Biology subjects

Suliman, S.

Publications and source records attributed to Suliman, S..

10 recordsLinked to original sources

bioRxiv2026

CD1b-specific T cells are transcriptionally closer to conventional CD4 T cells than to innate-like NKT and MAIT cells

Unconventional T cells recognize non-peptide antigens presented by molecules other than the major histocompatibility complex (MHC) proteins. Among unconventional T cells, natural killer T (NKT) cells, which recognize CD1d-lipid complexes, mucosal-associated invariant T (MAIT) cells, which recognize MR1-metabolite complexes, and {gamma}{delta} T cells, are thoroughly studied. CD1b presents self- and mycobacterial lipids to relatively understudied T cell subsets. Like MAIT cells and type I NKT cells, CD1b-specific cells include subpopulations with conserved TCRs. Consequent to their recognition of a nearly monomorphic antigen-presenting molecule, CD1b-specific T cells might share innate-like features with MAIT, type I NKT, and {gamma}{delta} T cells. Due to their low frequency in the peripheral blood, CD1a-, CD1b-, and CD1c-specific T cells have been studied predominantly as in vitro-expanded clones, so even basic information about their native ex vivo immunophenotypes is lacking. Here, we sort and transcriptionally profile ex vivo two T cell populations that recognize CD1b presenting mycobacterial mycolipids and compare them with conventional CD4 and CD8 T cells, {gamma}{delta} T cells, NK cells, MAIT cells, and NKT cells. We show that both the invariant TCR-expressing CD4+, CD1b-GMM-specific germline encoded mycolyl-reactive (GEM) T cells, as well as the diverse TCR-expressing CD1b-GMM-specific T cells, are transcriptionally closer to conventional T cells than to the innate-like T cell populations {gamma}{delta}, MAIT and type I NKT cells. Thus, despite their recognition of non-polymorphic antigen presenting molecules, CD1b-specific T cells show adaptive rather than innate-like transcriptional features.

immunology↗

bioRxiv2026

Regulatory T cells modulate bone marrow stromal cell osteogenesis by activating ROCK-myosin axis and cell contractility

Bone regeneration depends not only on the intrinsic signaling in bone marrow-derived mesenchymal stromal cells (BMSC), but also on immune cell-derived cues. Regulatory T cells (Treg) are emerging as immune regulators of tissue repair, yet their direct impact on BMSC osteogenesis remains unexplored. Here, we showed that direct human BMSC-Treg co-culture induced more pronounced osteogenic gene expression and cytokine modulation in BMSC than indirect co-culture. This contact-dependent interaction temporally enhanced BMSC osteogenic gene expression, alkaline phosphatase activity and matrix mineralization by interacting with ROCK-myosin signaling pathway. Exploratory proteomic profiling further revealed enrichment of cytoskeletal, mechanosensitive and osteogenic regulators in BMSC after direct Treg co-culture. Pharmacological inhibition of cell contractility impaired osteogenesis yet Treg co-culture partially restored cytoskeletal integrity and differentiation. These findings identify novel mechanisms behind Treg as direct modulators of BMSC mechanobiology and osteogenesis, highlighting their therapeutic potential in bone regeneration.

cell biology↗

bioRxiv2025

Continental-scale genomic surveillance of Plasmodium falciparum malaria with rapid nanopore sequencing

In sub-Saharan Africa, continental-scale genomic surveillance of Plasmodium falciparum malaria is needed to track the spread of antimalarial drug resistance and diagnostic test evasion, as well as to monitor parasite evolutionary responses to vaccine rollout. Yet implementation of malaria genomic surveillance at a continental-scale is hindered by resource constraints, the vastness of the continent, and the lack of sequencing protocols suitable for most local laboratories. To address this, we developed an approach to enable a decentralized scale-up of P. falciparum genomic surveillance and established it in six African countries in one year, locally sequencing 1,065 samples. The approach includes a rapid ([~] 5 hours) and cost-efficient (<$25 USD/sample) nanopore sequencing protocol that provides surveillance of drug resistance-associated genes, hrp2/3 deletions, the vaccine target csp, and the polymorphic gene ama1. We coupled this to a bioinformatics dashboard that runs offline on a laptop and displays mapping and variant calling results in real-time. We demonstrate robust sequencing coverage across parasitemia levels and laboratories, accurate identification of antimalarial resistance markers and hrp2/3 deletions; and, with a novel variant caller, sensitive detection of mutations carried by minor clones. Our approach will accelerate genomic surveillance of P. falciparum malaria across sub-Saharan Africa at a time of urgent need.

