Biology subjects

Williams, O. M.

Publications and source records attributed to Williams, O. M..

6 recordsLinked to original sources

bioRxiv2026

Microbial Crosstalk in the Neonatal Gut: Candida albicans Impacts Group B Streptococcus Pathogenicity

Background Group B Streptococcus (GBS) is a leading cause of bacterial sepsis globally. Late-onset (LO) GBS disease is preceded by colonization within the gastrointestinal tract in vulnerable neonates. Previous studies demonstrate that Candida albicans (C. albicans) promotes GBS colonization of host tissues including the bladder and vagina. However, its impact on GBS colonization of the intestinal tract is unknown. Methods We established a new animal model to study GBS and C. albicans co-colonization model in the context of the newborn host to examine C. albicans impact on GBS and further evaluated fluconazole prophylactic treatment to these same outcomes. Physical interactions between organisms in vivo were imaged and GBS gene expression was evaluated. Results C. albicans increased GBS burden in the neonatal gut and GBS was physically colocalized with C. albicans hyphae as evidenced by the colocalization analysis. Fluconazole treatment of co-colonized mice decreased extraintestinal GBS dissemination. C. albicans presence upregulated genes encoding proteins responsible for GBS adhesion and invasion of intestinal epithelial cells. Conclusion C. albicans enhances GBS burden and pathogenicity in the neonatal gut. These findings highlight the need for further investigation into C. albicans as a potential risk factor for GBS colonization and LO disease in human infants.

microbiology↗

bioRxiv2026

Host immune stress reveals a role for potassium homeostasis in Pseudomonas aeruginosa aggregate stability

Pseudomonas aeruginosa (Pa) forms multicellular aggregates during chronic airway infection, yet the physiological processes that regulate aggregate organization and dispersal remain incompletely understood. Here, we investigated how Pa aggregates respond to human neutrophil elastase (HNE), a host-derived protease abundant in the cystic fibrosis airway. Transcriptomic analysis of HNE-exposed aggregates identified strong induction of the kdpFABC high-affinity potassium transport system, with greater induction in aggregate than planktonic populations. Functional analysis of kdpA revealed a broader role in aggregate physiology: loss of kdpA increased total biomass while reducing average aggregate volume and accelerating dispersal, including in the absence of HNE. Genetic complementation restored key kdpA-dependent phenotypes, whereas co-culture with wild-type cells did not rescue the mutant. Increasing extracellular potassium modified aggregate volume, biomass, and dispersal in the kdpA mutant but did not uniformly restore these phenotypes to wild-type levels, demonstrating that kdpA-dependent aggregate behavior is potassium-responsive. Together, these findings identify KdpA as a link between potassium homeostasis and Pa aggregate behavior and suggest that host-derived stress increases engagement of a homeostatic system that contributes to the coordination of population growth, aggregate organization, and dispersal.

microbiology↗

bioRxiv2025

A Single Cell Atlas of the Newt Iris During Lens Regeneration

Iris pigmented epithelial (IPE) cells transdifferentiate to lens epithelial cells (LECs) during Wolffian lens regeneration in newts. Single cell RNA sequencing was used at multiple timepoints to further our understanding of this process and the cells involved in it. All major cell types present in and adjacent to the iris were identified including IPE cells, macrophages, non-pigmented ciliary epithelial cells, pigmented ciliary epithelial cells, and stroma-residing fibroblasts, endothelial cells, iridophores, and melanocytes. In the intact iris, IPE cell subpopulations were characterized by the expression of the dorsoventral genes TBX5 and VAX2, and newly identified markers LTBP2, CHRM3, and NTN1. During regeneration, IPE heterogeneity was correlated with functional states such as the cell cycle, migration, and lens vesicle formation. Pseudotime trajectory analysis revealed new insights into transcriptional and reprogramming factors during the IPE-to-LEC conversion and built a molecular and genetic blueprint of newt lens regeneration. Macrophages were identified as tissue-resident and underwent polarization from M1 early to M2 late during lens regeneration, an event that correlated temporally with the IPE-to-LEC reprogramming. Overall, this atlas provides data and analysis for iris cell types, IPE subpopulations, IPE cell states, gene expression changes as IPE cells reprogram to LECs, macrophage identity and function, and cell-to-cell interactions during newt lens regeneration. Highlights- Cell atlas identifying cells in the newt iris at multiple timepoints during lens regeneration - Intact iris contains multiple iris pigmented epithelial (IPE) cell subpopulations - Identification of IPE functional states during regeneration - Cellular trajectory analysis revealed a molecular and genetic blueprint of IPE-to-lens epithelial cell reprogramming - Identification of cell-to-cell interactions between IPE cells and other cell types - Macrophages interacting with IPE cells are tissue-resident and polarize from M1 to M2 subtypes during lens regeneration Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=195 SRC="FIGDIR/small/692619v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@1883f94org.highwire.dtl.DTLVardef@622d9org.highwire.dtl.DTLVardef@d9ed30org.highwire.dtl.DTLVardef@1631d03_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2023

