The evolutionary dynamics of hyperparasites.

Evolutionary theory has typically focused on pairwise interactions, such as those between hosts and parasites, with relatively little work having been carried out on more complex interactions including hyperparasites: parasites of parasites. Hyperparasites are common in nature, with the chestnut blight fungus virus CHV-1 a well-known natural example, but also notably include the phages of important human bacterial diseases. We build a general modeling framework for the evolution of hyperparasites that highlights the central role that the ability of a hyperparasite to be transmitted with its parasite plays in their evolution. A key result is that hyperparasites which transmit with their parasite hosts (hitchhike) will be selected for lower virulence, trending towards hypermutualism or hypercommensalism. We examine the impact on the evolution of hyperparasite systems of a wide range of host and parasite traits showing, for example, that high parasite virulence selects for higher hyperparasite virulence resulting in reductions in parasite virulence when hyperparasitized. Furthermore, we show that acute parasite infection will also select for increased hyperparasite virulence. Our results have implications for hyperparasite research, both as biocontrol agents and for their role in shaping community ecology and evolution and moreover emphasize the importance of understanding evolution in the context of multitrophic interactions.

The evolution of parasite virulence under targeted culling and harvesting in wildlife and livestock.

There is a clear need to understand the effect of human intervention on the evolution of infectious disease. In particular, culling and harvesting of both wildlife and managed livestock populations are carried out in a wide range of management practices, and they have the potential to impact the evolution of a broad range of disease characteristics. Applying eco-evolutionary theory we show that once culling/harvesting becomes targeted on specific disease classes, the established result that culling selects for higher virulence is only found when sufficient infected individuals are culled. If susceptible or recovered individuals are targeted, selection for lower virulence can occur. An important implication of this result is that when culling to eradicate an infectious disease from a population, while it is optimal to target infected individuals, the consequent evolution can increase the basic reproductive ratio of the infection, R0, and make parasite eradication more difficult. We show that increases in evolved virulence due to the culling of infected individuals can lead to excess population decline when sustainably harvesting a population. In contrast, culling susceptible or recovered individuals can select for decreased virulence and a reduction in population decline through culling. The implications to the evolution of virulence are typically the same in wildlife populations, that are regulated by the parasite, and livestock populations, that have a constant population size where restocking balances the losses due to mortality. However, the well-known result that vertical transmission selects for lower virulence and transmission in wildlife populations is less marked in livestock populations for parasites that convey long-term immunity since restocking can enhance the density of the immune class. Our work emphasizes the importance of understanding the evolutionary consequences of intervention strategies and the different ecological feedbacks that can occur in wildlife and livestock populations.

Emergency powers and the pandemic: Reflecting on state legislative reforms and the future of public health response.

The first 2 years of combatting the COVID-19 pandemic necessitated an unprecedented use of emergency powers. States responded with an equally unprecedented flurry of legislative changes to the legal underpinnings of emergency response and public health authorities. In this article, we provide a brief background on the framework and use of governors and state health officials' emergency powers. We then analyze several key themes, including both the enhancement and restriction of powers, emerging from emergency management and public health legislation introduced in state and territorial legislatures. During the 2020 and 2021 state and territorial legislative sessions, we tracked legislation related to the emergency powers of governors and state health officials. Legislators introduced hundreds of bills impacting these powers, some enhancing and others restricting emergency powers. Enhancements included increasing vaccine access and expanding the pool of eligible medical professions that could administer vaccinations, strengthening public health investigation and enforcement authority for state agencies, and preclusion of local orders by orders at the state level. Restrictions included establishing oversight mechanisms for executive actions, limits on the duration of the emergency, limiting the scope of emergency powers allowed during a declared emergency, and other restraints. By -describing these legislative trends, we hope to inform governors, state health officials, -policymakers, and emergency managers about how changes in the law may impact future public health and emergency response capabilities. Understanding this new legal landscape is critical to effectively preparing for future threats.

The Impact of Host Abundance on the Epidemiology of Tick-Borne Infection.

