Host Lifespan Research Articles

Influence of multiple infection and relatedness on virulence: disease dynamics in an experimental plant population and its castrating parasite.

The level of parasite virulence, i.e., the decrease in host's fitness due to a pathogen, is expected to depend on several parameters, such as the type of the disease (e.g., castrating or host-killing) and the prevalence of multiple infections. Although these parameters have been extensively studied theoretically, few empirical data are available to validate theoretical predictions. Using the anther smut castrating disease on Silene latifolia caused by Microbotryum lychnidis-dioicae, we studied the dynamics of multiple infections and of different components of virulence (host death, non-recovery and percentage of castrated stems) during the entire lifespan of the host in an experimental population. We monitored the number of fungal genotypes within plants and their relatedness across five years, using microsatellite markers, as well as the rates of recovery and host death in the population. The mean relatedness among genotypes within plants remained at a high level throughout the entire host lifespan despite the dynamics of the disease, with recurrent new infections. Recovery was lower for plants with multiple infections compared to plants infected by a single genotype. As expected for castrating parasites, M. lychnidis-dioicae did not increase host mortality. Mortality varied across years but was generally lower for plants that had been diseased the preceding year. This is one of the few studies to have empirically verified theoretical expectations for castrating parasites, and to show particularly i) that castrated hosts live longer, suggesting that parasites can redirect resources normally used in reproduction to increase host lifespan, lengthening their transmission phase, and ii) that multiple infections increase virulence, here in terms of non-recovery and host castration.

Parasitic castration byXenos vesparumdepends on host gender

Host castration represents a mechanism used by parasites to exploit energy resources from their hosts by interfering with their reproductive development or to extend host lifespan by removing risks associated with reproductive activity. One of the most intriguing groups of parasitic castrators is represented by the insects belonging to the order Strepsiptera. The macroparasite Xenos vesparum can produce dramatic phenotypic alterations in its host, the paper wasp Polistes dominula. Parasitized female wasps have undeveloped ovaries and desert the colony without performing any social task. However, very little attention has been given to the parasitic impact of X. vesparum on the male phenotype. Here, we investigated the effects of this parasite on the sexual behaviour and the morpho-physiology of P. dominula males. We found that, differently from female wasps, parasitized males are not heavily affected by Xenos: they maintain their sexual behaviour and ability to discriminate between female castes. Furthermore, the structure of their reproductive apparatus is not compromised by the parasite. We think that our results, demonstrating that the definition of X. vesparum as a parasitoid does not apply to infected males of P. dominula, provide a new perspective to discuss and maybe reconsider the traditional view of strepsipteran parasites.

Diagnosis and treatment of ulcerative colitis with cytomegalovirus infection: importance of controlling mucosal inflammation to prevent cytomegalovirus reactivation.

Human cytomegalovirus (HCMV) is a member of the herpesvirus family. HCMV infection persists throughout the host lifespan in a latent state following primary infection. The ability of HCMV to escape control by the host immune system and its resulting reactivation suggests the importance of ongoing immune surveillance in the prevention of HCMV reactivation. HCMV is a common cause of opportunistic infection that causes severe and fatal disease in immune-compromised individuals. In inflammatory bowel disease patients, particularly those with ulcerative colitis (UC), HCMV is often reactivated because these patients are frequently treated with immunosuppressive agents. This reactivation exacerbates colitis. Additionally, HCMV infection can induce severe colitis, even in patients with UC who have never been treated with immunosuppressive agents. However, the role of HCMV in colonic inflammation in patients with UC remains unclear. Here, we present previous and current clinical data on the diagnosis and treatment of HCMV infection in UC. Additionally, our experimental data from a newly established mouse model mimicking UC with concomitant CMV infection clearly demonstrate that inflammation could result in the exacerbation of UC disease activity with induction of HCMV reactivation. In summary, optimal control of colonic inflammation should be achieved in UC patients who are refractory to conventional immunosuppressive therapies and are positive for HCMV.

Wolbachia variants induce differential protection to viruses in Drosophila melanogaster: a phenotypic and phylogenomic analysis.

