Biology subjects

Ribeiro, S. P.

Publications and source records attributed to Ribeiro, S. P..

7 recordsLinked to original sources

bioRxiv2026

An eicosanoid-enriched follicular microenvironment shapes germinal centre immune dynamics in antiretroviral-treated PLWH

Delineating the follicular (F) cellular and molecular landscape in HIV infection is essential for understanding neutralizing antibody responses and HIV reservoir maintenance. Multiplex imaging analysis revealed a less differentiated profile for follicular helper CD4 T cells (TFH) and significantly increased follicular CD25lo/hiFoxp3hi T cells in lymph nodes (LNs) from antiretroviral treated (cART) compared to viremic (Vir) people living with HIV (PLWH). Spatial transcriptomics identified distinct inflammatory follicular microenvironments in Vir and cART LNs, characterized by interferon and eicosanoid enrichment, respectively. In an independent cohort, scRNA-sequencing analysis of LN-derived cells revealed an enrichment of eicosanoid-related pathways in follicular immune cell types in non-neutralizers compared to neutralizers PLWH. In vitro infection and in situ multimodal investigation of HIV DNA+ cell microenvironments suggested a potential role of PGE2/Eicosanoids in maintaining viral reservoirs in cART LNs. Our data highlight cellular and molecular factors that could regulate both antibody responses and viral reservoir persistence in PLWH.

immunology↗

bioRxiv2026

Microenvironment-informed inference of transcriptional progression geometry

We present BIOCURRENT, a causal inference framework that reconstructs donor-specific pseudotime geometry in transcriptomic data. By modeling gene expression as a function of baseline characteristics, microenvironmental context, and latent pseudotime, BIOCURRENT enables comparison of compressed or expanded progression intervals across transcriptional state transitions. We introduce $\Delta\Delta T$, a geometry-based estimator that quantifies differences in pseudotime intervals across conditions, enabling evaluation of changes in pseudotime intervals under hypothetical modulation of microenvironmental programs. Applications to thymic T-cell developmental lineages and to COVID-19 immune dysregulation reveal condition- and donor-specific distortions of progression intervals. Counterfactual simulation links microenvironmental context to changes in specific intracellular state transition intervals. By localizing deviations in pseudotime geometry, BIOCURRENT identifies whether shifts in transcriptomic programs emerge early or later along transcriptomic coordinates and reveals upstream programs associated with these distortions. Such localization supports transcriptional stage-aware mechanistic hypotheses and suggests candidate intervention checkpoints in complex biological systems.

bioinformatics↗

bioRxiv2025

A unified network systems approach uncovers a core novel program underlying T follicular helper cell differentiation

T follicular helper (Tfh) cells are central to the adaptive immune response and exhibit remarkable functional diversity and plasticity. The complex nature of Tfh cell populations, inconsistent findings across experimental systems and potential differences across species have fueled ongoing debate regarding core regulatory pathways that govern Tfh differentiation. Many studies have experimentally investigated individual proteins and circuits involved in Tfh differentiation in limited contexts, each providing only a partial understanding of the process. To address this, we adopted a novel multi-scale network systems approach that incorporates both regulatory and protein-protein interactions. Our approach integrates diverse data types, captures regulation across multiple levels of immune system organization, and recapitulates known drivers. Further, we discover a core Tfh gene set that is conserved across tissue types and disease contexts, and is consistent across data modalities - bulk, single-cell and spatial. While components of this set have been individually reported, a novel aspect of our work lies in the discovery, characterization, and connectivity of this core signature using a single unbiased approach. Using this method, we also uncover a novel function of IL-12, a molecule with reported conflicting functions, in the regulation of Tfh differentiation. Notably, we find that, in both humans and mice, IL-12 is permissive for the differentiation of Tfh precursors, but blocks subsequent differentiation into GC Tfh cells. Overall, this work elucidates novel networks with unexplored roles in governing Tfh cell differentiation across species and tissues, paving the way for novel -therapeutic interventions.

immunology↗

bioRxiv2024

Intestinal helminth infection impairs vaccine-induced T cell responses and protection against SARS-CoV-2

Although vaccines have reduced COVID-19 disease burden, their efficacy in helminth infection endemic areas is not well characterized. We evaluated the impact of infection by Heligmosomoides polygyrus bakeri (Hpb), a murine intestinal hookworm, on the efficacy of an mRNA vaccine targeting the Wuhan-1 spike protein of SARS-CoV-2. Although immunization generated similar B cell responses in Hpb-infected and uninfected mice, polyfunctional CD4+ and CD8+ T cell responses were markedly reduced in Hpb-infected mice. Hpb-infected and mRNA vaccinated mice were protected against the ancestral SARS-CoV-2 strain WA1/2020, but control of lung infection was diminished against an Omicron variant compared to animals immunized without Hpb infection. Helminth mediated suppression of spike-specific CD8+ T cell responses occurred independently of STAT6 signaling, whereas blockade of IL-10 rescued vaccine-induced CD8+ T cell responses. In mice, intestinal helminth infection impairs vaccine induced T cell responses via an IL-10 pathway and compromises protection against antigenically shifted SARS-CoV-2 variants.

