Dynamics of virus and immune response in multi-epitope network.

The host immune response can often efficiently suppress a virus infection, which may lead to selection for immune-resistant viral variants within the host. For example, during HIV infection, an array of CTL immune response populations recognize specific epitopes (viral proteins) presented on the surface of infected cells to effectively mediate their killing. However HIV can rapidly evolve resistance to CTL attack at different epitopes, inducing a dynamic network of interacting viral and immune response variants. We consider models for the network of virus and immune response populations, consisting of Lotka-Volterra-like systems of ordinary differential equations. Stability of feasible equilibria and corresponding uniform persistence of distinct variants are characterized via a Lyapunov function. We specialize the model to a "binary sequence" setting, where for n epitopes there can be [Formula: see text] distinct viral variants mapped on a hypercube graph. The dynamics in several cases are analyzed and sharp polychotomies are derived characterizing persistent variants. In particular, we prove that if the viral fitness costs for gaining resistance to each epitope are equal, then the system of [Formula: see text] virus strains converges to a "perfectly nested network" with less than or equal to [Formula: see text] persistent virus strains. Overall, our results suggest that immunodominance, i.e. relative strength of immune response to an epitope, is the most important factor determining the persistent network structure.

Persistence versus extinction for a class of discrete-time structured population models.

We provide sharp conditions distinguishing persistence and extinction for a class of discrete-time dynamical systems on the positive cone of an ordered Banach space generated by a map which is the sum of a positive linear contraction A and a nonlinear perturbation G that is compact and differentiable at zero in the direction of the cone. Such maps arise as year-to-year projections of population age, stage, or size-structure distributions in population biology where typically A has to do with survival and individual development and G captures the effects of reproduction. The threshold distinguishing persistence and extinction is the principal eigenvalue of (II−A)(−1)G'(0) provided by the Krein-Rutman Theorem, and persistence is described in terms of associated eigenfunctionals. Our results significantly extend earlier persistence results of the last two authors which required more restrictive conditions on G. They are illustrated by application of the results to a plant model with a seed bank.

A model of optimal dosing of antibiotic treatment in biofilm.

Biofilms are heterogeneous matrix enclosed micro-colonies of bacteria mostly found on moist surfaces. Biofilm formation is the primary cause of several persistent infections found in humans. We derive a mathematical model of biofilm and surrounding fluid dynamics to investigate the effect of a periodic dose of antibiotic on elimination of microbial population from biofilm. The growth rate of bacteria in biofilm is taken as Monod type for the limiting nutrient. The pharmacodynamics function is taken to be dependent both on limiting nutrient and antibiotic concentration. Assuming that flow rate of fluid compartment is large enough, we reduce the six dimensional model to a three dimensional model. Mathematically rigorous results are derived providing sufficient conditions for treatment success. Persistence theory is used to derive conditions under which the periodic solution for treatment failure is obtained. We also discuss the phenomenon of bi-stability where both infection-free state and infection state are locally stable when antibiotic dosing is marginal. In addition, we derive the optimal antibiotic application protocols for different scenarios using control theory and show that such treatments ensure bacteria elimination for a wide variety of cases. The results show that bacteria are successfully eliminated if the discrete treatment is given at an early stage in the infection or if the optimal protocol is adopted. Finally, we examine factors which if changed can result in treatment success of the previously treatment failure cases for the non-optimal technique.

Chemostats and epidemics: competition for nutrients/hosts.

In a chemostat, several species compete for the same nutrient, while in an epidemic, several strains of the same pathogen may compete for the same susceptible hosts. As winner, chemostat models predict the species with the lowest break-even concentration, while epidemic models predict the strain with the largest basic reproduction number. We show that these predictions amount to the same if the per capita functional responses of consumer species to the nutrient concentration or of infective individuals to the density of susceptibles are proportional to each other but that they are different if the functional responses are nonproportional. In the second case, the correct prediction is given by the break-even concentrations. In the case of nonproportional functional responses, we add a class for which the prediction does not only rely on local stability and instability of one-species (strain) equilibria but on the global outcome of the competition. We also review some results for nonautonomous models.

Allelopathy of plasmid-bearing and plasmid-free organisms competing for two complementary resources in a chemostat.

We consider a model of competition between plasmid-bearing and plasmid-free organisms for two complementary nutrients in a chemostat. We assume that the plasmid-bearing organism produces an allelopathic agent at the cost of its reproductive abilities which is lethal to plasmid-free organism. Our analysis leads to different thresholds in terms of the model parameters acting as conditions under which the organisms associated with the system cannot thrive even in the absence of competition. Local stability of the system is obtained in the absence of one or both the organisms. Also, global stability of the system is obtained in the presence of both the organisms. Computer simulations have been carried out to illustrate various analytical results.

Persistence of bacteria and phages in a chemostat.

The model of bacteriophage predation on bacteria in a chemostat formulated by Levin et al. (Am Nat 111:3-24, 1977) is generalized to include a distributed latent period, distributed viral progeny release from infected bacteria, unproductive adsorption of phages to infected cells, and possible nutrient uptake by infected cells. Indeed, two formulations of the model are given: a system of delay differential equations with infinite delay, and a more general infection-age model that leads to a system of integro-differential equations. It is shown that the bacteria persist, and sharp conditions for persistence and extinction of phages are determined by the reproductive ratio for phage relative to the phage-free equilibrium. A novel feature of our analysis is the use of the Laplace transform.