Wolbachia are intracellular bacterial symbionts that are able to protect various insect hosts from viral infections. This tripartite interaction was initially described in Drosophila melanogaster carrying wMel, its natural Wolbachia strain. wMel has been shown to be genetically polymorphic and there has been a recent change in variant frequencies in natural populations. We have compared the antiviral protection conferred by different wMel variants, their titres and influence on host longevity, in a genetically identical D. melanogaster host. The phenotypes cluster the variants into two groups — wMelCS-like and wMel-like. wMelCS-like variants give stronger protection against Drosophila C virus and Flock House virus, reach higher titres and often shorten the host lifespan. We have sequenced and assembled the genomes of these Wolbachia, and shown that the two phenotypic groups are two monophyletic groups. We have also analysed a virulent and over-replicating variant, wMelPop, which protects D. melanogaster even better than the closely related wMelCS. We have found that a ∼21 kb region of the genome, encoding eight genes, is amplified seven times in wMelPop and may be the cause of its phenotypes. Our results indicate that the more protective wMelCS-like variants, which sometimes have a cost, were replaced by the less protective but more benign wMel-like variants. This has resulted in a recent reduction in virus resistance in D. melanogaster in natural populations worldwide. Our work helps to understand the natural variation in wMel and its evolutionary dynamics, and inform the use of Wolbachia in arthropod-borne disease control.

Commensals, probiotics and pathogens in theCaenorhabditis elegansmodel

Caenorhabditis elegans is a useful model host for a wide variety of microorganisms that have implications for human health. Recent surveys of mammalian and metazoan microbiota demonstrate the often profound effects of gut commensal bacteria on host lifespan, health and development. Work using C. elegans has revealed the surprising extent to which bacterial metabolism can interact with host pathways with examples from Escherichia coli folate metabolism and Bacillus subtilis nitric oxide synthesis. The C. elegans model has also shed light on the mechanisms by which probiotic bacteria influence lifespan.

Effect of high temperature on survival of Drosophila melanogaster infected with pathogenic strain of Wolbachia bacteria

The pathogenic Wolbachia strain wMelPop is detected in the central nervous system, muscles, and retina of Drosophila melanogaster. It reduces the host lifespan by a factor of two. This fact makes it promising for the control of insect pests and vectors of human diseases. Any symbiotic association is exposed to various stress factors: starvation, heat, cold and etc., which affect the symbiont interaction significantly. This study considers the influence of low (16°C) and high (29°C) temperature on the survival and lifespan of D. melanogaster females infected with the Wolbachia strain wMelPop. The ultrastructure of brain cells and distribution of the bacteria in this cells were studied. On day 7 of exposure to high temperature, electron-dense bodies occur in brain cells of the flies, resembling degrading bacteria. The amount of these bodies increases dramatically by day 13 of incubation at 29°C. On the basis of population and EM analysis, we identified the critical period (7–13 days) of high temperature influence, which dramatically decreases the survival of D. melanogaster.

Optimal immune defence in the light of variation in lifespan

There is good evidence for costs to both the uses of immune defences and their development and maintenance. The optimal defence will be a balance of these costs with the risk of infection and the virulence of the disease. It is therefore clear that the life-history characteristics of both host and parasite will impact the optimal level of defence, and that this may in part explain the variation in immune defence against different pathogens and parasites. For instance, it has traditionally been suggested that long-lived hosts should invest in immune memory. Ecological evolutionary theory can be used to examine in detail how different host characteristics will affect the optimal immune response that evolves. Here, we review theoretical studies on the impact of host lifespan on various immune defence characteristics including acquired immunity and highlight the importance of population-level epidemiological feedbacks on the outcome. In particular, we discuss when longer-lived hosts may invest less in acquired immunity and develop new theory to highlight the importance of the mechanism of host population regulation to the outcome. We finish by discussing where more theory is needed and how comparative and experimental studies may test the theory.

What drives population-level effects of parasites? Meta-analysis meets life-history

Parasites are considered drivers of population regulation in some species; unfortunately the research leading to this hypothesis has all been conducted on managed populations. Still unclear is whether parasites have population-level effects in truly wild populations and what life-history traits drive observed virulence. A meta-analysis of 38 data sets where parasite loads were altered on non-domesticated, free-ranging wild vertebrate hosts (31 birds, 6 mammals, 1 fish) was conducted and found a strong negative effect of parasites at the population-level (g=0.49). Among different categories of response variables measured, parasites significantly affected clutch size, hatching success, young produced, and survival, but not overall breeding success. A meta-regression of effect sizes and life-history traits thought to determine parasite virulence indicate that average host life span may be the single most important driver for understanding the effects of parasites. Further studies, especially of long-lived hosts, are necessary to prove this hypothesis.

