Biology subjects

Marth, J. D.

Publications and source records attributed to Marth, J. D..

4 recordsLinked to original sources

bioRxiv2025

An ultrasensitive and modular platform to detect Siglec ligands and control immune cell function

Siglecs are immunomodulatory receptors that regulate immune cell function. A fundamental challenge in studying Siglec-ligand interactions is the low affinity of Siglecs for their ligands. Inspired by how nature uses multivalency, we developed Siglec-liposomes as a highly multivalent and versatile platform for detecting Siglec glycan ligands in which recombinant Siglecs were conjugated to liposomes using the SpyCatcher-SpyTag system. Siglec-liposomes offer tunable multivalency and a modular assembly, enabling presentation of different Siglecs on the same liposome. Using Siglec-liposomes, we profiled Siglec ligands on human leukocytes, revealing new insights into Siglec ligands. Moreover, Siglec-liposomes are in vivo compatible, where we demonstrated that Siglec-7-liposomes bind to the brain vasculature in a mucin-dependent manner. Given the abundance of Siglec ligands on T cells, we investigated whether Siglec-liposomes modulate T cell function and find that Siglec-7-liposomes increase T cell proliferation in a ST3Gal1-dependent and CD43-independent manner. Taken together, Siglec-liposomes are a versatile and sensitive tool for detecting Siglec ligands and immunomodulation.

biochemistry↗

bioRxiv2025

Modeling the Aging Human Lung: Generation of a Senescent Human Lung Organoid Culture System

IntroductionThe aging lung enters into a state of irreversible cellular growth arrest characterized by senescence. While senescence is beneficial in preventing oncogenic cell proliferation, it becomes detrimental when persistent, promoting chronic inflammation and fibrosis through the senescence-associated secretory phenotype (SASP). Such senescence-related pathophysiological processes play key roles in lung diseases like chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). However, few models accurately represent senescence in the human lung. MethodsTo generate a human lung senescence in vitro model, we first generated a human induced pluripotent stem cell (hiPSC)-derived lung organoid (LO) system which was dissociated into monolayers and air-liquid interface (ALI) cultures to enhance visualization and allow uniform exposure to agents. Cellular senescence was induced using doxorubicin, a DNA-damaging agent. Senescence markers, such as {beta}-galactosidase ({beta}-gal) activity, SASP cytokine production and secretion, cell morphology, proliferative capacity, and barrier integrity were evaluated to validate the senescent phenotype. ResultsThe doxorubicin-induced senescent hiPSC-derived lung cells demonstrated the hallmark characteristics of cellular senescence, including increased {beta}-gal activity and increased production of the pro-inflammatory SASP cytokine IL-6 and increased secretion of TNF-. Senescent cells displayed enlarged morphology, decreased proliferation, and reduced wound repair capacity. Barrier integrity was impaired with decreased electrical resistance, and increased permeability, as well as expression of abnormal tight junction proteins and increased fibrosis, all consistent with the senescent lung. ConclusionOur hiPSC-derived lung cell senescent model reproduces key aspects of human lung senescence and offer an in vitro tool for studying age-related lung disease mechanisms and therapeutic interventions. This model has potential applications in exploring the impact of environmental factors (e.g., toxins, infectious pathogens, etc.) on the senescent lung and assessing treatments that could mitigate pathologies associated with pulmonary aging including barrier impairment, inflammation and fibrosis.

cell biology↗

bioRxiv2020

Glycomic analysis reveals a conserved response to bacterial sepsis induced by different bacterial pathogens.

Sepsis is an extreme inflammatory response to infection (bacterial, viral, fungal) that occurs in the bloodstream and causes damage throughout the body. Currently, there are few diagnostic biomarkers of sepsis and new effective treatments have not been developed. There is a clear need to study the molecular underpinnings of this disease. Glycosylation is known to play a role in immunity and inflammation, but the role of glycans in sepsis is not well defined. Herein, we profiled the serum glycomes of experimental mouse sepsis models to identify changes induced by 4 different clinical bacterial pathogens (Gram-positive: Streptococcus pneumoniae, Staphylococcus aureus, Gram-negative: Escherichia coli and Salmonella Typhimurium) using our lectin microarray technology. We observed global shifts in the blood sera glycome that were conserved across all four species, regardless of whether they were Gram positive or negative. Bisecting GlcNAc was decreased upon sepsis and a strong increase in core 1/3 O-glycans was observed. Lectin blot analysis revealed a high molecular weight protein induced in sepsis by all four bacteria as the major cause of the core 1/3 O-glycan shift. While the identity of this protein remains to be elucidated, its presence indicates a common feature of bacterial sepsis associated with this glycomic signature.

biochemistry↗

bioRxiv2020

Repurposed Drugs Block Toxin-Driven Platelet Clearance by the Hepatic Ashwell-Morell Receptor to Clear Staphylococcus aureus Bacteremia

ABSTRACTStaphylococcus aureus (SA) bloodstream infections cause high morbidity and mortality (20-30%) despite modern supportive care. In a human bacteremia cohort, development of thrombocytopenia was correlated to increased mortality and increased α-toxin expression by the pathogen. Platelet-derived antibacterial peptides are important in bloodstream defense against SA, but α-toxin decreased platelet viability, induced platelet sialidase to cause desialylation of platelet glycoproteins, and accelerated platelet clearance by the hepatic Ashwell-Morell receptor (AMR). Ticagrelor (Brilinta®), a commonly prescribed P2Y12 receptor inhibitor used post-myocardial infarction, blocked α-toxin-mediated platelet injury and resulting thrombocytopenia, thus providing protection from lethal SA infection in a murine intravenous challenge model. Genetic deletion or pharmacological inhibition of AMR stabilized platelet counts and enhanced resistance to SA infection, and the anti-influenza sialidase inhibitor oseltamivir (Tamiflu®) provided similar therapeutic benefit. Thus a “toxin-platelet-AMR” regulatory pathway plays a critical role in the pathogenesis of SA bloodstream infection, and its elucidation provides proof-of-concept for repurposing two FDA-approved drugs as adjunctive therapies to improve patient outcomes.Competing Interest StatementThe authors have declared no competing interest.View Full Text

microbiology↗