Biology subjects

Morris, M. T.

Publications and source records attributed to Morris, M. T..

9 recordsLinked to original sources

bioRxiv2026

B7-H4 represents a site-specific immunotherapy target in small bowel gastrointestinal stromal tumor

Small bowel gastrointestinal stromal tumors (GISTs) are more aggressive than gastric GISTs, yet the biologic basis for this difference remains poorly understood. We hypothesized that differential expression of immune checkpoints contributes to this site-specific behavior. Bulk RNA sequencing of 42 primary GISTs (36 gastric, 6 small bowel) revealed marked upregulation of VTCN1, which encodes the inhibitory checkpoint B7-H4, in small bowel tumors (log2FC = 7.95, adjusted P < 0.001). In contrast, expression of the therapeutically targeted checkpoints PD-L1, PD-1, and CTLA-4 was comparable between sites. Concordantly, B7-H4 enrichment was accompanied by an immunosuppressive tumor microenvironment, characterized by reduced antigen-presenting cells, fewer effector-memory CD8+ T cells, lower granzyme B expression, and suppression of interferon and inflammatory signaling pathways. Notably, the differences in B7-H4 expression were independent of imatinib-treatment status. These findings were corroborated in an external cohort of 77 untreated GISTs, in which VTCN1 was similarly enriched in small bowel tumors. Independent immunohistochemical analysis of a tissue microarray comprising 68 untreated primary GISTs confirmed the pattern, showing median B7-H4 positivity of 78.6% in duodenal, 20.5% in jejunal/ileal, and 0% in gastric tumors, with staining localized to tumor cells rather than stroma. Collectively, these data identify B7-H4 as a site-specific feature of small bowel GISTs and a potential therapeutic target for tumors that have not responded to conventional checkpoint blockade.

immunology↗

bioRxiv2025

Endogenous glucocorticoids moderate the gastric inflammatory response to Helicobacter infection and protect from autoimmunity.

Background and AimsImmune responses to infection must balance pathogen clearance with minimizing tissue damage and autoimmunity. Chronic gastric inflammation caused by H. pylori damages the gastric mucosa and promotes carcinogenesis. Glucocorticoids are immunoregulatory hormones that limit immune activation in the stomach. This study aimed to determine how endogenous glucocorticoids regulate the gastric immune response to Helicobacter infection and their impact on preneoplastic lesion development. MethodsWe examined the role of endogenous glucocorticoids in shaping the gastric immune response to Helicobacter felis colonization. Gastric immune cell infiltration, atrophy, metaplasia, and preneoplastic lesion development were evaluated in adrenal-intact control mice and adrenalectomized (ADX) mice. Auto-reactive IgG antibodies were assessed using a mouse self-antigen array and by measuring their binding to healthy gastric tissue. ResultsLoss of endogenous glucocorticoids led to significantly increased H. felis-induced gastric T cell infiltration and proinflammatory cytokine expression compared to intact-infected controls. While all intact mice maintained chronic infection for up to 12 months, nearly all ADX mice eradicated H. felis within 2-3 weeks. Despite bacterial clearance, ADX mice continued to exhibit chronic gastric inflammation and developed dysplasia. Autoantibody profiling showed that both intact and ADX groups generated self-reactive IgG during active infection. However, only ADX mice sustained autoantibody production following bacterial eradication. ConclusionsEndogenous glucocorticoids attenuate gastric inflammation during Helicobacter infection, supporting bacterial persistence while maintaining immune tolerance. These findings suggest that heightened immune responses to H. pylori may trigger autoimmune gastritis (AIG) development, which can persist after H. pylori clearance and continue to drive gastric cancer risk.

immunology↗

bioRxiv2025

Decoding PDI diversity: insights into structure, domains, and functionality in sorghum

Proteins play indispensable roles in cellular function, acting as both structural components and catalysts for essential biological processes. Their proper folding into three-dimensional structures is critical for functionality. To ensure correct folding, proteins interact with chaperones and folding catalysts such as Protein Disulfide Isomerases (PDIs), which assist in the formation and rearrangement of disulfide bonds that stabilize proteins by linking cysteine residues. PDIs are part of the thioredoxin (TRX) superfamily and are characterized by a conserved CXXC motif that contributes to their redox potential. They exhibit isomerase and oxidoreductase activities, that enable them to rearrange and form new disulfide bonds. PDI family members in sorghum (SbPDI) present a broad and largely unexplored diversity in domain order, structure, and architecture between or even within species. To shed light on this diversity, we identified and characterized PDI family members in sorghum in silico to explore their domain architecture, three-dimensional structure and functionality. Author summaryIn this work, we explore how genomic and molecular tools can improve our understanding of the function and diversity of the protein disulfide isomerase (PDI) family in plants, using sorghum as a model and humans as a reference. By analysing domain architecture and predicted structures across the PDI family, we lay the groundwork for future studies investigating their roles in plant development and stress responses, including through targeted gene editing approaches. Although PDIs have been widely studied in humans, their structural and functional diversity in plants remains largely unexplored. With this study, I aim to help close this knowledge gap and highlight the structural differences of PDIs in plants.

