Multiple outbreaks and flu containment plans.
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Animals↗
Biomedical subjects
Carl T Bergstrom
Publications and source records attributed to Carl T Bergstrom.
How do adaptive immune systems control pathogens while avoiding autoimmunity?
Immune systems face a daunting control challenge. On the one hand, they need to minimize damage from pathogens, without wasting energy and resources, but on the other must avoid initiating or perpetuating autoimmune responses. Finally, because pathogens interfere with immune function, immune systems must be robust against sabotage. We describe here how these challenges are met by two immune systems, the intracellular RNA interference system and the vertebrate CD8 T-cell response. We extrapolate from these two systems to propose principles for strategically robust control.
Adaptation, Physiological↗
A population-epigenetic model to infer site-specific methylation rates from double-stranded DNA methylation patterns.
Cytosine methylation is an epigenetic mechanism in eukaryotes that is often associated with stable transcriptional silencing, such as in X-chromosome inactivation and genomic imprinting. Aberrant methylation patterns occur in several inherited human diseases and in many cancers. To understand how methylated and unmethylated states of cytosine residues are transmitted during DNA replication, we develop a population-epigenetic model of DNA methylation dynamics. The model is informed by our observation that de novo methylation can occur on the daughter strand while leaving the opposing cytosine unmethylated, as revealed by the patterns of methylation on the two complementary strands of individual DNA molecules. Under our model, we can infer site-specific rates of both maintenance and de novo methylation, values that determine the fidelity of methylation inheritance, from double-stranded methylation data. This approach can be used for populations of cells obtained from individuals without the need for cell culture. We use our method to infer cytosine methylation rates at several sites within the promoter of the human gene FMR1.
Base Sequence↗
On RNA interference as template immunity.
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Animals↗
The disadvantage of combinatorial communication.
Combinatorial communication allows rapid and efficient transfer of detailed information, yet combinatorial communication is used by few, if any, non-human species. To complement recent studies illustrating the advantages of combinatorial communication, we highlight a critical disadvantage. We use the concept of information value to show that deception poses a greater and qualitatively different threat to combinatorial signalling than to non-combinatorial systems. This additional potential for deception may represent a strategic barrier that has prevented widespread evolution of combinatorial communication. Our approach has the additional benefit of drawing clear distinctions among several types of deception that can occur in communication systems.
Animal Communication↗
Invited commentary: real-time tracking of control measures for emerging infections.
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Canada↗
Ecological theory suggests that antimicrobial cycling will not reduce antimicrobial resistance in hospitals.
Hospital-acquired infections caused by antibiotic-resistant bacteria pose a grave and growing threat to public health. Antimicrobial cycling, in which two or more antibiotic classes are alternated on a time scale of months to years, seems to be a leading candidate in the search for treatment strategies that can slow the evolution and spread of antibiotic resistance in hospitals. We develop a mathematical model of antimicrobial cycling in a hospital setting and use this model to explore the efficacy of cycling programs. We find that cycling is unlikely to reduce either the evolution or the spread of antibiotic resistance. Alternative drug-use strategies such as mixing, in which each treated patient receives one of several drug classes used simultaneously in the hospital, are predicted to be more effective. A simple ecological explanation underlies these results. Heterogeneous antibiotic use slows the spread of resistance. However, at the scale relevant to bacterial populations, mixing imposes greater heterogeneity than does cycling. As a consequence, cycling is unlikely to be effective and may even hinder resistance control. These results may explain the limited success reported thus far from clinical trials of antimicrobial cycling.
Anti-Bacterial Agents↗
The costs and benefits of library site licenses to academic journals.
Scientific publishing is rapidly shifting from a paper-based system to one of predominantly electronic distribution, in which universities purchase site licenses for online access to journal contents. Will these changes necessarily benefit the scientific community? By using basic microeconomics and elementary statistical theory, we address this question and find a surprising answer. If a journal is priced to maximize the publisher's profits, scholars on average are likely to be worse off when universities purchase site licenses than they would be if access were by individual subscriptions only. However, site licenses are not always disadvantageous. Journals issued by professional societies and university presses are often priced so as to maximize subscriptions while recovering average costs. When such journals are sustained by institutional site licenses, the net benefits to the scientific community are larger than if these journals are sold only by individual subscriptions.
Cost-Benefit Analysis↗
The role of evolution in the emergence of infectious diseases.
