Biology subjects

Basting, C. M.

Publications and source records attributed to Basting, C. M..

7 recordsLinked to original sources

bioRxiv2026

Spatial Transcriptomics Reveals Compartment-Specific Immune Activation Signatures in Ileal and Lymph Node Tissue in Treated HIV Infection

People with HIV (PWH) on long-term antiretroviral therapy (ART) continue to experience elevated rates of morbidities and mortality driven by persistent immune activation despite viral suppression. Known contributors include low-level HIV provirus activity, microbial translocation in part from epithelial barrier dysfunction, microbiome dysfunction, and co-infections. However, how these interact and where they predominate across tissue compartments remains incompletely defined. Here, we applied spatial transcriptomics to characterize compartment-specific transcriptional programs in ileum (epithelium, Peyer's patches, lamina propria) and inguinal lymph nodes (B Cell follicles and T cell zone) from ten PWH on long-term ART, stratified by CD4/CD8 ratio into low-ratio and high-ratio groups, with low-ratio as a proxy for immune activation and increased risk for non-AIDS related serious event. Comparison of global expression found significant differences between groups in four of five compartments. Differential expression analysis identified 483 differentially expressed genes across four of five compartments, with the greatest burden in the T-cell zone and none in the lamina propria. Gene set enrichment analysis identified 116 enriched pathways predominantly in the low-ratio group, spanning immune activation, infection-associated, and metabolic programs, with Peyer's patches showing the broadest transcriptional divergence of any compartment. Cross-compartment signals included higher expression of ORMDL3 and ARL17B in the low-ratio group implicating mitochondrial stress and inflammasome activation, lower expression of CCL3L3 and FCMR in the low-ratio group suggesting impaired immune execution, and divergent ribosomal protein programs between B-cell follicles and the T-cell zone. Cell deconvolution identified compartment-specific differences in estimated immune cell proportions, and T-cell zone gene expression showed significant associations with HIV reservoir measures and plasma markers of microbial translocation and immune activation. Together these findings support spatially heterogeneous immune activation as a feature of persistent immune dysregulation in treated HIV infection and provide compartment-resolved, hypothesis-generating evidence for the tissue-specific mechanisms driving inflammation in this population.

bioinformatics↗

bioRxiv2026

Plasma metabolomics reveals lipid-predominant metabolic disruptions in virologically suppressed people with HIV

People with HIV (PWH) on antiretroviral therapy (ART) experience excess morbidity and mortality from comorbidities including cardiovascular and metabolic disease, yet the biological mechanisms underlying these outcomes in virally suppressed PWH (VS-PWH) remain incompletely understood. We applied high-dimensional targeted plasma metabolomics to quantify 254 small molecules and 750 lipids across 49 classes in viremic PWH (Vi-PWH), VS-PWH, and people without HIV (PWoH), analyzed alongside multiple T cell metrics and plasma cytokine concentrations. Globally, the plasma metabolome of VS-PWH was indistinguishable from PWoH, while Vi-PWH exhibited substantial metabolic disruption characterized by depletion of phosphatidylcholines, sphingomyelins, and hexosylceramides alongside triglyceride accumulation, dysregulation of the tryptophan-kynurenine and arginine-citrulline axes, and elevations in diacetylated polyamines and N4-acetylcytidine. Ordinal trend analysis identified subtle but consistent residual alterations in VS-PWH, particularly within phosphatidylcholine and sphingomyelin classes, that correlated with elevated TNF and reduced CD4+ T cell counts and CD4/CD8 ratio. Together, these findings indicate that residual TNF-associated inflammation and incomplete T cell recovery continue to shape the plasma metabolome in treated HIV, identifying candidate biomarkers for further mechanistic and clinical investigation.

microbiology↗

bioRxiv2026

Multi-omics links microbial dysbiosis, systemic inflammation and metabolomic disruptions to SNAE risk in treated HIV