bioinformatics↗

bioRxiv2025

Androgen Signaling in Type 2 Innate Lymphoid Cells Drives Sex Differences in Helicobacter-Induced Gastric Inflammation and Atrophy

Background & AimsGastric cancer is the fifth most common cancer worldwide. Men are disproportionately affected by gastric cancer, which ranks as the fourth most common cancer in men compared to eighth in women worldwide. Chronic inflammation driven by Helicobacter pylori infection remains the leading gastric cancer risk factor. Emerging evidence suggests that sex hormones modulate immune responses, contributing to sex differences in infection outcomes and cancer susceptibility. This study investigates how androgens influence the gastric inflammatory response to Helicobacter infection and contribute to sex disparities in disease progression. MethodsMale and female C57BL/6 mice were colonized with Helicobacter felis to investigate sex differences in gastric inflammation. Androgen levels were manipulated by bilateral castration in males and dihydrotestosterone (DHT) treatment in females. Single-cell RNA sequencing was used to identify androgen-responsive leukocyte populations and to establish cell communication networks between leukocyte clusters. The functional roles of these cells were further defined using ILC2- and T cell-deficient mouse models. ResultsInfected female mice developed significantly more severe gastric inflammation, atrophy, and metaplasia infection compared to males. Androgen depletion by castration increased gastric inflammation and accelerated preneoplastic lesion development, while these pathological features were reduced by DHT treatment. Androgen-responsive type 2 innate lymphoid cells (ILC2s) were key initiators of gastric inflammation and ILC2 depletion abolished the sex differences in H. felis pathogenesis. ConclusionsThis study reveals that androgens suppress Helicobacter-induced gastric inflammation by modulating ILC2 activation. We found that androgens are protective, as androgen depletion exacerbated gastric inflammation and accelerated preneoplastic lesion development. These findings provide mechanistic insight into the age-related increase in male gastric cancer incidence, coinciding with declining androgen levels. Our results suggest that circulating androgen concentrations may serve as a prognostic biomarker for gastric cancer risk in men. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=120 HEIGHT=200 SRC="FIGDIR/small/643321v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@6cf3c3org.highwire.dtl.DTLVardef@f797d6org.highwire.dtl.DTLVardef@1118c21org.highwire.dtl.DTLVardef@106e2ab_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

In vitro to in vivo evidence for chemical disruption of glucocorticoid receptor signaling

Glucocorticoids are steroid hormones that regulate stress homeostasis, metabolism, and inflammatory responses. Dysregulation of the glucocorticoid receptor (GR) is linked to diseases such as obesity, mood disorders, and immune dysfunction. Endocrine-disrupting chemicals (EDCs) are widespread environmental contaminants known to interfere with hormone signaling, but their impact on glucocorticoid signaling remains unclear. While several GR-disrupting compounds have been identified in vitro, their in vivo effects remain largely unknown. In this study, we identified the agricultural agents dichlorodiphenyltrichloroethane (DDT) and ziram as GR-disruptors in vitro. In vivo, corticosterone co-treatment with DDT or the GR antagonist RU-486 inhibited the expression of classic GR-regulated transcripts in the liver. Furthermore, chronic exposure to DDT or RU-486 significantly reduced circulating B and T lymphocyte populations, respectively. These findings underscore the need to translate in vitro discoveries into in vivo models to assess the clinical relevance of GR-disrupting compounds. Moreover, they highlight the potential for xenobiotic-induced GR disruption to impair metabolic and immune homeostasis, potentially increasing disease susceptibility.

pharmacology and toxicology↗

bioRxiv2024

Chronic cigarette smoke exposure masks pathological features of Helicobacter pylori infection while promoting tumor initiation

Gastric cancer is the fifth most common cancer and the fifth leading cause of cancer deaths worldwide. Chronic infection by the bacterium Helicobacter pylori is the most prominent gastric cancer risk factor, but only 1-3% of infected individuals will develop gastric cancer. Cigarette smoking is another independent gastric cancer risk factor, and H. pylori-infected smokers are at a 2-11-fold increased risk of gastric cancer development, but the direct impacts of cigarette smoke on H. pylori pathogenesis remain unknown. In this study, male C57BL/6 mice were infected with H. pylori and began smoking within one week of infection. The mice were exposed to cigarette smoke (CS) five days/week for 8 weeks. CS exposure had no notable impact on gross gastric morphology or inflammatory status compared to filtered-air (FA) exposed controls in mock-infected mice. However, CS exposure significantly blunted H. pylori-induced gastric inflammatory responses, reducing gastric atrophy and pyloric metaplasia development. Despite blunting these classic pathological features of H. pylori infection, CS exposures increased DNA damage within the gastric epithelial cells and accelerated H. pylori-induced dysplasia onset in the INS-GAS gastric cancer model. These data suggest that cigarette smoking may clinically silence classic clinical symptoms of H. pylori infection but enhance the accumulation of mutations and accelerate gastric cancer initiation.

cancer biology↗

bioRxiv2024

A mitochondrial SET domain protein is essential in Trypanosoma brucei and required for mitochondrial morphology and function