immunology↗

bioRxiv2021

TREM2+ and interstitial macrophages orchestrate airway inflammation in SARS-CoV-2 infection in rhesus macaques

The COVID-19 pandemic remains a global health crisis, yet, the immunopathological mechanisms driving the development of severe disease remain poorly defined. Here, we utilize a rhesus macaque (RM) model of SARS-CoV-2 infection to delineate perturbations in the innate immune system during acute infection using an integrated systems analysis. We found that SARS-CoV-2 initiated a rapid infiltration (two days post infection) of plasmacytoid dendritic cells into the lower airway, commensurate with IFNA production, natural killer cell activation, and induction of interferon-stimulated genes. At this early interval, we also observed a significant increase of blood CD14-CD16+ monocytes. To dissect the contribution of lung myeloid subsets to airway inflammation, we generated a novel compendium of RM-specific lung macrophage gene expression using a combination of sc-RNA-Seq data and bulk RNA-Seq of purified populations under steady state conditions. Using these tools, we generated a longitudinal sc-RNA-seq dataset of airway cells in SARS-CoV-2-infected RMs. We identified that SARS-CoV-2 infection elicited a rapid recruitment of two subsets of macrophages into the airway: a C206+MRC1-population resembling murine interstitial macrophages, and a TREM2+ population consistent with CCR2+ infiltrating monocytes, into the alveolar space. These subsets were the predominant source of inflammatory cytokines, accounting for ~75% of IL6 and TNF production, and >90% of IL10 production, whereas the contribution of CD206+MRC+ alveolar macrophages was significantly lower. Treatment of SARS-CoV-2 infected RMs with baricitinib (Olumiant(R)), a novel JAK1/2 inhibitor that recently received Emergency Use Authorization for the treatment of hospitalized COVID-19 patients, was remarkably effective in eliminating the influx of infiltrating, non-alveolar macrophages in the alveolar space, with a concomitant reduction of inflammatory cytokines. This study has delineated the major subsets of lung macrophages driving inflammatory and anti-inflammatory cytokine production within the alveolar space during SARS-CoV-2 infection. One sentence summaryMulti-omic analyses of hyperacute SARS-CoV-2 infection in rhesus macaques identified two population of infiltrating macrophages, as the primary orchestrators of inflammation in the lower airway that can be successfully treated with baricitinib

microbiology↗

bioRxiv2020

Microbiome and Metabolome driven differentiation of TGF-β producing Tregs leads to Senescence and HIV latency

Current therapeutic interventions to eradicate latent HIV ("reservoir") and restore immune function in ART-treated HIV infection have yet to show efficacy. To explore mechanisms of HIV persistence, we apply an integrated systems biology approach and identify a distinct group of individuals with poor CD4 T-cell reconstitution (Immunologic non-responders, "INRs") and high frequencies of cells with inducible HIV. Contrary to the prevailing notion that immune activation drives HIV persistence and immune dysfunction, peripheral blood leukocytes from these subjects have enhanced expression of a network of genes regulated by cellular senescence driving transcription factors (TFs) FOXO3, SMAD2 and IRF3. In these subjects, increased frequencies of regulatory T cells and expression of the TGF-{beta} signaling cascade are complimented by the downregulation of cell cycle, metabolic and pro-inflammatory pathways. Lactobacillaceae family and metabolites (members of the butyrate family - i.e. -ketobutyrate) were correlated with Treg frequencies in "Senescent-INRs" ex vivo, triggered the differentiation of TGF-{beta} producing Tregs and promoted HIV latency establishment in vitro. These cascades, downstream of PD-1/TGF-{beta}, prevent memory T cell differentiation and are associated with an increase in frequencies of cells with inducible HIV ex vivo. Our findings identify cellular senescence responses that can be targeted by PD-1 or TGF-{beta} specific interventions that have shown safety and efficacy in cancer, and may prove to be crucial for HIV eradication.

immunology↗

bioRxiv2020

Baricitinib treatment resolves lower airway inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques

Effective therapeutics aimed at mitigating COVID-19 symptoms are urgently needed. SARS-CoV-2 induced hypercytokinemia and systemic inflammation are associated with disease severity. Baricitinib, a clinically approved JAK1/2 inhibitor with potent anti-inflammatory properties is currently being investigated in COVID-19 human clinical trials. Recent reports suggest that baricitinib may also have antiviral activity in limiting viral endocytosis. Here, we investigated the immunologic and virologic efficacy of baricitinib in a rhesus macaque model of SARS-CoV-2 infection. Viral shedding measured from nasal and throat swabs, bronchoalveolar lavages and tissues was not reduced with baricitinib. Type I IFN antiviral responses and SARS-CoV-2 specific T cell responses remained similar between the two groups. Importantly, however, animals treated with baricitinib showed reduced immune activation, decreased infiltration of neutrophils into the lung, reduced NETosis activity, and more limited lung pathology. Moreover, baricitinib treated animals had a rapid and remarkably potent suppression of alveolar macrophage derived production of cytokines and chemokines responsible for inflammation and neutrophil recruitment. These data support a beneficial role for, and elucidate the immunological mechanisms underlying, the use of baricitinib as a frontline treatment for severe inflammation induced by SARS-CoV-2 infection.

immunology↗