Biology subjects

Mueller, A. L.

Publications and source records attributed to Mueller, A. L..

4 recordsLinked to original sources

bioRxiv2025

Perfusable 3D human urothelial model for real-time analysis of bacterial infection dynamics and therapeutic interventions

Urinary tract infections (UTIs) remain a major health burden, yet mechanistic studies are limited by the lack of experimental models that enable high spatiotemporal resolution tracking of infection dynamics, while recapitulating the stratified architecture of the bladder epithelium, urine tolerance and fluid dynamics. Here, we present a modular microphysiological platform integrating a fully stratified, urine-tolerant human urothelium cultured on standard transwell inserts within a custom-designed perfusion device compatible with live imaging. Urine flow enables real-time, high-resolution imaging of uropathogenic Escherichia coli (UPEC) infections under physiologically relevant conditions, including clearance of planktonic bacteria and nutrients replenishment, while retaining tissue-associated populations. This system revealed UPEC attachment via the type 1 fimbrial adhesin FimH and its inhibition by D-mannose treatment. Moreover, the platform captured L-form formation upon treatment with the frontline antibiotic fosfomycin and regrowth of walled bacteria following drug withdrawal. The platform further uncovered strain-specific lysis through bacteriophages in contrast to the activity of broad-spectrum antibiotics. In summary, this system constitutes a scalable platform with high predictive power for studying UTI pathogenesis and preclinical therapeutic testing.

bioengineering↗

bioRxiv2025

Diversity and prevalence of sulfate- and sulfite-reducing microorganisms in the human gut microbiome

Microorganisms capable of producing hydrogen sulfide have been associated with inflammatory diseases within the human gastrointestinal tract. Using a weighted protein homology search followed by phylogenetic fragment insertion, we sought to characterize the diversity and prevalence of microbial dissimilatory sulfite reduction genes (dsrAB) from over 70,000 human gut samples from publicly available metagenomic sequencing data. We found over 1,700 unique dsrAB sequences that were predominantly within two clades of sulfate- and sulfite-reducing microorganisms (SSRM): the well-studied Desulfovibrionaceae family and the Firmicutes group sensu lato (s.l.). We detected SSRM in over a third of adults, but very few children. Bilophila wadsworthia was the most prevalent SSRM, and along with other members of Desulfovibrionaceae, constituted the majority of SSRM found. About one fifth of people with SSRM contained members of the Firmicutes group s.l. Our study characterizes the overall diversity of SSRM in the human gut from different global populations while highlighting the potential importance of SSRM from the Firmicutes group, which have commonly been overlooked as contributors to microbial hydrogen sulfide production in the human gut.

microbiology↗

bioRxiv2022

Greater breadth of vaccine-induced immunity in females than males is mediated by increased antibody diversity in germinal center B cells

Inactivated influenza vaccines induce greater antibody responses in females than males among both humans and mice. To test the breadth of protection, we used recombinant mouse-adapted A/California/2009 (maA/Cal/09) H1N1 viruses containing mutations at one (1M), two (2M), or three (3M) antigenic sites, in addition to a virus containing the 1M mutation and a substitution of the Ca2 antigenic site (Sub) with one derived from an H5 hemagglutinin (HA) to challenge mice of both sexes. Following maA/Cal/09 vaccination, females produced greater virus-specific class-switched IgG and IgG2c antibodies against the vaccine and all mutant viruses, and antibodies from females recognized more unique, linear HA epitopes than antibodies from males. While females had greater neutralizing antibody (nAb) titers against the vaccine virus, both sexes showed lower neutralization capacity against mutant viruses. After virus challenge, vaccinated females had lower pulmonary virus titers and reduced morbidity than males against the 1M and 2M viruses, but not the Sub virus. Females generated greater numbers of germinal center (GC) B cells containing superior somatic hypermutation frequencies than vaccinated males. Deletion of activation-induced cytidine deaminase (Aicda) eliminated female-biased immunity and protection against the 2M virus. Harnessing methods to improve GC B cell responses and frequencies of somatic hypermutations, especially in males, should be considered in the development of universal influenza vaccines. SummaryCompared with males, inactivated influenza vaccination of female mice causes greater production of class-switched, somatically-hypermutated antibodies and a more robust germinal center B cell response, leading to more diverse H1N1 antigen recognition and better protection against mutant influenza A viruses.

immunology↗

bioRxiv2021

Ultra-cheap and scalable epigenetic age predictions with TIME-Seq

Epigenetic "clocks" based on DNA methylation (DNAme) have emerged as the most robust and widely employed aging biomarkers, but conventional methods for applying them are expensive and laborious. Here, we develop Tagmentation-based Indexing for Methylation Sequencing (TIME-Seq), a highly multiplexed and scalable method for low-cost epigenetic clocks. Using TIME-Seq, we applied multi-tissue and tissue-specific epigenetic clocks to over 1,600 mouse DNA samples. We also discovered a novel approach for age prediction from shallow sequencing (e.g., 10,000 reads) by adapting scAge for bulk measurements. In benchmarking experiments, TIME-Seq performed favorably against prevailing methods and could quantify the effects of interventions thought to accelerate, slow, and reverse aging in mice. Finally, we built and validated a highly accurate human blood clock from 1,056 demographically representative individuals. Our methods increase the scalability and reduce the cost of epigenetic age predictions by more than 100-fold, enabling accurate aging biomarkers to be applied in more large-scale animal and human studies.

genomics↗