Resident memory T cell precursors in tumor draining lymph nodes require type-1 IFN for optimal differentiation

Resident memory (Trm) cells play an essential role in anti-tumor immunity. However, little is known about the precursors that differentiate into protective Trm populations against cancer. Here we employed an established model of B16 melanoma neoadjuvant anti-CD4 therapy, to track tumor antigen-specific CD8+ T cells through tissues and across time; from their priming as effectors to their differentiation into Trm. We show that tumor-draining lymph nodes (TDLNs) contain Teff cells that begin to express canonical Trm markers CD103 and CD69. These tumor-specific Teff cells seeded skin and tumor during the effector phase of the response, although egress from these tissues was not required Trm development in LNs. Paired scRNAseq/scTCRseq was used to identify Teff clonotypes in TDLNs and trace their differentiation, in real-time, into Trm populations. We found that expanded clonotypes favored the Trm fate and were unlikely to co-differentiate into other lineages. Precursors of Trm (pre-Trm) clonotypes that subsequently seeded populations throughout tumors, LNs, and skin, were characterized by early expression of tissue residency, stemness, and type-1 IFN sensing genes. These multipotent pre-Trm cells sensed plasmacytoid dendritic cell-derived type-1 interferons in TDLNs, and their expression of interferon alpha receptor was required for their formation of Trm populations in LNs but not in skin. These findings reveal the defining features of pre-Trm cells in response to tumor antigens, and reveal a previously unappreciated role for type-1 IFNs in programming regional Trm immunity to cancer. One Sentence SummaryAnti-tumor effector CD8 T cells adopt early characteristics of tissue residency and stemness, and rely on the sensing of type-1 interferons for their local differentiation into resident memory T cells.

immunology↗

bioRxiv2022

Characterizing control of memory CD8 T cell differentiation by BTB-ZF transcription factor Zbtb20

Members of the BTB-ZF transcription factor family regulate the immune system. Our lab identified that family member Zbtb20 contributes to the differentiation, recall responses and metabolism of CD8 T cells. Here, we report a characterization of the transcriptional and epigenetic signatures controlled by Zbtb20 at single-cell resolution during the effector and memory phases of the CD8 T cell response. Without Zbtb20, transcriptional programs associated with memory CD8 T cell formation were upregulated throughout the CD8 T response. A signature of open chromatin was associated with genes controlling T cell activation, consistent with the known impact on differentiation. Additionally, memory CD8 T cells lacking Zbtb20 were characterized by open chromatin regions with overrepresentation of AP-1 transcription factor motifs and elevated RNA- and protein-level expression of the corresponding AP-1 components. Finally, we describe motifs and genomic annotations from the DNA targets of Zbtb20 in CD8 T cells identified by CUT&RUN. Together, these data establish the transcriptional and epigenetic networks contributing to the control of CD8 T cell responses by Zbtb20.

immunology↗

bioRxiv2022

Identification and characterisation of Klebsiella pneumoniae and Pseudomonas aeruginosa clinical isolates with atypical β-lactam susceptibility profiles using Orbitrap liquid chromatography-tandem mass spectrometry

There is significant interest in the possibility of predicting antibacterial drug susceptibility directly though the analysis of bacterial DNA or protein. We report the use of Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa and Acinetobacter baumannii transformants to define baseline predictive rules for the {beta}- lactam susceptibility profiles of {beta}-lactamase positive clinical isolates. We then deployed a robust and reproducible shotgun proteomics methodology to identify {beta}-lactamase positivity and predict {beta}-lactam susceptibility by reference to our baseline predictive rules both in cultured bacteria and in extracts of culture-positive blood. Proteomics and whole genome sequencing then allowed us to characterise K. pneumoniae and P. aeruginosa isolates that differed from the expected {beta}-lactam susceptibility profile, iteratively expanding our predictive rules. Proteomics added considerable value over and above the information generated by whole genome sequencing, allowing for gene expression, not just gene presence to be considered. Specifically, in K. pneumoniae, we identified key differences between acrR and ramR regulatory mutations and compared the effects of OmpK36 Aspartate-Threonine or Glycine-Aspartate dipeptide porin insertions on susceptibility to cefepime and carbapenems. In P. aeruginosa, we identified differences in the gene expression effects of mexR versus nalC mutations and related these to differences in {beta}-lactam MICs against isolates hyper-producing AmpC {beta}-lactamase and or producing a metallo-{beta}-lactamase.

microbiology↗