Bacteriophage-resistant and bacteriophage-sensitive bacteria in a chemostat.

In this paper a mathematical model of the population dynamics of a bacteriophage-sensitive and a bacteriophage-resistant bacteria in a chemostat where the resistant bacteria is an inferior competitor for nutrient is studied. The focus of the study is on persistence and extinction of bacterial strains and bacteriophage.

Bacteriophage and bacteria in a flow reactor.

The Levin-Stewart model of bacteriophage predation of bacteria in a chemostat is modified for a flow reactor in which bacteria are motile, phage diffuse, and advection brings fresh nutrient and removes medium, cells and phage. A fixed latent period for phage results in a system of delayed reaction-diffusion equations with non-local nonlinearities. Basic reproductive numbers are obtained for bacteria and for phage which predict survival of each in the bio-reactor. These are expressed in terms of physical and biological parameters. Persistence and extinction results are obtained for both bacteria and phage. Numerical simulations are in general agreement with those for the chemostat model.

Bacterial competition in serial transfer culture.

A mathematical model of bacterial competition for a single growth-limiting substrate in serial transfer culture is formulated. Each bacterial strain is characterized by a growth response function, e.g. Monod function determined by a maximum growth rate and half-saturation nutrient concentration, and the length of its lag phase following the dilution event. The goal of our study is to understand what factors determine an organisms fitness or competitive ability in serial transfer culture. A motivating question is: how many strains can coexist in serial transfer culture? Unlike competition in the chemostat, coexistence of two strains can occur in serial transfer culture. Numerical simulations suggest that more than two may coexist.

Persistence in a discrete-time stage-structured fungal disease model.

A discrete-time susceptible and infected (SI) epidemic model, with less than 100% vertical disease transmission, for the spread of a fungal disease in a structured amphibian host population, is analysed. Criteria for persistence of the population as well as the disease are established. Stability results for host extinction and for the disease-free equilibrium are presented. Bifurcation theory is used to establish existence of an endemic equilibrium.

Does dormancy increase fitness of bacterial populations in time-varying environments?

A simple family of models of a bacterial population in a time varying environment in which cells can transit between dormant and active states is constructed. It consists of a linear system of ordinary differential equations for active and dormant cells with time-dependent coefficients reflecting an environment which may be periodic or random, with alternate periods of low and high resource levels. The focus is on computing/estimating the dominant Lyapunov exponent, the fitness, and determining its dependence on various parameters and the two strategies-responsive and stochastic-by which organisms switch between dormant and active states. A responsive switcher responds to good and bad times by making timely and appropriate transitions while a stochastic switcher switches continuously without regard to the environmental state. The fitness of a responsive switcher is examined and compared with fitness of a stochastic switcher, and with the fitness of a dormancy-incapable organism. Analytical methods show that both switching strategists have higher fitness than a dormancy-incapable organism when good times are rare and that responsive switcher has higher fitness than stochastic switcher when good times are either rare or common. Numerical calculations show that stochastic switcher can be most fit when good times are neither too rare or too common.

Global dynamics of microbial competition for two resources with internal storage.

We study a chemostat model that describes competition between two species for two essential resources based on storage. The model incorporates internal resource storage variables that serve the direct connection between species growth and external resource availability. Mathematical analysis for the global dynamics of the model is carried out by using the monotone dynamical system theory. It is shown that the limiting system of the model basically exhibits the familiar Lotka-Volterra alternatives: competitive exclusion, coexistence, and bi-stability, and most of these results can be carried over to the original model.

Multiple limit cycles in the standard model of three species competition for three essential resources.

We consider the dynamics of the standard model of 3 species competing for 3 essential (non-substitutable) resources in a chemostat using Liebig's law of the minimum functional response. A subset of these systems which possess cyclic symmetry such that its three single-population equilibria are part of a heteroclinic cycle bounding the two-dimensional carrying simplex is examined. We show that a subcritical Hopf bifurcation from the coexistence equilibrium together with a repelling heteroclinic cycle leads to the existence of at least two limit cycles enclosing the coexistence equilibrium on the carrying simplex -- the "inside'' one is an unstable separatrix and the "outside'' one is at least semi-stable relative to the carrying simplex. Numerical simulations suggest that there are exactly two limit cycles and that almost every positive solution approaches either the stable limit cycle or the stable coexistence equilibrium, depending on initial conditions. Bifurcation diagrams confirm this picture and show additional features. In an alternative scenario, we show that the subcritical Hopf together with an attracting heteroclinic cycle leads to an unstable periodic orbit separatrix.

Periodic coexistence of four species competing for three essential resources.

We show the existence of a periodic solution in which four species coexist in competition for three essential resources in the standard model of resource competition. By assuming that species i is limited by resource i for each i near the positive equilibrium, and that the matrix of contents of resources in species is a combination of cyclic matrix and a symmetric matrix, we obtain an asymptotically stable periodic solution of three species on three resources via Hopf bifurcation. A simple bifurcation argument is then employed which allows us to add a fourth species. In principle, the argument can be continued to obtain a periodic solution adding one new species at a time so long as asymptotic stability can be assured at each step. Numerical simulations are provided to illustrate our analytical results. The results of this paper suggest that competition can generate coexistence of species in the form of periodic cycles, and that the number of coexisting species can exceed the number of resources in a constant and homogeneous environment.