Biology subjects

Wang, B. X.

Publications and source records attributed to Wang, B. X..

4 recordsLinked to original sources

bioRxiv2025

Peptide-Specific CAR T cells Recognize WT1 Promiscuously Presented by Diverse HLA Class II Alleles

Chimeric antigen receptor (CAR) technology has revolutionized B-cell malignancy treatment by enabling T cells to effectively recognize and target cancer-specific surface antigens. However, CAR T cells show limited efficacy against other blood cancers and solid tumors due to challenges in identifying suitable surface targets. Here, we present a novel approach to CAR development, targeting the intracellular Wilms tumor 1 (WT1) oncoprotein, cross-presented by surface HLA-class II (HLA-II) alleles. WT1-CAR T cells, derived from an antibody raised solely against a WT1 peptide, recognized the WT1330-348 peptide promiscuously presented by 18 out of 20 tested HLA-II alleles, overcoming traditional HLA restrictions. WT1-CAR T cells specifically recognized leukemic cells in a WT1 and HLA-II-dependent manner and mediated an antitumor response in vitro and in vivo. This innovative approach to CAR T cell development transcends traditional HLA restrictions and offers a promising therapeutic option to a wide and genetically diverse patient population. Statement of significanceThis study describes a novel CAR T therapy approach leveraging the distinctive and shared characteristic of HLA-II-peptide binding promiscuity, enabling targeting of the intracellular oncoprotein WT1 presented across diverse HLA-II families. Our study demonstrates a viable framework for designing CAR T therapies that benefit genetically diverse patient populations.

immunology↗

bioRxiv2023

Temporal profiling of Salmonella transcriptional dynamics during macrophage infection using a comprehensive reporter library

The transcriptome of Salmonella enterica serovar Typhimurium (S. Tm) dynamically responds to the rapid environmental shifts intrinsic to S. Tm lifestyle, exemplified by entry into the Salmonella-containing vacuole (SCV) within macrophages. Intracellular S. Tm must respond to the acidity of the SCV, accumulation of reactive oxygen/nitrogen species, and fluctuations in nutrient availability. Despite thorough RNA-seq-based investigations, the precise transcriptional timing of the expression of many secretion systems, metabolic pathways, and virulence effectors involved in infection has yet to be elucidated. Here, we construct a comprehensive library of GFP-reporter strains representing [~]3,000 computationally identified S. Tm promoter regions to study the dynamics of transcriptional regulation. We quantified promoter activity during in vitro growth in defined and complex media and throughout the timeline of intracellular infection of RAW 246.7 macrophages. Using bulk measurements and single-cell imaging, we uncovered condition-specific transcriptional regulation and population-level heterogeneity in the activity of virulence-related promoters, including SPI2 genes such as ssaR and ssaG. We discovered previously unidentified transcriptional activity from 234 genes, including ones with novel activity during infection that are associated with pathogenecity islands and are involved in metabolism and metal homeostasis. Our library and data sets should provide powerful resources for systems-level interrogation of Salmonella transcriptional dynamics.

microbiology↗

bioRxiv2020

Host adaptations in the fixLJ pathway of the Burkholderia cepacia complex increase virulence

The Burkholderia cepacia complex (BCC) is composed of multiple species, including B. multivorans and B. dolosa, that are significant pathogens for people with cystic fibrosis (CF) and are extensively resistant to many antibiotics. The fixL gene of the fixLJ 2-component system (TCS) in these BCC species shows evidence of positive selection for nonsynonymous mutations during chronic lung infection in CF. Previous work showed that the B. dolosa fixLJ system regulates 11% of the genome and modulates biofilm formation, motility, persistence within macrophages, and virulence in a murine pneumonia model. Here, we assess the impacts of clinically observed FixL evolved variants in fixLJ pathway-mediated phenotypes in B. dolosa and B. multivorans. BCC carrying the ancestral fixL sequence are less pathogenic than constructs carrying evolved variants in both a macrophage infection model and a murine pneumonia model. In vitro phospho-transfer experiments demonstrate that the evolved B. dolosa FixL variants are able to reduce fixLJ pathway activity by either having lower levels of kinase activity or increased phosphatase activity. Notably, the ancestral fixL genotype has increased ability to survive within the soil compared to isogenic constructs with evolved fixL genotypes, demonstrating that increased virulence comes at an expense. Modulation of the FixLJ system has profound effects on many BCC phenotypes including full pathogenicity, and this modulation is critical for BCC adaptation to the host.

microbiology↗

bioRxiv2020

Mucin glycans signal through the sensor kinase RetS to inhibit virulence-associated traits in Pseudomonas aeruginosa

Mucus is a densely populated ecological niche that coats all epithelia, and plays a critical role in protecting the human body from infections. Although traditionally viewed as a physical barrier, emerging evidence suggests that mucus can directly suppress virulence traits in opportunistic pathogens like Pseudomonas aeruginosa. However, the molecular mechanisms by which mucus affords this protection are unclear. Here, we show that mucins, and particularly their associated glycans, activate the sensor kinase RetS via its Dismed2 domain in P. aeruginosa. We find that this RetS-dependent signaling leads to the direct inhibition of the GacS-GacA two-component system, the activity of which is associated with a chronic infection state. This signaling includes the downregulation of the type VI secretion system (T6SS), and prevents T6SS-dependent bacterial killing by P. aeruginosa. Overall, these results shed light on how mucus impacts P. aeruginosa behavior in the human host, and may inspire novel approaches for controlling P. aeruginosa infections.

microbiology↗