Browsing by Author "Boribong, Brittany P."

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    Bistable Mathematical Model of Neutrophil Migratory Patterns After LPS-Induced Epigenetic Reprogramming
    Ciupe, Stanca M.; Boribong, Brittany P.; Kadelka, Sarah; Jones, Caroline N. (2021-02-23)
    The highly controlled migration of neutrophils toward the site of an infection can be altered when they are trained with lipopolysaccharides (LPS), with high dose LPS enhancing neutrophil migratory pattern toward the bacterial derived source signal and super-low dose LPS inducing either migration toward an intermediary signal or dysregulation and oscillatory movement. Empirical studies that use microfluidic chemotaxis-chip devices with two opposing chemoattractants showed differential neutrophil migration after challenge with different LPS doses. The epigenetic alterations responsible for changes in neutrophil migratory behavior are unknown. We developed two mathematical models that evaluate the mechanistic interactions responsible for neutrophil migratory decision-making when exposed to competing chemoattractants and challenged with LPS. The first model, which considers the interactions between the receptor densities of two competing chemoattractants, their kinases, and LPS, displayed bistability between high and low ratios of primary to intermediary chemoattractant receptor densities. In particular, at equilibrium, we observe equal receptor densities for low LPS (< 15ng/mL); and dominance of receptors for the primary chemoattractant for high LPS (> 15ng/mL). The second model, which included additional interactions with an extracellular signal-regulated kinase in both phosphorylated and non-phosphorylated forms, has an additional dynamic outcome, oscillatory dynamics for both receptors, as seen in the data. In particular, it found equal receptor densities in the absence of oscillation for super-low and high LPS challenge (< 0.4 and 1.1 376 ng/mL). Predicting the mechanisms and the type of external LPS challenge responsible for neutrophils migration toward pro-inflammatory chemoattractants, migration toward pro-tolerant chemoattractants, or oscillatory movement is necessary knowledge in designing interventions against immune diseases, such as sepsis.
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    The peptidoglycan-associated protein NapA plays an important role in the envelope integrity and in the pathogenesis of the lyme disease spirochete
    Davis, Marisela M.; Brock, Aaron M.; DeHart, Tanner G.; Boribong, Brittany P.; Lee, Katherine; McClune, Mecaila E.; Chang, Yunjie; Cramer, Nicholas; Liu, Jun; Jones, Caroline N.; Jutras, Brandon L. (PLOS, 2021-05-13)
    The bacterial pathogen responsible for causing Lyme disease, Borrelia burgdorferi, is an atypical Gram-negative spirochete that is transmitted to humans via the bite of an infected Ixodes tick. In diderms, peptidoglycan (PG) is sandwiched between the inner and outer membrane of the cell envelope. In many other Gram-negative bacteria, PG is bound by protein( s), which provide both structural integrity and continuity between envelope layers. Here, we present evidence of a peptidoglycan-associated protein (PAP) in B. burgdorferi. Using an unbiased proteomics approach, we identified Neutrophil Attracting Protein A (NapA) as a PAP. Interestingly, NapA is a Dps homologue, which typically functions to bind and protect cellular DNA from damage during times of stress. While B. burgdorferi NapA is known to be involved in the oxidative stress response, it lacks the critical residues necessary for DNA binding. Biochemical and cellular studies demonstrate that NapA is localized to the B. burgdorferi periplasm and is indeed a PAP. Cryo-electron microscopy indicates that mutant bacteria, unable to produce NapA, have structural abnormalities. Defects in cell-wall integrity impact growth rate and cause the napA mutant to be more susceptible to osmotic and PG-specific stresses. NapA-linked PG is secreted in outer membrane vesicles and augments IL-17 production, relative to PG alone. Using microfluidics, we demonstrate that NapA acts as a molecular beacon—exacerbating the pathogenic properties of B. burgdorferi PG. These studies further our understanding of the B. burgdorferi cell envelope, provide critical information that underlies its pathogenesis, and highlight how a highly conserved bacterial protein can evolve mechanistically, while maintaining biological function.