic phenotype). To gain a clearer perspective on the potential functions of PPO and its possible connection to cell death, we compared the leaf transcriptomes and metabolomes of wild-type and PPO-silenced plants. Silencing of PPO caused major alterations in the metabolism of phenolic compounds and their derivatives (e.g. coumaric acid and catechin) and in the expression of phenylpropanoid pathway genes. Several observed metabolic changes point to a direct role for PPO in the metabolism of tyrosine and in the biosynthesis of the hydroxycoumarin esculetin in vivo. In addition, PPOsilenced plants displayed massive (9-fold) increases in the tyrosine-derived metabolite tyramine, whose exogenous application elicits cell death in walnut and several other plant species. Overall, these results suggest that PPO plays a novel and fundamental role in secondary metabolism and acts as an indirect regulator of cell death in walnut.

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Plasma metabolomics identifies lipid abnormalities linked to markers of inflammation, microbial translocation, and hepatic function in HIV patients receiving protease inhibitors

Cited by 115 publications

References 95 publications

Global Metabolomic Analysis of a Mammalian Host Infected with Bacillus anthracis

Global Metabolomic Analysis of a Mammalian Host Infected with Bacillus anthracis

Acylcarnitine Profiles in HIV-Exposed, Uninfected Neonates in the United States

Novel Roles for the Polyphenol Oxidase Enzyme in Secondary Metabolism and the Regulation of Cell Death in Walnut

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