Diversity and function of bacterial microbiota in the mosquito holobiont

Mosquitoes (Diptera: Culicidae) have been shown to host diverse bacterial communities that vary depending on the sex of the mosquito, the developmental stage, and ecological factors. Some studies have suggested a potential role of microbiota in the nutritional, developmental and reproductive biology of mosquitoes. Here, we present a review of the diversity and functions of mosquito-associated bacteria across multiple variation factors, emphasizing recent findings. Mosquito microbiota is considered in the context of possible extended phenotypes conferred on the insect hosts that allow niche diversification and rapid adaptive evolution in other insects. These kinds of observations have prompted the recent development of new mosquito control methods based on the use of symbiotically-modified mosquitoes to interfere with pathogen transmission or reduce the host life span and reproduction. New opportunities for exploiting bacterial function for vector control are highlighted.

Antitumor and antioxidant status of Terminalia catappa against Ehrlich ascites carcinoma in Swiss albino mice.

Objective:The present study was undertaken to evaluate the antitumor and antioxidant status of ethanol extract of Terminalia catappa leaves against Ehrlich ascites carcinoma (EAC) in Swiss albino mice.Materials and Methods:The leaves powder was extracted with Soxhlet apparatus and subjected to hot continuous percolation using ethanol (95% v/v). Tumor bearing animals was treated with 50 and 200 mg/kg of ethanol extract. EAC induced in mice by intraperitoneal injection of EAC cells 1 × 106 cells/mice. The study was assed using life span of EAC-bearing hosts, hematological parameters, volume of solid tumor mass and status of antioxidant enzymes such as lipid peroxidation (LPO), reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) activities. Total phenolics and flavonoids contents from the leaves extract were also determined.Results:Total phenolics and flavonoids contents from the leaves extract were found 354.02 and 51.67 mg/g extract. Oral administration of ethanol extract of T. catappa (50 and 200 mg/kg) increased the life span (27.82% and 60.59%), increased peritoneal cell count (8.85 ± 0.20 and 10.37 ± 0.26) and significantly decreased solid tumor mass (1.16 ± 0.14 cm2) at 200 mg/kg as compared with EAC-tumor bearing mice (P < 0.01). Hematological profile including red blood cell count, white blood cell count, hemoglobin (11.91 ± 0.47 % g) and protein estimation were found to be nearly normal levels in extract-treated mice compared with tumor bearing control mice. Treatment with T. catappa significantly decreased levels of LPO and GSH, and increased levels of SOD and CAT activity (P < 0.01).Conclusion:T. catappa exhibited antitumor effect by modulating LPO and augmenting antioxidant defense systems in EAC bearing mice. The phenolic and flavonoid components in this extract may be responsible for antitumor activity.

VACCINATION AND REDUCED COHORT DURATION CAN DRIVE VIRULENCE EVOLUTION: MAREK’S DISEASE VIRUS AND INDUSTRIALIZED AGRICULTURE

Marek's disease virus (MDV), a commercially important disease of poultry, has become substantially more virulent over the last 60 years. This evolution was presumably a consequence of changes in virus ecology associated with the intensification of the poultry industry. Here, we assess whether vaccination or reduced host life span could have generated natural selection, which favored more virulent strains. Using previously published experimental data, we estimated viral fitness under a range of cohort durations and vaccine treatments on broiler farms. We found that viral fitness maximized at intermediate virulence, as a result of a trade-off between virulence and transmission previously reported. Our results suggest that vaccination, acting on this trade-off, could have led to the evolution of increased virulence. By keeping the host alive, vaccination prolongs infectious periods of virulent strains. Improvements in host genetics and nutrition, which reduced broiler life spans below 50 days, could have also increased the virulence of the circulating MDV strains because shortened cohort duration reduces the impact of host death on viral fitness. These results illustrate the dramatic impact anthropogenic change can potentially have on pathogen virulence.

