Biology subjects

Oduor, C. I.

Publications and source records attributed to Oduor, C. I..

5 recordsLinked to original sources

bioRxiv2026

Not so cold after all: tumor infiltrating CD8+ T cells in EBV-positive Burkitt lymphoma are quiescent, not exhausted

Abstract / SummarySurvival outcomes for pediatric Burkitt lymphoma (BL) substantially vary depending on geography (50-90%), which also serves as a proxy for the prevalence of Epstein-Barr virus (EBV) within the tumors. Although BL is considered an immunologically "cold" tumor with few tumor-infiltrating lymphocytes (TILs), their functional status has not been fully evaluated, especially for EBV-positive disease. Here, we characterize the exhaustion and activation profiles of T cells in the tumor microenvironment (TME) of EBV-positive BL using orthogonal methods, single-cell gene expression analysis, spectral flow cytometry, and immuno-histochemistry staining (IHC). We found that CD8+ TILs displayed a mosaic of immune inhibitory gene expression encoding, PD1, TIGIT, LAG3 and HAVCR2/TIM3. IHC validated the expression of PD1 and TIGIT on CD8+ TILs, as well as their respective ligands, PDL-1, PVR, and Nectin-2 on malignant B cells. Despite exhaustion-associated signatures, CD8+ TILs retain cytotoxic potential, expressing granules (i.e. Granzyme A, Perforin) and cytokines (i.e. IFN{gamma}) and demonstrate an increased uptake of metabolites such as glucose, arginine, and methionine. In peripheral blood, pediatric BL patients exhibited a significantly higher abundance of PD1+TIGIT+ CD8+ T cells compared to healthy children. Notably, these circulating T cells from BL patients express significantly lower levels of TOX, suggesting they are not irreversibly dysfunctional. Together, our results indicate that CD8+ T cells both in the TME and in circulation of children with BL are not terminally exhausted but remain poised for functional re-invigoration. These findings support the potential integration of immune checkpoint inhibitors into combination chemotherapeutic regimens to improve outcomes for these children. SignificanceEBV-positive BL tumors contain functional, metabolically active CD8+ T cells. Circulating PD1+TIGIT+CD8+ T cells found in BL patients blood are a biomarker for those in the tumor microenvironment.

immunology↗

bioRxiv2025

The Impact of Malaria-Induced Neutrophil Subset Shift and a Link to Burkitt Lymphoma

Burkitt lymphoma (BL) is an aggressive B-cell lymphoma that remains a leading cause of childhood cancer mortality in sub-Saharan Africa. Although the epidemiological link between Plasmodium falciparum (Pf) malaria and BL has been established, our understanding of the underlying immunological mechanisms conducive to tumorigenesis is incomplete. To address a noted gap in our knowledge of the immune landscape, we profiled neutrophil subsets from children with different exposure histories to Pf-malaria and children diagnosed with BL from Western Kenya, along with healthy malaria-naive Kenyan adults. Using multiparameter flow cytometry, we characterized neutrophils by expression of CD15, CD16, CD10, CD11b, CD182, CD184, and CD62L and found that malaria-exposed children exhibited increased frequencies of aged neutrophil subsets, accompanied by a reduction in the mature subset frequencies compared to malaria-naive children. Malaria-exposed children also had neutrophil profiles that closely resembled those seen in the adults. Notably, a positive correlation (rs = 0.7; p < 0.0001) was observed in immature neutrophils between malaria-exposed healthy and BL children, indicating a similar expansion pattern of this subset in both groups. This finding suggests a malaria-driven expansion of the immature subset, potentially promoting a permissive environment for BL. Our data suggests that the observed shift in neutrophil profiles could contribute to the malaria-induced immunopathology associated with BL Visual abstractCreated in BioRender. Forconi, C. (2025) https://BioRender.com/oz60qvq O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC="FIGDIR/small/681992v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@1640dc4org.highwire.dtl.DTLVardef@1c3e794org.highwire.dtl.DTLVardef@98bf12org.highwire.dtl.DTLVardef@2851b8_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

Loss of developmentally derived Irf8+ macrophages promotes hyperinnervation and arrhythmia in the adult zebrafish heart