Serious non-AIDS events (SNAEs), including non-AIDS malignancies, cardiovascular disease, and hepatic complications, remain major causes of mortality in treated HIV infection. These outcomes are driven by persistent immune activation, systemic inflammation, and metabolic dysfunction despite effective viral suppression with antiretroviral therapy (ART). To investigate mechanisms underlying SNAE pathogenesis, we performed a cross-site multi-omic analysis integrating plasma proteins, plasma metabolites, and mucosal microbiomes (ileum and rectum) in 82 ART-treated people with HIV (PWH) and 10 people without HIV (PWoH) from the United States and Mexico. Geography was the dominant source of variation, particularly across lipid classes. However, individuals at high risk for SNAEs, defined by low CD4 T cell counts and low CD4/CD8 ratios, shared a consistent signature of systemic inflammation, mitochondrial dysfunction, and microbial dysbiosis including elevated plasma IL-6, {omega}-oxidation products (adipic and suberic acids), and depletion of short-chain fatty acid-producing commensals in the gut mucosa, including Akkermansia muciniphila, Bacteroides uniformis, and Ruminococcus. Notably, A. muciniphila abundance correlated with lower IL-6 levels, fewer HIV RNA-producing cells in lymph nodes, and higher CD4/CD8 ratios. Together, these findings identify a shared inflammatory and metabolic phenotype in PWH and implicate A. muciniphila as a potential microbiome-based target to mitigate immune activation and SNAE risk in treated HIV.

immunology↗

bioRxiv2026

Ongoing lymphoid HIV production drives pyroptosis and GLP-1 counter-regulation in ART-suppressed infection

Despite effective antiretroviral therapy (ART), many people with HIV (PWH) exhibit persistent immune activation (IA) and suffer metabolic comorbidities. We investigated whether residual HIV production in lymphoid tissues drives IA. Among 20 ART-suppressed PWH, HIV RNA+ cells were detected in lymph nodes and correlated directly with markers of pyroptosis, assessed via cleaved gasdermin D positivity, but not with most plasma cytokines or IA markers. Notably, glucagon-like peptide 1 (GLP-1), an enteroendocrine hormone with anti-inflammatory roles, was upregulated in the ileum of PWH and correlated directly with systemic cytokines but inversely with lymph node pyroptosis. These findings suggest that chronic occult inflammation in people with successfully suppressed HIV infection is mediated by persistent virus production in lymph nodes leading to pyroptosis, which may trigger compensatory anti-inflammatory enteroendocrine activation that may dampen pyroptosis. Targeting pyroptosis or enhancing GLP-1 signaling represent potential therapeutic strategies for modulating IA and managing metabolic comorbidities in PWH. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/698696v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@af8909org.highwire.dtl.DTLVardef@4dbc95org.highwire.dtl.DTLVardef@197ff48org.highwire.dtl.DTLVardef@1f9051a_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2025

Pre-treatment Microbiome Diversity and Function is associated with Expansion of Cytotoxic and Regulatory Immune Populations after N-803 treatment in People with HIV

BackgroundN-803, an IL-15 superagonist, is currently being studied in clinical trials as a treatment to reverse HIV latency. However, its effects on the gut microbiome are not well understood. MethodsIn this longitudinal metagenomic study, we analyzed fecal microbiomes from ART-suppressed people with HIV at four different timepoints before, during, and after N-803 treatment. ResultsOverall taxonomic and functional diversity did not change significantly, yet beneficial microbial taxa and pathways were enriched after N-803. Specifically, the relative abundance of Faecalibacterium prausnitzii increased significantly after N-803, whereas histidine degradation pathways, often associated with pro-inflammatory mucosal state, decreased. A higher baseline microbial diversity correlated with stronger CD8+ and natural killer (NK) cells activation and reduced frequency of rectal HIV RNA+ cells. MaAsLin2 analyses further associated short-chain fatty acid (SCFA)-producing taxa and pathways with increased immune activation markers. ConclusionsThese results indicate that gut microbiome diversity prior to immunotherapy influences host response and suggest that microbiome-based strategies could improve efforts to cure HIV.

