Biology subjects

Ghale, R.

Publications and source records attributed to Ghale, R..

3 recordsLinked to original sources

bioRxiv2026

Dietary fiber intake associates with improved survival and microbiomecomposition in allogeneic hematopoietic cell transplantation

Diet is linked to changes in gut microbiota and metabolite production with clinical relevance in several disease settings, although these effects remain poorly defined. We performed prospective, real-time diet monitoring (37,929 food items, 3,837 patient days) and longitudinal microbiome and metabolite profiling (1,230 fecal samples) in a clinical cohort of 173 patients undergoing allogeneic hematopoietic cell transplantation. Patients with pre-transplant fiber intake above the cohort average had significantly improved overall survival (p=0.014) and reduced incidence of grades 2-4 acute graft-versus-host disease (GVHD) (p=0.032) post-transplant. Those consuming insoluble fiber had increased microbial diversity, enriched butyrate-producing taxa, and depleted Enterococcus. Those who developed lower gastrointestinal GVHD had reduced fecal butyrate levels. In a GVHD preclinical model, we confirmed that a fiber-enriched diet increased survival, cecal butyrate, and regulatory-to-conventional T cell ratio. Thus, we demonstrated that dietary fiber has clinical significance as a modifiable factor with microbiome-mediated effects.

cancer biology↗

bioRxiv2025

T cells use TNF and IFNγ for paracrine killing with target discrimination programmed by pathogen-derived factors

Cytotoxic T lymphocytes (CTLs) are known to eliminate target cells through perforin-mediated, contact-dependent killing - a process limited by the number of effector T cells despite its serial nature. CTLs likely also possess a mass killing mechanism that can eliminate target cells more efficiently. Using CAR-T cells against B7H3 present on B16 tumor targets, we demonstrate that activated T cells can also kill targets in a perforin-independent manner by releasing diffusible TNF and IFN{gamma} capable of killing nearby targets in a paracrine fashion even if they bear no antigen. Against an unperturbed target, paracrine killing is inefficient but is enhanced by the deletion of TNFR1 signaling molecules such as TAK1, HOIP, or TBK1/IKK{varepsilon}. Notably, these molecules are inhibited naturally by pathogen-encoded antagonists. Expression of a microbial-encoded antagonist, such as the Yersinia-encoded YopJ that antagonizes TAK1 or Ebola-encoded VP35 that antagonizes TBK1/IKK{varepsilon}, alters the target cell response to these cytokines from non-lethal to lethal. We propose that target cells are inherently resistant to killing by TNF and IFN{gamma}, but the presence of a microbial factor alters this sensitivity, providing for the selective elimination of the infected cell while minimizing harm to uninfected bystander cells. We propose the term pathogen-restriction to describe this discriminatory mechanism. Potentially, any microbial-derived factor that crosstalks with the TNF and IFN{gamma} signaling pathways can function as a pathogen-restriction element. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=129 SRC="FIGDIR/small/696308v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@ea6418org.highwire.dtl.DTLVardef@517489org.highwire.dtl.DTLVardef@1ba0e22org.highwire.dtl.DTLVardef@1f5fef8_HPS_FORMAT_FIGEXP M_FIG C_FIG Short SummaryT cells use TNF and IFN{gamma} to kill target cells in a paracrine manner where target elimination is restricted by the presence of pathogen-derived factors.

immunology↗

bioRxiv2025

Galectin-3 is a Nanotherapeutic Target in Graft-versus-Host Disease Mediated Kidney Injury

Kidney injury is a frequent and serious complication of allogeneic hematopoietic cell transplantation (HCT), yet its pathophysiology remains poorly understood and effective treatments are lacking. Through analysis of kidney tissue from HCT recipients, we identified substantial acute tubular injury and T cell infiltration that correlated with extra-renal graft-versus-host disease (GVHD) severity, linking systemic alloreactivity and post-transplant renal pathology. In murine models, GVHD was similarly associated with acute kidney injury, renal Th1-type T cell infiltration, and hyperactivation of NF-{kappa}B and JAK-STAT signalling. Notably, galectin-3, a damage-associated lectin, was upregulated in both patient biopsies and experimental GVHD target organs. Leveraging this pathological feature, we engineered galectin-3-targeted lipid nanoparticles for tissue-specific delivery of ruxolitinib, an approved GVHD therapy. Galectin-3 upregulation was also identified in canonical acute GVHD target organs including the liver and intestinal tract, and nanoparticle-delivered ruxolitinib substantially enhanced renal function, reduced systemic GVHD, and minimized hematologic toxicity compared to conventional drug administration. Our findings demonstrate renal involvement in acute GVHD and establish a nanoparticle-based strategy for precision delivery of immunomodulatory therapies to affected tissues.

bioengineering↗