Biomedical subjects

Jana N Radin

Publications and source records attributed to Jana N Radin.

4 recordsLinked to original sources

PubMed2025

Multiple clades of regulators contribute to bacterial phosphate homeostasis and pathogenesis.

Phosphate is both essential for life and toxic, necessitating the tight regulation of its acquisition. Based on Escherichia coli, most bacteria are thought to use a single accessory protein that monitors import to regulate phosphate homeostasis. This work reveals that most bacteria possess multiple distinct families of accessory regulators with each family regulating homeostasis in conjunction with a unique importer family. The antibiotic-resistant pathogen Staphylococcus aureus can obtain phosphate from divergent environments and possesses accessory-transporter pairs from all three identified groups. Investigations with S. aureus revealed that all three accessory proteins can regulate phosphate homeostasis, but that there is a hierarchy, which is dictated by the environment. Multiple accessory regulators are independently necessary for S. aureus to cause infection. Thus, microbes possess not one, but multiple distinct groups of accessory regulatory proteins and this diversity enables them to control phosphate homeostasis across environments, including those encountered during infection.

PhoPR↗

PubMed2006

Platelet-activating factor receptor and innate immunity: uptake of gram-positive bacterial cell wall into host cells and cell-specific pathophysiology.

The current model of innate immune recognition of Gram-positive bacteria suggests that the bacterial cell wall interacts with host recognition proteins such as TLRs and Nod proteins. We describe an additional recognition system mediated by the platelet-activating factor receptor (PAFr) and directed to the pathogen-associated molecular pattern phosphorylcholine that results in the uptake of bacterial components into host cells. Intravascular choline-containing cell walls bound to endothelial cells and caused rapid lethality in wild-type, Tlr2(-/-), and Nod2(-/-) mice but not in Pafr(-/-) mice. The cell wall exited the vasculature into the heart and brain, accumulating within endothelial cells, cardiomyocytes, and neurons in a PAFr-dependent way. Physiological consequences of the cell wall/PAFr interaction were cell specific, being noninflammatory in endothelial cells and neurons but causing a rapid loss of cardiomyocyte contractility that contributed to death. Thus, PAFr shepherds phosphorylcholine-containing bacterial components such as the cell wall into host cells from where the response ranges from quiescence to severe pathophysiology.

Animals↗

PubMed2005

beta-Arrestin 1 participates in platelet-activating factor receptor-mediated endocytosis of Streptococcus pneumoniae.

Pneumococci traverse eukaryotic cells within vacuoles without intracytoplasmic multiplication. The platelet-activating factor receptor (PAFr) has been suggested as a portal of entry. Pneumococci colocalized with PAFr on endothelial cells and PAFr-/- mice showed a substantially impaired ability to support bacterial translocation, particularly from blood to brain. Pneumococci-induced colocalization of PAFr and beta-arrestin 1 at the plasma membrane of endothelial cells and PAFr-mediated pneumococcal uptake in transfected COS cells were greatly increased by cotransfection with the scaffold/adapter protein beta-arrestin 1. Activation of extracellular signal-regulated kinase kinases was required for uptake and was limited to the cytoplasmic compartment, consistent with activation by beta-arrestin rather than PAFr. Uptake of the pneumococcal vacuole involved clathrin, and half the bacteria proceeded into vacuoles marked by Rab5 and later Rab7, the classical route to the lysosome. Overexpression of beta-arrestin in endothelial cells decreased colocalization with Rab7. We conclude that the association of beta-arrestin with the PAFr contributes to successful translocation of pneumococci.

Animals↗

PubMed2004

Microarray analysis of pneumococcal gene expression during invasive disease.

Streptococcus pneumoniae is a leading cause of invasive bacterial disease. This is the first study to examine the expression of S. pneumoniae genes in vivo by using whole-genome microarrays available from The Institute for Genomic Research. Total RNA was collected from pneumococci isolated from infected blood, infected cerebrospinal fluid, and bacteria attached to a pharyngeal epithelial cell line in vitro. Microarray analysis of pneumococcal genes expressed in these models identified body site-specific patterns of expression for virulence factors, transporters, transcription factors, translation-associated proteins, metabolism, and genes with unknown function. Contributions to virulence predicted for several unknown genes with enhanced expression in vivo were confirmed by insertion duplication mutagenesis and challenge of mice with the mutants. Finally, we cross-referenced our results with previous studies that used signature-tagged mutagenesis and differential fluorescence induction to identify genes that are potentially required by a broad range of pneumococcal strains for invasive disease.

Animals↗