Tick-borne diseases are an increasing global public health concern due to an expanding geographical range and increase in abundance of tick-borne infectious agents. A potential explanation for the rising impact of tick-borne diseases is an increase in tick abundance which may be linked to an increase in density of the hosts on which they feed. In this study, we develop a model framework to understand the link between host density, tick demography and tick-borne pathogen epidemiology. Our model links the development of specific tick stages to the specific hosts on which they feed. We show that host community composition and host density have an impact on tick population dynamics and that this has a consequent impact on host and tick epidemiological dynamics. A key result is that our model framework can exhibit variation in host infection prevalence for a fixed density of one host type due to changes in density of other host types that support different tick life stages. Our findings suggest that host community composition may play a crucial role in explaining the variation in prevalence of tick-borne infections in hosts observed in the field.

Restoring vertebrate predator populations can provide landscape-scale biological control of established invasive vertebrates: Insights from pine marten recovery in Europe.

Invasive species pose one of the greatest global threats to biodiversity. There has been a long history of importing coevolved natural enemies to act as biological control agents to try to suppress densities of invasive species, with historically limited success and frequent adverse impacts on native biodiversity. Our understanding of the processes and drivers of successful biological control has been focussed on invertebrates and is evidently limited and potentially ill-suited with respect to biological control of vertebrate populations. The restoration of native vertebrate predator populations provides a promising nature-based solution for slowing, halting, or even reversing the spread of some invasive vertebrates over spatial scales relevant to the management of wildlife populations. Here, we first review the growing literature and data from the pine marten-red and grey squirrel system in Europe. We synthesise a multi-decadal dataset to show that the recovery of a native predator has resulted in rapid, landscape-scale declines of an established invasive species. We then use the model system, predator-prey interaction theory, and examples from the literature to develop ecological theory relating to natural biological control in vertebrates and evolutionary processes in native-invasive predator-prey interactions. We find support for the hypotheses that evolutionary naivety of invasive species to native predators and lack of local refuges results in higher predation of naive compared to coevolved prey. We apply lessons learnt from the marten-squirrel model system to examine the plausibility of specific native predator solutions to some of the Earth's most devastating invasive vertebrates. Given the evidence, we conclude that depletion of vertebrate predator populations has increased ecosystem vulnerability to invasions and thus facilitated the spread of invasive species. Therefore, restoration of vertebrate predator populations is an underappreciated, fundamental, nature-based solution to the crisis of invasive species and should be a priority for vertebrate invasive species management globally.

A Predictive Modeling Approach to Support the Overfill Volume Definition of Liquid-in-Vial Drug Products.

Liquid-in-vial drug products are typically overfilled to meet the label claim volume specification while taking into account losses in the container-closure system and withdrawal device. Any overfill volume setting requires justification. The aim of this study was to estimate the overfill volume required for a liquid drug product in a vial using a prediction model. Glass vials sized from 2R to 20R capacity were filled with sorbitol-based aqueous solutions having a viscosity at 20°C ranging from 1 to 40 mPa·s. Viscosity and vial neck diameter were shown to be the main contributors to the hold-up volume of sorbitol-based aqueous solutions in vial and withdrawal syringe. The hold-up volume of various molecules of therapeutic interest was successfully estimated using a model built from sorbitol-based aqueous solutions data. A total variability approach is proposed for estimating the overfill volume of liquid-in-vial drug products, taking into account the product hold-up volume in vial and withdrawal syringe, the filling variability, and the extractable volume test variability. This prediction model could provide a first guess of the fill volume range to be tested to support overfill volume definition.

Application of tetrad testing to the evaluation of blinding strategies for ancillary supplies used in controlled clinical trials.

BACKGROUND/AIMS: Ensuring verum and placebo cannot be visually distinguished from each other is a critical aspect of blinded controlled clinical trials. Our objective was to propose a rational approach to the visual evaluation of placebo matching candidates. METHODS: Verum and placebo samples were prepared in clear clinical ancillary supplies (intravenous bags, syringes and administration lines) covered at different levels using opaque sleeves. Triangle and tetrad tests, two sensory discriminative testing methods widely used in the food industry, were applied to assess visual differences between verum and placebo. RESULTS: Triangle and tetrad test results allowed defining the level of opaque coverage required to ensure blinding for three biological drug molecules of therapeutic interest. While the limited number of panelists did not allow a statistically sound comparison of triangle and tetrad test methodologies, tetrad test has a theoretical higher power than triangle test, meaning fewer panelists are needed to reach the same statistical conclusion. CONCLUSION: Tetrad test offers a rational approach to define a blinding strategy for ancillary supplies used in a controlled clinical trial.