Protein lysine methylation is a ubiquitous post-translational modification. First identified in histone tails, many non-histone proteins are methylated at lysine residues. SET domain proteins catalyze the transfer of a methyl group from a donor such as S-adenosyl-L-methionine (SAM) to lysine residues. In this work, we identify a novel SET domain protein, TbSETD, in the African trypanosome, Trypanosoma brucei, and demonstrate that it is essential in both insect stage procyclic form and bloodstream form parasites. Epitope-tagged TbSETD localizes to the mitochondrion and TbSETD-deficient parasites exhibit growth defects, altered mitochondrial morphology, increased ROS levels, and increased sensitivity to apoptotic triggers. TbSETD binding proteins identified in immunoprecipitation experiments were enriched in mitoribosomal proteins. We also demonstrate that TbSETD immunoprecipitated from parasites has methyltransferase activity in vitro and methyllysine western blots reveal that TbSETD-deficient parasites have reduced levels of a 37 kDa mitochondrial protein. OrthoMCL DB indicates TbSETD is conserved only in kinetoplastids, suggesting a unique role in the biology of these parasites, and highlighting its potential as a drug target. SignificanceKinetoplastid parasites include several medically important organisms for which current treatments are insufficient. SET domain protein lysine methyltransferases (PKMTs) are highly druggable and have predominately been studied in the context of chromatin remodeling and gene expression. This work provides the first example of a SET domain PKMT that localizes to the mitochondria in any protozoan parasite and the first implication that protein lysine methylation may be important to mitoribosomal biogenesis.

microbiology↗

bioRxiv2023

Comparison of gastric inflammation and metaplasia induced by Helicobacter pylori or Helicobacter felis colonization in mice

BackgroundGastric cancer is the fifth most diagnosed cancer in the world. Infection by the bacteria Helicobacter pylori (HP) is associated with approximately 75% of gastric cancer cases. HP infection induces chronic gastric inflammation, damaging the stomach and fostering carcinogenesis. Most mechanistic studies on Helicobacter-induced gastric cancer initiation are performed in mice and utilize either mouse-adapted strains of HP or the natural mouse pathogen Helicobacter felis (HF). Each of these infection models is associated with strengths and weaknesses. Here, we identified the differences in immunogenicity and gastric pathological changes associated with HP and HF infection in mice. Material and MethodsPMSS1 HP strain or with the CS1 HF strain were co-cultured with mouse peritoneal macrophages to assess their immunostimulatory effects. C57BL/6J mice were infected with HP or HF, and gastric inflammation, atrophy, and metaplasia development were assessed 2 months post-infection. ResultsHP and HF induced similar cytokine production from cultured mouse peritoneal macrophages. HP-infected mice caused modest inflammation within both the gastric corpus and antrum and did not induce significant atrophy within the gastric corpus. In contrast, HF induced significant inflammation throughout the gastric corpus and antrum. Moreover, HF infection was associated with significant atrophy of the chief and parietal cell compartments and induced expression of pyloric metaplasia markers. ConclusionsHP is poorly immunogenic compared to HF. HF induces dramatic CD4+ T cell activation, which is associated with increased gastric cancer risk in humans. Thus, HP studies in mice are better suited for studies on colonization, while HF is more strongly suited for pathogenesis and cancer initiation studies.

immunology↗

bioRxiv2018

Trypanosoma brucei Pex13.2 is an accessory peroxin that functions in the import of PTS2 proteins and localizes to subdomains of the glycosome

Kinetoplastid parasites including Trypanosoma brucei, Trypanosoma cruzi and Leishmania harbor unique organelles known as glycosomes, which are evolutionarily related to peroxisomes. Glycosome/peroxisome biogenesis is mediated by proteins called peroxins that facilitate organelle formation, proliferation and degradation, and import of proteins housed therein. Import of matrix proteins occurs via one of two pathways that are dictated by their peroxisome targeting sequence (PTS). In PTS1 import, a C-terminal tripeptide sequence, most commonly SKL, is recognized by the soluble receptor Pex5. In PTS2 import, a less conserved N-terminal sequence is recognized by Pex7. The soluble receptors deliver their cargo to the import channel consisting minimally of Pex13 and Pex14. While much of the import process is conserved, kinetoplastids are the only organisms to have two Pex13s, TbPex13.1 and TbPex13.2. In previous studies, GFP-tagged TbPex13.1 localized to glycosomes and silencing either protein in the stage of the parasite that lives in the mammalian bloodstream impaired glycosome protein import and slowed parasite growth. While these findings suggest Pex13s are involved in protein import, the mechanisms by which they function are unknown and it is unclear why kinetoplastids would require two Pex13s. In this work, we demonstrate that TbPex13.2 is associated with the glycosome membrane with its N-terminus facing the cytoplasm. Super-resolution microscopy reveals that TbPex13.2 localizes to a few (1-3) foci per glycosome and import of PTS2 proteins was disrupted in TbPex13.2-deficient cells suggesting it may be an accessory factor for PTS2 import.

cell biology↗