A laboratory study on the effect of Paraiotonchium autumnale parasitism on the longevity of Musca autumnalis

Paraiotonchium autumnale (Nickle) (Tylenchida: Iotonchiidae) causes parasitic sterilization in female Musca autumnalis DeGeer (Diptera: Muscidae). In addition to sterilization, P. autumnale causes physiological and behavioural changes within its host. However, there have been no records of reduced host lifespan in this system. Studies were conducted in 2009 and 2010 with wild M. autumnalis collected as larvae from cow dung pats from Browns Valley, California, USA. Field-collected larvae were reared to adulthood and flies of the same eclosion dates were caged together, regardless of whether or not they were parasitized. Dead flies were collected daily, and parasitism status was confirmed by dissection. Due to the very different effects of P. autumnale-parasitism on male versus female face flies, flies were analysed separately by sex. Kaplan-Meier analysis revealed a non-significant difference in longevity between non-parasitized and parasitized flies for female and male flies in 2009. In 2010, however, significant differences (P < 0·05) were found between parasitized and non-parasitized female and male flies. In 2010, the median time to death for non-parasitized female flies was 20 days and 15 days for parasitized females. The 2010 median survival time for non-parasitized male flies was 33 days and 15 days for parasitized males. This is a parasite-mediated cost to the host that has not been recorded previously. Based on our results and results from another published study we suggest that the potential for sterilizing parasites to alter host longevity is condition dependent.

Chronic contamination decreases disease spread: aDaphnia–fungus–copper case study

Chemical contamination and disease outbreaks have increased in many ecosystems. However, connecting pollution to disease spread remains difficult, in part, because contaminants can simultaneously exert direct and multi-generational effects on several host and parasite traits. To address these challenges, we parametrized a model using a zooplankton-fungus-copper system. In individual-level assays, we considered three sublethal contamination scenarios: no contamination, single-generation contamination (hosts and parasites exposed only during the assays) and multi-generational contamination (hosts and parasites exposed for several generations prior to and during the assays). Contamination boosted transmission by increasing contact of hosts with parasites. However, it diminished parasite reproduction by reducing the size and lifespan of infected hosts. Multi-generational contamination further reduced parasite reproduction. The parametrized model predicted that a single generation of contamination would enhance disease spread (via enhanced transmission), whereas multi-generational contamination would inhibit epidemics relative to unpolluted conditions (through greatly depressed parasite reproduction). In a population-level experiment, multi-generational contamination reduced the size of experimental epidemics but did not affect Daphnia populations without disease. This result highlights the importance of multi-generational effects for disease dynamics. Such integration of models with experiments can provide predictive power for disease problems in contaminated environments.

Feminizing Wolbachia: a transcriptomics approach with insights on the immune response genes in Armadillidium vulgare

BackgroundWolbachia are vertically transmitted bacteria known to be the most widespread endosymbiont in arthropods. They induce various alterations of the reproduction of their host, including feminization of genetic males in isopod crustaceans. In the pill bug Armadillidium vulgare, the presence of Wolbachia is also associated with detrimental effects on host fertility and lifespan. Deleterious effects have been demonstrated on hemocyte density, phenoloxidase activity, and natural hemolymph septicemia, suggesting that infected individuals could have defective immune capacities. Since nothing is known about the molecular mechanisms involved in Wolbachia-A. vulgare interactions and its secondary immunocompetence modulation, we developed a transcriptomics strategy and compared A. vulgare gene expression between Wolbachia-infected animals (i.e., “symbiotic” animals) and uninfected ones (i.e., “asymbiotic” animals) as well as between animals challenged or not challenged by a pathogenic bacteria.ResultsSince very little genetic data is available on A. vulgare, we produced several EST libraries and generated a total of 28 606 ESTs. Analyses of these ESTs revealed that immune processes were over-represented in most experimental conditions (responses to a symbiont and to a pathogen). Considering canonical crustacean immune pathways, these genes encode antimicrobial peptides or are involved in pathogen recognition, detoxification, and autophagy. By RT-qPCR, we demonstrated a general trend towards gene under-expression in symbiotic whole animals and ovaries whereas the same gene set tends to be over-expressed in symbiotic immune tissues.ConclusionThis study allowed us to generate the first reference transcriptome ever obtained in the Isopoda group and to identify genes involved in the major known crustacean immune pathways encompassing cellular and humoral responses. Expression of immune-related genes revealed a modulation of host immunity when females are infected by Wolbachia, including in ovaries, the crucial tissue for the Wolbachia route of transmission.