Modelling the transmission and persistence of African swine fever in wild boar in contrasting European scenarios.

African swine fever (ASF) is a severe viral disease that is currently spreading among domestic pigs and wild boar (Sus scrofa) in large areas of Eurasia. Wild boar play a key role in the spread of ASF, yet despite their significance, little is known about the key mechanisms that drive infection transmission and disease persistence. A mathematical model of the wild boar ASF system is developed that captures the observed drop in population density, the peak in infected density and the persistence of the virus observed in ASF outbreaks. The model results provide insight into the key processes that drive the ASF dynamics and show that environmental transmission is a key mechanism determining the severity of an infectious outbreak and that direct frequency dependent transmission and transmission from individuals that survive initial ASF infection but eventually succumb to the disease are key for the long-term persistence of the virus. By considering scenarios representative of Estonia and Spain we show that faster degradation of carcasses in Spain, due to elevated temperature and abundant obligate scavengers, may reduce the severity of the infectious outbreak. Our results also suggest that the higher underlying host density and longer breeding season associated with supplementary feeding leads to a more pronounced epidemic outbreak and persistence of the disease in the long-term. The model is used to assess disease control measures and suggests that a combination of culling and infected carcass removal is the most effective method to eradicate the virus without also eradicating the host population, and that early implementation of these control measures will reduce infection levels whilst maintaining a higher host population density and in some situations prevent ASF from establishing in a population.

The Critical Role of Infectious Disease in Compensatory Population Growth in Response to Culling.

Despite the ubiquity of disease in nature, the role that disease dynamics play in the compensatory growth response to harvesting has been ignored. We use a mathematical approach to show that harvesting can lead to compensatory growth due to a release from disease-induced mortality. Our findings imply that culling in systems that harbor virulent parasites can reduce disease prevalence and increase population density. Our models predict that this compensation occurs for a broad range of infectious disease characteristics unless the disease induces long-lasting immunity in hosts. Our key insight is that a population can be regulated at a similar density by disease or at reduced prevalence by a combination of culling and disease. We illustrate our predictions with a system-specific model representing wild boar tuberculosis infection, parameterized for central Spain, and find significant compensation to culling. Given that few wildlife diseases are likely to induce long-lived immunity, populations with virulent diseases may often be resilient to harvesting.

CD56dim CD16- Natural Killer Cell Profiling in Melanoma Patients Receiving a Cancer Vaccine and Interferon-α.

Natural killer (NK) cells are innate cytotoxic and immunoregulatory lymphocytes that have a central role in anti-tumor immunity and play a critical role in mediating cellular immunity in advanced cancer immunotherapies, such as dendritic cell (DC) vaccines. Our group recently tested a novel recombinant adenovirus-transduced autologous DC-based vaccine that simultaneously induces T cell responses against three melanoma-associated antigens for advanced melanoma patients. Here, we examine the impact of this vaccine as well as the subsequent systemic delivery of high-dose interferon-α2b (HDI) on the circulatory NK cell profile in melanoma patients. At baseline, patient NK cells, particularly those isolated from high-risk patients with no measurable disease, showed altered distribution of CD56dim CD16+ and CD56dim CD16- NK cell subsets, as well as elevated serum levels of immune suppressive MICA, TN5E/CD73 and tactile/CD96, and perforin. Surprisingly, patient NK cells displayed a higher level of activation than those from healthy donors as measured by elevated CD69, NKp44 and CCR7 levels, and enhanced K562 killing. Elevated cytolytic ability strongly correlated with increased representation of CD56dim CD16+ NK cells and amplified CD69 expression on CD56dim CD16+ NK cells. While intradermal DC immunizations did not significantly impact circulatory NK cell activation and distribution profiles, subsequent HDI injections enhanced CD56bright CD16- NK cell numbers when compared to patients that did not receive HDI. Phenotypic analysis of tumor-infiltrating NK cells showed that CD56dim CD16- NK cells are the dominant subset in melanoma tumors. NanoString transcriptomic analysis of melanomas resected at baseline indicated that there was a trend of increased CD56dim NK cell gene signature expression in patients with better clinical response. These data indicate that melanoma patient blood NK cells display elevated activation levels, that intra-dermal DC immunizations did not effectively promote systemic NK cell responses, that systemic HDI administration can modulate NK cell subset distributions and suggest that CD56dim CD16- NK cells are a unique non-cytolytic subset in melanoma patients that may associate with better patient outcome.