It is unclear when, where and how novel pathogens such as human immunodeficiency virus (HIV), monkeypox and severe acute respiratory syndrome (SARS) will cross the barriers that separate their natural reservoirs from human populations and ignite the epidemic spread of novel infectious diseases. New pathogens are believed to emerge from animal reservoirs when ecological changes increase the pathogen's opportunities to enter the human population and to generate subsequent human-to-human transmission. Effective human-to-human transmission requires that the pathogen's basic reproductive number, R(0), should exceed one, where R(0) is the average number of secondary infections arising from one infected individual in a completely susceptible population. However, an increase in R(0), even when insufficient to generate an epidemic, nonetheless increases the number of subsequently infected individuals. Here we show that, as a consequence of this, the probability of pathogen evolution to R(0) > 1 and subsequent disease emergence can increase markedly.
Animals↗
Mathematical models of RNA silencing: unidirectional amplification limits accidental self-directed reactions.
RNA silencing, found broadly throughout the eukaryotes, posttranscriptionally suppresses the expression of "aberrant" genes including those of many viruses and transposons. Similar to the specific immune system of vertebrates, RNA silencing works by generating specific responses against foreign elements and rapidly amplifying these responses to clear or otherwise inactivate the threat. Also like the vertebrate immune system, RNA-silencing systems risk making mistakes and mounting undesirable responses against the self. We develop a set of mathematical models of RNA silencing. We show that current models of RNA silencing do little to explain what prevents mistaken reactions from silencing vital organismal genes. We extend the basic models to show that the presumed unidirectional nature of the amplification process (namely, unidirectional RNA-directed RNA polymerase-mediated synthesis of secondary double-stranded RNA as observed in Caenorhabditis elegans) serves as a "safety mechanism" that safeguards against accidental generation of damaging self-directed reactions.
DNA Transposable Elements↗
Models of CD8+ responses: 1. What is the antigen-independent proliferation program.
Recent experimental results show that even brief stimulation with antigen can cause antigen-specific CD8 T-cells to undergo sustained proliferation followed by differentiation into memory cells. These results show that the dynamics of these immune responses are not governed by constant monitoring of antigen levels, but rather that following stimulation immune cells commit to a "program". At present relatively little is known about the program which governs CD8 cell proliferation and differentiation. For example, we do not know whether the program is completely specified by the initial encounter of a T cell with antigen, or whether it subsequently can be modified by the amount of antigen present. Nor do we know whether the entire program for T cell proliferation and differentiation resides within the T cell itself, or whether some component(s) of the program are determined by cells or molecules external to the CD8 cell. In this paper we construct simple mathematical models which incorporate antigen-independent proliferation and differentiation of CD8 cells during acute infections. We use these models to determine what characteristics the program must have in order to be consistent with the existing data on the dynamics of CD8 responses, and in particular to answer the questions posed above. Our results suggest that the program is not completely defined by the initial encounter of T cell with antigen but may be augmented by exposure to antigen in a brief window shortly after infection; furthermore, parts of the program may reside external to the T-cells. Finally we examine some of the consequences of the "program" for pathogen-host coevolution.
Animals↗
Effect of human leukocyte antigen heterozygosity on infectious disease outcome: the need for allele-specific measures.
BACKGROUND: Doherty and Zinkernagel, who discovered that antigen presentation is restricted by the major histocompatibility complex (MHC, called HLA in humans), hypothesized that individuals heterozygous at particular MHC loci might be more resistant to particular infectious diseases than the corresponding homozygotes because heterozygotes could present a wider repertoire of antigens. The superiority of heterozygotes over either corresponding homozygote, which we term allele-specific overdominance, is of direct biological interest for understanding the mechanisms of immune response; it is also a leading explanation for the observation that MHC loci are extremely polymorphic and that these polymorphisms have been maintained through extremely long evolutionary periods. Recent studies have shown that in particular viral infections, heterozygosity at HLA loci was associated with a favorable disease outcome, and such findings have been interpreted as supporting the allele-specific overdominance hypothesis in humans. METHODS: An algebraic model is used to define the expected population-wide findings of an epidemiologic study of HLA heterozygosity and disease outcome as a function of allele-specific effects and population genetic parameters of the study population. RESULTS: We show that overrepresentation of HLA heterozygotes among individuals with favorable disease outcomes (which we term population heterozygote advantage) need not indicate allele-specific overdominance. On the contrary, partly due to a form of confounding by allele frequencies, population heterozygote advantage can occur under a very wide range of assumptions about the relationship between homozygote risk and heterozygote risk. In certain extreme cases, population heterozygote advantage can occur even when every heterozygote is at greater risk of being a case than either corresponding homozygote. CONCLUSION: To demonstrate allele-specific overdominance for specific infections in human populations, improved analytic tools and/or larger studies (or studies in populations with limited HLA diversity) are necessary.
