Estimates of differential toxin expression governing heterogeneous intracellular lifespans of Streptococcus pneumoniae.

Following invasion of the host cell, pore-forming toxins secreted by pathogens compromise vacuole integrity and expose the microbe to diverse intracellular defence mechanisms. However, the quantitative correlation between toxin expression levels and consequent pore dynamics, fostering the intracellular life of pathogens, remains largely unexplored. In this study, using Streptococcus pneumoniae and its secreted pore-forming toxin pneumolysin (Ply) as a model system, we explored various facets of host-pathogen interactions in the host cytosol. Using time-lapse fluorescence imaging, we monitored pore formation dynamics and lifespans of different pneumococcal subpopulations inside host cells. Based on experimental histograms of various event timescales such as pore formation time, vacuolar death or cytosolic escape time and total degradation time, we developed a mathematical model based on first-passage processes that could correlate the event timescales to intravacuolar toxin accumulation. This allowed us to estimate Ply production rate, burst size and threshold Ply quantities that trigger these outcomes. Collectively, we present a general method that illustrates a correlation between toxin expression levels and pore dynamics, dictating intracellular lifespans of pathogens.

Impact of IL-21 on Natural Killer cell proliferation and function - a mathematical and functional assessment.

Natural killer (NK) cells are currently in use as immunotherapeutic agents for cancer. Many different cytokines are used to generate NK cells including IL-2, IL-12, IL-15 and IL-18 in solution and membrane bound IL-21. These cytokines drive NK cell activation through the integration of STAT and NF-κB pathways, which overlap and synergize, making it challenging to predict optimal cytokine combinations. We integrated functional assays for NK cells cultured in a variety of cytokine combinations with feature selection and mechanistic regression models. Our regression model successfully predicts NK cell proliferation for different cytokine combinations and indicates synergy between STAT3 and NF-κB transcription factors. Use of IL-21 in solution in the priming, but not post-priming phase of NK cell culture resulted in optimal NK cell proliferation, without compromising cytotoxicity or IFN-γ secretion against hepatocellular carcinoma cell lines. Our work provides a mathematical framework for interrogating NK cell activation for cancer immunotherapy.

Capture of a diffusive prey by multiple predators in confined space.

The first passage search of a diffusing target (prey) by multiple searchers (predators) in confinement is an important problem in the stochastic process literature. While the analogous problem in open space has been studied in some detail, a systematic study in confined space is still lacking. In this paper, we study the first passage times for this problem in one, two, and three dimensions. Due to confinement, the survival probability of the target takes a form ∼e^{-t/τ} at large times t. The characteristic capture timescale τ associated with the rare capture events are rather challenging to measure. We use a computational algorithm that allows us to estimate τ with high accuracy. We study in detail the behavior of τ as a function of the system parameters, namely, the number of searchers N, the relative diffusivity r of the target with respect to the searcher, and the system size. We find that τ deviates from the ∼1/N scaling seen in the case of a static target, and this deviation varies continuously with r and the spatial dimensions.

First passage of a particle in a potential under stochastic resetting: A vanishing transition of optimal resetting rate.

First passage in a stochastic process may be influenced by the presence of an external confining potential, as well as "stochastic resetting" in which the process is repeatedly reset back to its initial position. Here, we study the interplay between these two strategies, for a diffusing particle in a one-dimensional trapping potential V(x), being randomly reset at a constant rate r. Stochastic resetting has been of great interest as it is known to provide an "optimal rate" (r_{*}) at which the mean first passage time is a minimum. On the other hand, an attractive potential also assists in the first capture process. Interestingly, we find that for a sufficiently strong external potential, the advantageous optimal resetting rate vanishes (i.e., r_{*}→0). We derive a condition for this optimal resetting rate vanishing transition, which is continuous. We study this problem for various functional forms of V(x), some analytically, and the rest numerically. We find that the optimal rate r_{*} vanishes with a deviation from the critical strength of the potential as a power law with an exponent ß which appears to be universal.