Identification of Selective Acyl Sulfonamide-Cycloalkylether Inhibitors of the Voltage-Gated Sodium Channel (NaV) 1.7 with Potent Analgesic Activity.

Herein, we report the discovery and optimization of a series of orally bioavailable acyl sulfonamide NaV1.7 inhibitors that are selective for NaV1.7 over NaV1.5 and highly efficacious in in vivo models of pain and hNaV1.7 target engagement. An analysis of the physicochemical properties of literature NaV1.7 inhibitors suggested that acyl sulfonamides with high fsp3 could overcome some of the pharmacokinetic (PK) and efficacy challenges seen with existing series. Parallel library syntheses lead to the identification of analogue 7, which exhibited moderate potency against NaV1.7 and an acceptable PK profile in rodents, but relatively poor stability in human liver microsomes. Further, design strategy then focused on the optimization of potency against hNaV1.7 and improvement of human metabolic stability, utilizing induced fit docking in our previously disclosed X-ray cocrystal of the NaV1.7 voltage sensing domain. These investigations culminated in the discovery of tool compound 33, one of the most potent and efficacious NaV1.7 inhibitors reported to date.

Understanding the role of eco-evolutionary feedbacks in host-parasite coevolution.

It is widely recognised that eco-evolutionary feedbacks can have important implications for evolution. However, many models of host-parasite coevolution omit eco-evolutionary feedbacks for the sake of simplicity, typically by assuming the population sizes of both species are constant. It is often difficult to determine whether the results of these models are qualitatively robust if eco-evolutionary feedbacks are included. Here, by allowing interspecific encounter probabilities to depend on population densities without otherwise varying the structure of the models, we provide a simple method that can test whether eco-evolutionary feedbacks per se affect evolutionary outcomes. Applying this approach to explicit genetic and quantitative trait models from the literature, our framework shows that qualitative changes to the outcome can be directly attributable to eco-evolutionary feedbacks. For example, shifting the dynamics between stable monomorphism or polymorphism and cycling, as well as changing the nature of the cycles. Our approach, which can be readily applied to many different models of host-parasite coevolution, offers a straightforward method for testing whether eco-evolutionary feedbacks qualitatively change coevolutionary outcomes.

Host-parasite fluctuating selection in the absence of specificity.

Fluctuating selection driven by coevolution between hosts and parasites is important for the generation of host and parasite diversity across space and time. Theory has focused primarily on infection genetics, with highly specific 'matching-allele' frameworks more likely to generate fluctuating selection dynamics (FSD) than 'gene-for-gene' (generalist-specialist) frameworks. However, the environment, ecological feedbacks and life-history characteristics may all play a role in determining when FSD occurs. Here, we develop eco-evolutionary models with explicit ecological dynamics to explore the ecological, epidemiological and host life-history drivers of FSD. Our key result is to demonstrate for the first time, to our knowledge, that specificity between hosts and parasites is not required to generate FSD. Furthermore, highly specific host-parasite interactions produce unstable, less robust stochastic fluctuations in contrast to interactions that lack specificity altogether or those that vary from generalist to specialist, which produce predictable limit cycles. Given the ubiquity of ecological feedbacks and the variation in the nature of specificity in host-parasite interactions, our work emphasizes the underestimated potential for host-parasite coevolution to generate fluctuating selection.

The Angiotensin Converting Enzyme Insertion/Deletion Polymorphism Modifies Exercise-Induced Muscle Metabolism.