genomics↗

bioRxiv2023

Immunosuppression is a conserved driver of tuberculosis susceptibility

Mycobacterium tuberculosis (Mtb) causes 1.25 million deaths a year; however, tuberculosis (TB) pathogenesis remains poorly understood. Here we find that gene signatures from three different Mtb-susceptible mouse models predict active TB disease in humans significantly better than a signature from resistant C57BL/6 (B6) mice. Conserved among susceptible mice, non-human primates, and humans, but largely absent from B6 mice, was Mtb-induced Spp1+ macrophage differentiation. Spp1+ macrophages expressed high levels of immunosuppressive molecules including IL-1 receptor antagonist (IL-1Ra). Here we report that enhancement of IL-1 signaling via deletion of IL-1Ra promoted bacterial control across three susceptible mouse models. We found that IL-1 signaling promotes pulmonary control of Mtb infection through amplifying TNF production by uninfected bystander cells. Our results indicate that myeloid cell expression of immunosuppressive molecules, in particular IL-1 receptor antagonist, is a conserved mechanism limiting Mtb control in mice, non-human primates, and humans.

immunology↗

bioRxiv2022

Neutrophil degranulation, NETosis and platelet degranulation pathway genes are co-induced in whole blood up to six months before tuberculosis diagnosis

Mycobacterium tuberculosis (M.tb) causes tuberculosis (TB) and remains one of the leading causes of mortality due to an infectious pathogen. Host immune responses have been implicated in driving the progression from infection to severe lung disease. We analyzed longitudinal RNA sequencing (RNAseq) data from the whole blood of 74 TB progressors whose samples were grouped into four six-month intervals preceding diagnosis (the GC6-74 study). We additionally analyzed RNAseq data from an independent cohort of 90 TB patients with positron emission tomography-computed tomography (PET-CT) scan results which were used to categorize them into groups with high and low levels of lung damage (the Catalysis TB Biomarker study). These groups were compared to non-TB controls to obtain a complete whole blood transcriptional profile for individuals spanning from early stages of M.tb infection to TB diagnosis. The results revealed a steady increase in the number of genes that were differentially expressed in progressors at time points closer to diagnosis with 278 genes at 13-18 months, 742 at 7-12 months and 5,131 detected 1-6 months before diagnosis and 9,205 detected in TB patients. A total of 2,144 differentially expressed genes were detected when comparing TB patients with high and low levels of lung damage. There was a large overlap in the genes upregulated in progressors 1-6 months before diagnosis (86%) with those in TB patients. A comprehensive pathway analysis revealed a potent activation of neutrophil and platelet mediated defenses including neutrophil and platelet degranulation, and NET formation at both time points. These pathways were also enriched in TB patients with high levels of lung damage compared to those with low. These findings suggest that neutrophils and platelets play a critical role in TB pathogenesis, and provide details of the timing of specific effector mechanisms that may contribute to TB lung pathology. Author summaryMycobacterium tuberculosis (M.tb) causes tuberculosis (TB) and remains one of the leading causes of mortality due to an infectious pathogen. Human immune responses must be balanced to inhibit disease progression while limiting self-damage, however in defense against M.tb host responses have been implicated in lung damage and in driving progression of M.tb infection to severe lung disease. The identification of immune responses that are activated during the development of TB could provide potential targets for interventions that might suppress disease progression, and possibly limit tissue damage. Here we identify a subset of genes that function in several biological processes that are strongly activated in the late stages of TB development and in TB patients. The proteins encoded by these genes are known to degrade lung tissue and contribute to severe lung disease.

genomics↗

bioRxiv2021

Modeling memory T cell states at single-cell resolution identifies in vivo state-dependence of eQTLs influencing disease

Many non-coding genetic variants cause disease by modulating gene expression. However, identifying these expression quantitative trait loci (eQTLs) is complicated by gene-regulation differences between cell states. T cells, for example, have fluid, multifaceted functional states in vivo that cannot be modeled in eQTL studies that aggregate cells. Here, we modeled T cell states and eQTLs at single-cell resolution. Using >500,000 resting memory T cells from 259 Peruvians, we found over one-third of the 6,511 cis-eQTLs had state-dependent effects. By integrating single-cell RNA and surface protein measurements, we defined continuous cell states that explained more eQTL variation than discrete states like CD4+ or CD8+ T cells and could have opposing effects on independent eQTL variants in a locus. Autoimmune variants were enriched in cell-state-dependent eQTLs, such as a rheumatoid-arthritis variant near ORMDL3 strongest in cytotoxic CD8+ T cells. These results argue that fine-grained cell state context is crucial to understanding disease-associated eQTLs.

genetics↗

bioRxiv2021

Effects of BCG vaccination on donor unrestricted T cells in humans

Antigen classes other than proteins can be presented to T cells by near-monomorphic antigen-presenting molecules such as CD1, MR1, and butyrophilin 3A1. We sought to define the roles of donor unrestricted T (DURT) cells, including MR1-reactive MAIT cells, CD1b-reactive glucose monomycolate (GMM)-specific T cells, CD1d-reactive NKT cells, and {gamma}{delta} T cells, in vaccination against Mycobacterium tuberculosis. We characterized DURT cells following primary bacille Calmette-Guerin (BCG) vaccination in infants or BCG-revaccination in adults. BCG (re)vaccination did not modulate peripheral blood frequencies, T cell activation or memory profiles of MAIT cells, CD1b-restricted GMM-specific and germline-encoded mycolyl-reactive (GEM) cells or CD1d- restricted NKT cells. By contrast, BCG vaccination was associated with increased frequencies of {gamma}{delta} T cells as well as a novel subset of IFN-{gamma}-expressing CD4+ T cells with a CD26+CD161+TRAV1-2- phenotype in infants. More studies are required to understand the full potential of DURT cells in new TB vaccine strategies.

