Biology subjects

Heath, S. L.

Publications and source records attributed to Heath, S. L..

8 recordsLinked to original sources

bioRxiv2025

Systemic translocation of S. aureus Drives Anti-CD4 Autoimmunity in Treated HIV Infection

BackgroundIn 2017, our group first demonstrated that autoimmunity contributes to HIV pathogenesis, even without autoimmune disease. This concept is now broadly recognized, exemplified by the role of autoimmunity in severe COVID-19. In people with HIV (PWH) on suppressive ART, anti-CD4 autoantibodies may impair CD4+ T cell recovery, though the mechanisms driving their production remain unclear. Building on evidence from our group and others that Staphylococcus aureus and its peptidoglycan (PGN) promote autoimmunity, we investigated their contribution to anti-CD4 IgG in HIV. MethodsPlasma from 32 ART-naive PWH, 53 ART-treated PWH, and 32 HIV-negative controls was analyzed for IgG autoantibodies and markers of S. aureus translocation using protein array, ELISA, and microarray. EcoHIV mice were injected intraperitoneally with saline, S. aureus PGN, or Bacillus subtilis PGN. PGN structures were compared by mass spectrometry. ResultsAmong 87 autoantibodies, 40% were elevated in ART-naive PWH and largely normalized by ART; however, anti-CD4 IgGs remained elevated in PWH on ART. Anti-CD4 IgG levels inversely correlated with CD4+ T cell counts in ART-treated PWH and positively with S. aureus translocation. In mice, S. aureus PGN induced anti-CD4 IgGs, reduced gut CD4+ T cells, and promoted surface IgG binding and apoptosis in CD4+ T cells. ConclusionS. aureus and its PGN translocation may drive anti-CD4 autoimmunity and hinder immune recovery in PWH on suppressive ART, highlighting S. aureus colonization as a therapeutic target and supporting the development of competitive probiotic interventions such as Bacillus subtilis.

immunology↗

bioRxiv2023

Hue selectivity from recurrent circuitry in Drosophila

A universal principle of sensory perception is the progressive transformation of sensory information from broad non-specific signals to stimulus-selective signals that form the basis of perception. To perceive color, our brains must transform the wavelengths of light reflected off objects into the derived quantities of brightness, saturation and hue. Neurons responding selectively to hue have been reported in primate cortex, but it is unknown how their narrow tuning in color space is produced by upstream circuit mechanisms. To enable circuit level analysis of color perception, we here report the discovery of neurons in the Drosophila optic lobe with hue selective properties. Using the connectivity graph of the fly brain, we construct a connectomics-constrained circuit model that accounts for this hue selectivity. Unexpectedly, our model predicts that recurrent connections in the circuit are critical for hue selectivity. Experiments using genetic manipulations to perturb recurrence in adult flies confirms this prediction. Our findings reveal the circuit basis for hue selectivity in color vision.

neuroscience↗

bioRxiv2022

Exploiting Color Space Geometry for Visual Stimulus Design across Animals

Color vision represents a vital aspect of perception that ultimately enables a wide variety of species to thrive in the natural world. However, unified methods for constructing chromatic visual stimuli in a laboratory setting are lacking. Here, we present stimulus design methods and an accompanying programming package to efficiently probe the color space of any species in which the photoreceptor spectral sensitivities are known. Our hardware-agnostic approach incorporates photoreceptor models within the framework of the principle of univariance. This enables experimenters to identify the most effective way to combine multiple light sources to create desired distributions of light, and thus easily construct relevant stimuli for mapping the color space of an organism. We include methodology to handle uncertainty of photoreceptor spectral sensitivity as well as to optimally reconstruct hyperspectral images given recent hardware advances. Our methods support broad applications in color vision science and provide a framework for uniform stimulus designs across experimental systems.

neuroscience↗

bioRxiv2020

Combined protein and transcript single cell RNA sequencing reveals cardiovascular disease and HIV signatures

Cryopreserved peripheral blood mononuclear cells (PBMCs) are frequently collected and provide disease- and treatment-relevant data in clinical studies. Here, we developed combined protein (40 antibodies) and transcript single cell (sc)RNA sequencing in PBMCs. Among 31 participants in the WIHS Study, we sequenced 41,611 cells. Using Boolean gating followed by Seurat UMAPs and Louvain clustering, we identified 58 subsets among CD4 T, CD8 T, B, NK cells and monocytes. This resolution was superior to flow cytometry, mass cytometry or scRNA-sequencing without antibodies. Since the transcriptome was not needed for cell identification, combined protein and transcript scRNA-Seq allowed for the assessment of disease-related changes in transcriptomes and cell type proportion. As a proof-of-concept, we showed such differences between healthy and matched individuals living with HIV with and without cardiovascular disease. In conclusion, combined protein and transcript scRNA sequencing is a suitable and powerful method for clinical investigations using PBMCs.