OBJECTIVE: A silencer region (I-allele) within intron 16 of the gene for the regulator of vascular perfusion, angiotensin-converting enzyme (ACE), is implicated in phenotypic variation of aerobic fitness and the development of type II diabetes. We hypothesised that the reportedly lower aerobic performance in non-carriers compared to carriers of the ACE I-allele, i.e. ACE-DD vs. ACE-ID/ACE-II genotype, is associated with alterations in activity-induced glucose metabolism and capillarisation in exercise muscle. METHODS: Fifty-three, not-specifically trained Caucasian men carried out a one-legged bout of cycling exercise to exhaustion and/or participated in a marathon, the aim being to identify and validate genotype effects on exercise metabolism. Respiratory exchange ratio (RER), serum glucose and lipid concentration, glycogen, and metabolite content in vastus lateralis muscle based on ultra-performance lipid chromatography-mass spectrometry (UPLC-MS), were assessed before and after the cycling exercise in thirty-three participants. Serum metabolites were measured in forty subjects that completed the marathon. Genotype effects were assessed post-hoc. RESULTS: Cycling exercise reduced muscle glycogen concentration and this tended to be affected by the ACE I-allele (p = 0.09). The ACE-DD genotype showed a lower maximal RER and a selective increase in serum glucose concentration after exercise compared to ACE-ID and ACE-II genotypes (+24% vs. +2% and -3%, respectively). Major metabolites of mitochondrial metabolism (i.e. phosphoenol pyruvate, nicotinamide adenine dinucleotide phosphate, L-Aspartic acid, glutathione) were selectively affected in vastus lateralis muscle by exercise in the ACE-DD genotype. Capillary-to-fibre ratio was 24%-lower in the ACE-DD genotype. Individuals with the ACE-DD genotype demonstrated an abnormal increase in serum glucose to 7.7 mM after the marathon. CONCLUSION: The observations imply a genetically modulated role for ACE in control of glucose import and oxidation in working skeletal muscle. ACE-DD genotypes thereby transit into a pre-diabetic state with exhaustive exercise, which relates to a lowered muscle capillarisation, and deregulation of mitochondria-associated metabolism.

Legal Innovations to Advance a Culture of Health.

As conceptualized by the Robert Wood Johnson Foundation and its partners, a culture of health centers on a society in which health flourishes across all populations and sectors. Law, among other tools, is critical to advancing a culture of health across multiple arenas. In this manuscript, Network for Public Health Law colleagues illustrate how legal innovations at all levels of government contribute to societal health. Examples include modern laws that promote healthy and safe low-income housing, telemedicine reimbursement, paid sick and safe time, healthy food and beverages, reduced smoking rates, child vaccinations, universal pre-k, adolescents' healthy sleep, overdose prevention, and medical-legal partnerships.

Evolution, the loss of diversity and the role of trade-offs.

We investigate how the loss of previously evolved diversity in host resistance to disease is dependent on the complexity of the underlying evolutionary trade-off. Working within the adaptive dynamics framework, using graphical tools (pairwise invasion plots, PIPs; trait evolution plots, TEPs) and algebraic analysis we consider polynomial trade-offs of increasing degree. Our focus is on the evolutionary trajectory of the dimorphic population after it has been attracted to an evolutionary branching point. We show that for sufficiently complex trade-offs (here, polynomials of degree three or higher) the resulting invasion boundaries can form closed 'oval' areas of invadability and strategy coexistence. If no attracting singular strategies exist within this region, then the population is destined to evolve outside of the region of coexistence, resulting in the loss of one strain. In particular, the loss of diversity in this model always occurs in such a way that the remaining strain is not attracted back to the branching point but to an extreme of the trade-off, meaning the diversity is lost forever. We also show similar results for a non-polynomial but complex trade-off, and for a different eco-evolutionary model. Our work further highlights the importance of trade-offs to evolutionary behaviour.

Low bone mineral density linked to colorectal adenomas: a cross-sectional study of a racially diverse population.

BACKGROUND: Epidemiologic studies suggest that lower bone mineral density (BMD) is associated with an increased risk for colorectal adenoma/cancer, especially in postmenopausal women. The aim of this study is to investigate the association between osteopenia and/or osteoporosis and colorectal adenomas in patients from a New York community hospital. METHODS: We performed a cross-sectional observational study on 200 patients who underwent screening colonoscopies and bone density scan (dual-energy X-ray absorptiometry) at Nassau University Medical Center from November 2009 to March 2011. Among these, 83 patients were identified as osteoporosis (T score of -2.5 or below) and 67 were osteopenia (T score between -1.0 and -2.5). Logistic regression model was performed to assess the association between osteopenia and/or osteoporosis and colorectal adenomas. RESULTS: Among the patients with osteopenia and osteoporosis, the mean ages were 59.1 years [standard deviation (SD) =8.9] and 61.5 (SD =8.9), respectively. There were 94.0%, 85.1% and 74.7% women, respectively, in normal BMD, osteopenia and osteoporosis groups. The prevalence of colorectal adenomas was 17.9% and 25.3% in the osteopenia and osteoporosis groups, respectively, and 18.0% in the normal BMD group. After adjustment for potential confounders including age, sex, race, body mass index (BMI), tobacco use, alcohol use, history of diabetes, hypertension, or dyslipidemia, osteoporosis was found to be associated with presence of colorectal adenomas more than 2, compared to the normal BMD group. No significant associations were found for the prevalence, size, and location of adenomas. CONCLUSIONS: Our study suggests that osteoporosis is significantly associated with the presence of multiple colorectal adenomas. Prospective studies with a larger sample size are warranted in the future.

