Browsing by Author "Kadelka, Sarah"

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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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    Linked within-host and between-host models and data for infectious diseases: a systematic review
    Childs, Lauren M.; El Moustaid, Fadoua; Gajewski, Zachary J.; Kadelka, Sarah; Nikin-Beers, Ryan; Smith, John W. Jr.; Walker, Melody; Johnson, Leah R. (PeerJ, 2019-06-19)
    The observed dynamics of infectious diseases are driven by processes across multiple scales. Here we focus on two: within-host, that is, how an infection progresses inside a single individual (for instance viral and immune dynamics), and between-host, that is, how the infection is transmitted between multiple individuals of a host population. The dynamics of each of these may be influenced by the other, particularly across evolutionary time. Thus understanding each of these scales, and the links between them, is necessary for a holistic understanding of the spread of infectious diseases. One approach to combining these scales is through mathematical modeling. We conducted a systematic review of the published literature on multi-scale mathematical models of disease transmission (as defined by combining within-host and between-host scales) to determine the extent to which mathematical models are being used to understand across-scale transmission, and the extent to which these models are being confronted with data. Following the PRISMA guidelines for systematic reviews, we identified 24 of 197 qualifying papers across 30 years that include both linked models at the within and between host scales and that used data to parameterize/calibrate models. We find that the approach that incorporates both modeling with data is under-utilized, if increasing. This highlights the need for better communication and collaboration between modelers and empiricists to build well-calibrated models that both improve understanding and may be used for prediction.
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    Mathematical investigation of HBeAg seroconversion
    Kadelka, Sarah; Ciupe, Stanca M. (2019-08-20)
    Spontaneous or drug-induced loss of hepatitis B e antigen is considered a beneficial event in the disease progression of chronic hepatitis B virus infections. Mathematical models of within-host interactions are proposed; which provide insight into hepatitis B e antibody formation, its influence on hepatitis B e antigen seroclearance, and reversion of anergic cytotoxic immune responses. They predict that antibody expansion causes immune activation and hepatitis B e antigen seroclearance. Quantification of the time between antibody expansion and hepatitis B e antigen seroclearance in the presence and absence of treatment shows that potent short-term treatment speeds up the time between antibody expansion and hepatitis B e antigen seroclearance. The monthly hepatocyte turnover during this time can be increased or decreased by treatment depending on the amount of core promoter or precore mutated virus produced. The results can inform human interventions.
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    Understanding the antiviral effects of RNAi-based therapy in HBeAg-positive chronic hepatitis B infection
    Kadelka, Sarah; Dahari, Harel; Ciupe, Stanca M. (2021-01-08)
    The RNA interference (RNAi) drug ARC-520 was shown to be effective in reducing serum hepatitis B virus (HBV) DNA, hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) in HBeAg-positive patients treated with a single dose of ARC-520 and daily nucleosidic analogue (entecavir). To provide insights into HBV dynamics under ARC-520 treatment and its efficacy in blocking HBV DNA, HBsAg, and HBeAg production we developed a multi-compartmental pharmacokinetic-pharamacodynamic model and calibrated it with frequent measured HBV kinetic data. We showed that the time-dependent single dose ARC-520 efficacies in blocking HBsAg and HBeAg are more than 96% effective around day 1, and slowly wane to 50% in 1-4 months. The combined single dose ARC-520 and entecavir effect on HBV DNA was constant over time, with efficacy of more than 99.8%. The observed continuous HBV DNA decline is entecavir mediated, the strong but transient HBsAg and HBeAg decays are ARC-520 mediated. The modeling framework may help assess ongoing RNAi drug development for hepatitis B virus infection.