microbiology↗

bioRxiv2025

Gut barrier integrity biomarkers are associated with increased inflammation and predict disease status in hospitalized COVID-19 patients

The COVID-19 global pandemic persists as an endemic disease with frequent case spikes and a significant continued burden on public health. Although most COVID-19 cases are asymptomatic or mild, severe infections requiring hospitalization have resulted in likely more than 14 million cumulative deaths to date. One hallmark of severe COVID-19 is a dysregulated immune response that leads to systemic inflammation and contributes to disease severity and mortality but is not explained by viral replication alone. Severe COVID-19 has been shown to disrupt the gut microbiome and increase intestinal permeability which may contribute to immune dysregulation and systemic inflammation. In this study, we investigated the differences in plasma biomarkers for microbial translocation and gut barrier damage as well as circulating cytokines between healthy volunteers and patients hospitalized with COVID-19. We then performed a correlation analysis to understand how the relationships between these plasma biomarkers differed and used a random forest model to assess their accuracy in distinguishing between these two groups. Our results demonstrated that hospitalized COVID-19 patients have elevated concentrations of pro-inflammatory cytokines and markers of microbial translocation, and that the relationships between these biomarkers were significantly altered compared to healthy volunteers, especially those related to the mucosal associated homeostatic cytokines IL-17A and IL-23. Furthermore, IL-6 and LBP were the top biomarkers for prediction accuracy in our random forest model, highlighting the importance of managing microbial translocation in COVID-19 and its potential utility as a biomarker for disease severity. IMPORTANCECOVID-19 continues to be a burden on public health. Understanding how plasma biomarkers differ between healthy and acutely infected individuals can help in understanding pathogenesis and predict disease severity. It has been demonstrated that COVID-19 disrupts the gut microbiome and intestinal permeability, which contributes to systemic inflammation. Our study highlights the link between gut barrier integrity and inflammation in hospitalized SARS-CoV-2 cases, demonstrating the usefulness of gut barrier integrity biomarkers in predicting disease severity, and offers insights for therapeutic interventions in acute COVID-19 infection.

immunology↗

bioRxiv2023

SARS-CoV-2 infection is associated with intestinal permeability, systemic inflammation, and microbial dysbiosis in hospitalized COVID-19 patients

Coronavirus disease 2019 (COVID-19) and associated severity has been linked to uncontrolled inflammation and may be associated with changes in the microbiome of mucosal sites including the gastrointestinal tract and oral cavity. These sites play an important role in host-microbe homeostasis and disruption of epithelial barrier integrity during COVID-19 may potentially lead to exacerbated inflammation and immune dysfunction. Outcomes in COVID-19 are highly disparate, ranging from asymptomatic to fatal, and the impact of microbial dysbiosis on disease severity is unclear. Here, we obtained plasma, rectal swabs, oropharyngeal swabs, and nasal swabs from 86 patients hospitalized with COVID-19 and 12 healthy volunteers. We performed 16S rRNA sequencing to characterize the microbial communities in the mucosal swabs and measured circulating cytokines, markers of gut barrier integrity, and fatty acids in the plasma samples. We compared these plasma concentrations and microbiomes between healthy volunteers and the COVID-19 patients who had survived or unfortunately died by the end of study enrollment, and between severe disease and healthy controls, as well as performed a correlation analysis between plasma variables and bacterial abundances. The rectal swabs of COVID-19 patients had reduced abundances of several commensal bacteria including Faecalibacterium prausnitsii, and an increased abundance of the opportunistic pathogens Eggerthella lenta and Hungatella hathewayi. Furthermore, the oral pathogen Scardovia wiggsiae was more abundant in the oropharyngeal swabs of COVID-19 patients who died. The abundance of both H. hathewayi and S. wiggsiae correlated with circulating inflammatory markers including IL-6, highlighting the possible role of the microbiome in COVID-19 severity, and providing potential therapeutic targets for managing COVID-19.

microbiology↗