Profiling dose-dependent activation of p53-mediated signaling pathways by chemicals with distinct mechanisms of DNA damage.

As part of a larger effort to provide proof-of-concept in vitro-only risk assessments, we have developed a suite of high-throughput assays for key readouts in the p53 DNA damage response toxicity pathway: double-strand break DNA damage (p-H2AX), permanent chromosomal damage (micronuclei), p53 activation, p53 transcriptional activity, and cell fate (cell cycle arrest, apoptosis, micronuclei). Dose-response studies were performed with these protein and cell fate assays, together with whole genome transcriptomics, for three prototype chemicals: etoposide, quercetin, and methyl methanesulfonate. Data were collected in a human cell line expressing wild-type p53 (HT1080) and results were confirmed in a second p53 competent cell line (HCT 116). At chemical concentrations causing similar increases in p53 protein expression, p53-mediated protein expression and cellular processes showed substantial chemical-specific differences. These chemical-specific differences in the p53 transcriptional response appear to be determined by augmentation of the p53 response by co-regulators. More importantly, dose-response data for each of the chemicals indicate that the p53 transcriptional response does not prevent micronuclei induction at low concentrations. In fact, the no observed effect levels and benchmark doses for micronuclei induction were less than or equal to those for p53-mediated gene transcription regardless of the test chemical, indicating that p53's post-translational responses may be more important than transcriptional activation in the response to low dose DNA damage. This effort demonstrates the process of defining key assays required for a pathway-based, in vitro-only risk assessment, using the p53-mediated DNA damage response pathway as a prototype.

How specificity and epidemiology drive the coevolution of static trait diversity in hosts and parasites.

There is typically considerable variation in the level of infectivity of parasites and the degree of resistance of hosts within populations. This trait variation is critical not only to the evolutionary dynamics but also to the epidemiology, and potentially the control of infectious disease. However, we lack an understanding of the processes that generate and maintain this trait diversity. We examine theoretically how epidemiological feedbacks and the characteristics of the interaction between host types and parasites strains determine the coevolution of host-parasite diversity. The interactions include continuous characterizations of the key phenotypic features of classic gene-for-gene and matching allele models. We show that when there are costs to resistance in the hosts and infectivity in the parasite, epidemiological feedbacks may generate diversity but this is limited to dimorphism, often of extreme types, in a broad range of realistic infection scenarios. For trait polymorphism, there needs to be both specificity of infection between host types and parasite strains as well as incompatibility between particular strains and types. We emphasize that although the high specificity is well known to promote temporal "Red Queen" diversity, it is costs and combinations of hosts and parasites that cannot infect that will promote static trait diversity.

The coevolutionary implications of host tolerance.

Host tolerance to infectious disease, whereby hosts do not directly "fight" parasites but instead ameliorate the damage caused, is an important defense mechanism in both plants and animals. Because tolerance to parasite virulence may lead to higher prevalence of disease in a population, evolutionary theory tells us that while the spread of resistance genes will result in negative frequency dependence and the potential for diversification, the evolution of tolerance is instead likely to result in fixation. However, our understanding of the broader implications of tolerance is limited by a lack of fully coevolutionary theory. Here we examine the coevolution of tolerance across a comprehensive range of classic coevolutionary host-parasite frameworks, including equivalents of gene-for-gene and matching allele and evolutionary invasion models. Our models show that the coevolution of host tolerance and parasite virulence does not lead to the generation and maintenance of diversity through either static polymorphisms or through "Red-queen" cycles. Coevolution of tolerance may however lead to multiple stable states leading to sudden shifts in parasite impacts on host health. More broadly, we emphasize that tolerance may change host-parasite interactions from antagonistic to a form of "apparent commensalism," but may also lead to the evolution of parasites that are highly virulent in nontolerant hosts.