Recent developments in cardiac macrophage biology have broadened our understanding of the critical functions of macrophages in the heart. As a result, there is further interest in understanding the independent contributions of distinct subsets of macrophage to cardiac development and function. Here, we demonstrate that genetic loss of interferon regulatory factor 8 (Irf8)-positive embryonic-derived macrophages significantly disrupts cardiac conduction, chamber function, and innervation in adult zebrafish. At 4 months post-fertilization (mpf), homozygous irf8st96/st96 mutants have significantly shortened atrial action potential duration and significant differential expression of genes involved in cardiac contraction. Functional in vivo assessments via electro- and echocardiograms at 12 mpf reveal that irf8 mutants are arrhythmogenic and exhibit diastolic dysfunction and ventricular stiffening. To identify the molecular drivers of the functional disturbances in irf8 null zebrafish, we perform single cell RNA sequencing and immunohistochemistry, which reveal increased leukocyte infiltration, epicardial activation, mesenchymal gene expression, and fibrosis. Irf8 null hearts are also hyperinnervated and have aberrant axonal patterning, a phenotype not previously assessed in the context of cardiac macrophage loss. Gene ontology analysis supports a novel role for activated epicardial-derived cells (EPDCs) in promoting neurogenesis and neuronal remodeling in vivo. Together, these data uncover significant cardiac abnormalities following embryonic macrophage loss and expand our knowledge of critical macrophage functions in heart physiology and governing homeostatic heart health.

systems biology↗

bioRxiv2023

Single cell transcriptional changes across the blood stages of artemisinin resistant K13C580Y mutant Plasmodium falciparum upon dihydroartemisinin exposure

Artemisinin-based therapies have been central to malaria control, but partial resistance in Plasmodium falciparum, driven by mutations in the Kelch13 (K13) protein, threatens these gains. To investigate the molecular basis of this resistance, we applied single-cell RNA sequencing to coisogenic parasite lines, K13 wild-type (K13C580) and the artemisinin-resistant mutant (K13580Y), following a 6 hour pulse of dihydroartemisinin (DHA). This approach enabled high-resolution profiling across intraerythrocytic stages. Both lines exhibited stage-specific transcriptional responses, with pronounced changes in ring and trophozoite stages. Using Manifold Enhancement of Latent Dimensions (MELD), a computational framework for quantifying transcriptional perturbation, DHA-treatment induces stage-specific differences in protein export and metabolic pathways in K13C580 and K13580Y parasites, relating to an altered metabolic stress response state. GARP, a potential therapeutic target, was highly differentially expressed in untreated ring stages of K13580Y and K13C580. Functional assays confirmed that anti-GARP antibodies retained efficacy against K13580Y, supporting its potential as a therapeutic target. These findings provide a comprehensive view of the cellular responses related to artemisinin resistance, identify molecular features of pathogenesis, and highlight surface proteins like GARP as promising intervention targets. This work underscores the power of single-cell approaches to dissect drug responses and guide strategies to overcome resistant parasites.

microbiology↗

bioRxiv2019

Epstein Barr virus genomes reveal population structure and type 1 association with endemic Burkitt lymphoma

Endemic Burkitt lymphoma (eBL), the most prevalent pediatric cancer in sub-Saharan Africa, is associated with malaria and Epstein Barr virus (EBV). In order to better understand the role of EBV in eBL, we improved viral DNA enrichment methods and generated a total of 98 new EBV genomes from both eBL cases (N=58) and healthy controls (N=40) residing in the same geographic region in Kenya. Comparing cases and controls, we found that EBV type 1 was significantly associated with eBL with 74.5% of patients (41/55) versus 47.5% of healthy children (19/40) carrying type 1 (OR=3.24, 95% CI=1.36 - 7.71, P=0.007). Controlling for EBV type, we also performed a genome-wide association study identifying 6 nonsynonymous variants in the genes EBNA1, EBNA2, BcLF1, and BARF1 that were enriched in eBL patients. Additionally, we observed that viruses isolated from plasma of eBL patients were identical to their tumor counterpart consistent with circulating viral DNA originating from the tumor. We also detected three intertypic recombinants carrying type 1 EBNA2 and type 2 EBNA3 regions as well as one novel genome with a 20 kb deletion resulting in the loss of multiple lytic and virion genes. Comparing EBV types, genes show differential variation rates as type 1 appears to be more divergent. Besides, type 2 demonstrates novel substructures. Overall, our findings address the complexities of EBV population structure and provide new insight into viral variation, which has the potential to influence eBL oncogenesis.\n\nKey PointsO_LIEBV type 1 is more prevalent in eBL patients compared to the geographically matched healthy control group.\nC_LIO_LIGenome-wide association analysis between cases and controls identifies 6 eBL-associated nonsynonymous variants in EBNA1, EBNA2, BcLF1, and BARF1 genes.\nC_LIO_LIAnalysis of population structure reveals that EBV type 2 exists as two genomic sub groups.\nC_LI

genomics↗