immunology↗

bioRxiv2021

Dual TCR-alpha expression on MAIT cells as a potential confounder of TCR interpretation

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that are highly abundant in human blood and tissues. Most MAIT cells have an invariant T cell receptor (TCR) chain that uses TRAV1-2 joined to TRAJ33/20/12 and recognize metabolites from bacterial riboflavin synthesis bound to the antigen-presenting molecule, MR1. Recently, our attempts to identify alternative MR1-presented antigens led to the discovery of rare MR1-restricted T cells with non-TRAV1-2 TCRs. Because altered antigen specificity is likely to lead to altered affinity for the most potent known antigen, 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU), we performed bulk TCR and {beta} chain sequencing, and single cell-based paired TCR sequencing, on T cells that bound the MR1-5-OP-RU tetramer, but with differing intensities. Bulk sequencing showed that use of V genes other than TRAV1-2 was enriched among MR1-5-OP-RU tetramerlow cells. Whereas we initially interpreted these as diverse MR1-restricted TCRs, single cell TCR sequencing revealed that cells expressing atypical TCR chains also co-expressed an invariant MAIT TCR chain. Transfection of each non-TRAV1-2 TCR chain with the TCR{beta} chain from the same cell demonstrated that the non-TRAV1-2 TCR did not bind the MR1-5-OP-RU tetramer. Thus, dual TCR chain expression in human T cells and competition for the endogenous {beta} chain explains the existence of some MR1-5-OP-RU tetramerlow T cells. The discovery of simultaneous expression of canonical and non-canonical TCRs on the same T cell means that claims of roles for non-TRAV1-2 TCR in MR1 response must be validated by TCR transfer-based confirmation of antigen specificity.

immunology↗

bioRxiv2020

Multimodal memory T cell profiling identifies a reduction in a polyfunctional Th17 state associated with tuberculosis progression

Mycobacterium tuberculosis (M.tb) results in 10 million active tuberculosis (TB) cases and 1.5 million deaths each year1, making it the worlds leading infectious cause of death2. Infection leads to either an asymptomatic latent state or TB disease. Memory T cells have been implicated in TB disease progression, but the specific cell states involved have not yet been delineated because of the limited scope of traditional profiling strategies. Furthermore, immune activation during infection confounds underlying differences in T cell state distributions that influence risk of progression. Here, we used a multimodal single-cell approach to integrate measurements of transcripts and 30 functionally relevant surface proteins to comprehensively define the memory T cell landscape at steady state (i.e., outside of active infection). We profiled 500,000 memory T cells from 259 Peruvians > 4.7 years after they had either latent M.tb infection or active disease and defined 31 distinct memory T cell states, including a CD4+CD26+CD161+CCR6+ effector memory state that was significantly reduced in patients who had developed active TB (OR = 0.80, 95% CI: 0.73-0.87, p = 1.21 x 10-6). This state was also polyfunctional; in ex vivo stimulation, it was enriched for IL-17 and IL-22 production, consistent with a Th17-skewed phenotype, but also had more capacity to produce IFN{gamma} than other CD161+CCR6+ Th17 cells. Additionally, in progressors, IL-17 and IL-22 production in this cell state was significantly lower than in non-progressors. Reduced abundance and function of this state may be an important factor in failure to control M.tb infection.

immunology↗

bioRxiv2018

Progression of recent Mycobacterium tuberculosis exposure to active tuberculosis is a highly heritable complex trait driven by 3q23 in Peruvians

Among 1.8 billion people worldwide infected with Mycobacterium tuberculosis, 5-15% are expected to develop active tuberculosis (TB). Approximately half of these will progress to active TB within the first 18 months after infection, presumably because they fail to mount the initial immune response that contains the local bacterial spread. The other half will reactivate their latent infection later in life, likely triggered by a loss of immune competence due to factors such as HIV-associated immunosuppression or ageing. This natural history suggests that undiscovered host genetic factors may control early progression to active TB. Here, we report results from a large genome-wide genetic study of early TB progression. We genotyped a total of 4,002 active TB cases and their household contacts in Peru and quantified genetic heritability [Formula] of early TB progression to be 21.2% under the liability scale. Compared to the reported [Formula] of genome-wide TB susceptibility (15.5%), this result indicates early TB progression has a stronger genetic basis than population-wide TB susceptibility. We identified a novel association between early TB progression and variants located in an enhancer region on chromosome 3q23 (rs73226617, OR=1.19; P < 5x10-8). We used in silico and in vitro analyses to identify likely functional variants and target genes, highlighting new candidate mechanisms of host response in early TB progression.

genetics↗