immunology↗

bioRxiv2020

Heme Attenuates Endogenous Opioid Levels in Leukocytes of HIV positive individuals with Chronic Widespread Pain

ABSTRACTThe prevalence of chronic widespread pain (CWP) in people with HIV (PWH) is high, yet the underlying mechanisms are elusive. Leukocytes synthesize the endogenous opioid, β-endorphin (β-END), within their endoplasmic reticulum (ER). When released into plasma, β-END dampens nociceptive transmission by binding to opioid receptors on sensory neurons. In the present study, we hypothesized that heme-induced ER stress attenuates leukocyte levels/release of β-END, thereby increasing pain sensitivity in PWH. Results demonstrate that PWH with CWP have fragile erythrocytes, high plasma levels of cell-free heme, and impaired heme metabolism. Leukocytes from PWH with CWP also had high ER stress and low β-END compared to PWH without CWP and HIV-negative individuals with or without pain. In vitro heme exposure decreased β-END levels/secretion in murine monocytes/macrophages, which was prevented by treatment with sodium 4-phenylbutyrate, an ER stress inhibitor. To mimic hemolytic effects in a preclinical model in vivo, C57BL/6 mice were injected with phenylhydrazine hydrochloride (PHZ). PHZ increased cell-free heme and ER stress, decreased leukocyte β-END levels and hindpaw mechanical sensitivity thresholds. Treatment of PHZ-injected mice with the heme scavenger, hemopexin, blocked these effects, suggesting that heme-induced ER stress and a subsequent decrease in leukocyte β-END may contribute to CWP in PWH.Competing Interest StatementThe authors have declared no competing interest.View Full Text

pathology↗

bioRxiv2020

Impact of glycan positioning on HIV-1 Env glycan shield density, function, and antibody recognition

N-glycans, which represent >50% mass of the HIV-1 envelope (Env) trimer, play important roles for virus-cell entry and immune evasion. How each glycan unit interacts to shape the Env protein-sugar complex and affects Env function is not well understood. Here, high-resolution glycomics analysis of two Env variants from the same donor, with differing functional characteristics and N-glycosylation-site composition, revealed that changes to key N-glycosylation-site not only affected the Env structure at distant locations, but also had a ripple effect on Env-wide glycan processing, virus infectivity, and antibody recognition and virus neutralization. Specifically, the N262 glycan, although not located in the CD4-binding site, controlled Env binding to the CD4 receptor, affected the recognition of Env by several glycan-dependent broadly neutralizing antibodies, and altered heterogeneity of glycosylation at several sites, with N156, N160, and N448 displaying limited glycan processing. Molecular dynamic simulations visualized how specific oligosaccharide positions can move to compensate for loss of a glycan. This study demonstrates how changes in individual glycan units can alter molecular dynamics and processing of the Env-glycan shield and, consequently, Env function.

microbiology↗

bioRxiv2019

Circuit mechanisms underlying chromatic encoding in Drosophila photoreceptors

Spectral information is commonly processed in the brain through generation of antagonistic responses to different wavelengths. In many species, these color opponent signals arise as early as photoreceptor terminals. Here, we measure the spectral tuning of photoreceptors in Drosophila. In addition to a previously described pathway comparing wavelengths at each point in space, we find a horizontal-cell-mediated pathway similar to that found in mammals. This pathway enables additional spectral comparisons through lateral inhibition, expanding the range of chromatic encoding in the fly. Together, these two pathways enable optimal decorrelation of photoreceptor signals. A biologically constrained model accounts for our findings and predicts a spatio-chromatic receptive field for fly photoreceptor outputs, with a color opponent center and broadband surround. This dual mechanism combines motifs of both an insect-specific visual circuit and an evolutionarily convergent circuit architecture, endowing flies with the unique ability to extract chromatic information at distinct spatial resolutions.

neuroscience↗

bioRxiv2019

Inspiratory rhythmogenic activity is burst-independent and opioid-sensitive

How mammalian neural circuits generate rhythmic activity in motor behaviors, such as breathing, walking, and chewing, remains elusive. For breathing, rhythm generation can be localized to a brainstem nucleus called the preBotzinger Complex (preBotC). Rhythmic preBotC population activity consists of small amplitude burstlets, which we hypothesize are rhythmogenic, and larger inspiratory bursts, which drive motoneuronal activity. If burstlets are rhythmogenic, opioids, analgesics that can cause profound respiratory depression, should similarly reduce burstlet frequency. In conditions where burstlets were separated from bursts in medullary slices from neonatal mice, the -opioid receptor (OR) agonist DAMGO decreased burstlet frequency. DAMGO-mediated depression was abolished by genetic deletion of ORs in a glutamatergic preBotC subpopulation and was reduced by Substance P, but not blockade of inhibitory synaptic transmission. Our findings suggest that rhythmogenesis need not rely on strong bursts of activity associated with motor output and point to strategies for ameliorating opioid-induced depression of breathing.

neuroscience↗