Alleles↗
The Red King effect: when the slowest runner wins the coevolutionary race.
Mutualisms provide benefits to those who participate in them. As a mutualism evolves, how will these benefits come to be allocated among the participants? We approach this question by using evolutionary game theory and explore the ways in which the coevolutionary process determines the allocation of benefits in mutualistic interactions. Motivated by the Red Queen theory, which states that coevolutionary processes favor rapid rates of evolution, we pay particular attention to the role of evolutionary rates in the establishment of mutualism and the partitioning of benefits among mutualist partners. We find that, contrary to the Red Queen, in mutualism evolution the slowly evolving species is likely to gain a disproportionate share of the benefits. Moreover, population structure serves to magnify the advantage to the slower species.
Animals↗
The evolution of mutator genes in bacterial populations: the roles of environmental change and timing.
Recent studies have found high frequencies of bacteria with increased genomic rates of mutation in both clinical and laboratory populations. These observations may seem surprising in light of earlier experimental and theoretical studies. Mutator genes (genes that elevate the genomic mutation rate) are likely to induce deleterious mutations and thus suffer an indirect selective disadvantage; at the same time, bacteria carrying them can increase in frequency only by generating beneficial mutations at other loci. When clones carrying mutator genes are rare, however, these beneficial mutations are far more likely to arise in members of the much larger nonmutator population. How then can mutators become prevalent? To address this question, we develop a model of the population dynamics of bacteria confronted with ever-changing environments. Using analytical and simulation procedures, we explore the process by which initially rare mutator alleles can rise in frequency. We demonstrate that subsequent to a shift in environmental conditions, there will be relatively long periods of time during which the mutator subpopulation can produce a beneficial mutation before the ancestral subpopulations are eliminated. If the beneficial mutation arises early enough, the overall frequency of mutators will climb to a point higher than when the process began. The probability of producing a subsequent beneficial mutation will then also increase. In this manner, mutators can increase in frequency over successive selective sweeps. We discuss the implications and predictions of these theoretical results in relation to antibiotic resistance and the evolution of mutation rates.
Bacteria↗
Separating equilibria in continuous signalling games.
Much of the literature on costly signalling theory concentrates on separating equilibria of continuous signalling games. At such equilibria, every signaller sends a distinct signal, and signal receivers are able to exactly infer the signaller's condition from the signal sent. In this paper, we introduce a vector-field solution method that simplifies the process of solving for separating equilibria. Using this approach, we show that continuous signalling games can have low-cost separating equilibria despite conflicting interests between signaller and receiver. We find that contrary to prior arguments, honesty does not require wasteful signals. Finally, we examine signalling games in which different signallers have different minimal-cost signals, and provide a mathematical justification for the argument that even non-signalling traits will be exaggerated beyond their phenotypic optimum when they are used by other individuals to judge condition or quality.
Communication↗
Within-host population dynamics and the evolution of microparasites in a heterogeneous host population.
Why do parasites harm their hosts? The general understanding is that if the transmission rate and virulence of a parasite are linked, then the parasite must harm its host to maximize its transmission. The exact nature of such trade-offs remains largely unclear, but for vertebrate hosts it probably involves interactions between a microparasite and the host immune system. Previous results have suggested that in a homogeneous host population in the absence of super- or coinfection, within-host dynamics lead to selection of the parasite with an intermediate growth rate that is just being controlled by the immune system before it kills the host (Antia et al. 1994). In this paper, we examine how this result changes when heterogeneity is introduced to the host population. We incorporate the simplest form of heterogeneity--random heterogeneity in the parameters describing the size of the initial parasite inoculum, the immune response of the host, and the lethal density at which the parasite kills the host. We find that the general conclusion of the previous model holds: parasites evolve some intermediate growth rate. However, in contrast with the generally accepted view, we find that virulence (measured by the case mortality or the rate of parasite-induced host mortality) increases with heterogeneity. Finally, we link the within-host and between-host dynamics of parasites. We show how the parameters for epidemiological spread of the disease can be estimated from the within-host dynamics, and in doing so examine the way in which trade-offs between these epidemiological parameters arise as a consequence of the interaction of the parasite and the immune response of the host.
Animals↗