Emerging and re-emerging viruses: A global challenge illustrated by Chikungunya virus outbreaks

In recent decades, the issue of emerging and re-emerging infectious diseases, especially those related to viruses, has become an increasingly important area of concern in public health. It is of significance to anticipate future epidemics by accumulating knowledge through appropriate research and by monitoring their emergence using indicators from different sources. The objective is to alert and respond effectively in order to reduce the adverse impact on the general populations. Most of the emerging pathogens in humans originate from known zoonosis. These pathogens have been engaged in long-standing and highly successful interactions with their hosts since their origins are exquisitely adapted to host parasitism. They developed strategies aimed at: (1) maximizing invasion rate; (2) selecting host traits that can reduce their impact on host life span and fertility; (3) ensuring timely replication and survival both within host and between hosts; and (4) facilitating reliable transmission to progeny. In this context, Arboviruses (or ARthropod-BOrne viruses), will represent with certainty a threat for the coming century. The unprecedented epidemic of Chikungunya virus which occurred between 2005 and 2006 in the French Reunion Island in the Indian Ocean, followed by several outbreaks in other parts of the world, such as India and Southern Europe, has attracted the attention of medical and state authorities about the risks linked to this re-emerging mosquito-borne virus. This is an excellent model to illustrate the issues we are facing today and to improve how to respond tomorrow.

Antitumour activity of Terminalia arjuna leaf against Ehrlich ascites carcinoma in mice

Terminalia arjuna Roxb. (Combretaceae), commonly known as ‘Arjuna’, is a large tree occurring throughout the Indian peninsula. This study was undertaken to evaluate the methanol extract of T. arjuna leaf (META) for antitumour activity against Ehrlich ascites carcinoma (EAC) in Swiss albino mice. Twenty-four hours after intraperitonial inoculation of tumour (EAC) cells in mice, META was administered at 100 and 200 mg kg−1 body weights for 9 consecutive days. On day 10, half of the mice were sacrificed and the rest kept alive for an assessment of the increase in life span. The antitumour effect of META was assessed by evaluating tumour volume, tumour weight, viable and non-viable tumour cell counts, median survival time and increase in life span of EAC-bearing hosts. Haematological profiles were estimated. META showed a significant (p<0.001) decrease in tumour volume, tumour weight and viable cell count, and also increased the life span of EAC-bearing mice. Haematological profiles were significantly (p<0.001) restored to normal levels in META-treated mice compared to the EAC control. Therefore, from this study, it can be concluded that T. arjuna leaf exhibited remarkable antitumour activity against EAC in Swiss mice.

ANTITUMOR ACTIVITY OF CAPPARIS SEPIARIA ON EHRLICH ASCITES CARCINOMA IN MICE

The methanol extract of Capparis Sepiaria (Capparaceae) bark (MECS) were evaluated for antitumor activity against Ehrlich ascites carcinoma (EAC)-bearing Swiss albino mice. The extract was administered at the doses of 200, and 400 mg/kg body weight per day for 14 days after 24 h of tumor inoculation. After the last dose and 18 h fasting, the mice were sacrificed. The present study deals with the effect of MECS on the growth of transplantable murine tumor, life span of EAC-bearing hosts and hematological profile MECS caused significant (P < 0.01) decrease in tumor volume, packed cell volume, and viable cell count; and it prolonged the life span of EAC-tumor bearing mice. Hematological profile converted to more or less normal levels in extract-treated mice. The results indicate that MECS exhibited significant antitumor activity in EAC-bearing mice.

Antioxidant and Anticarcinogenic Effects of Methanolic Extract and Volatile Oil of Fennel Seeds (Foeniculum vulgare)

The present study evaluated the efficacy of fennel seed methanolic extract (FSME) for its antioxidant, cytotoxic, and antitumor activities and for its capacity to serve as a nontoxic radioprotector in Swiss albino mice. We also assessed the natural antioxidant compounds of FSME for use in industrial application. Cytotoxic activity of FSME was evaluated in a mouse model of Ehrlich ascites carcinoma (EAC) and on different types of human cell lines in vitro. The safety and optimum dose of FSME were determined. FSME, 100 mg/kg, was injected intraperitoneally into mice bearing EAC before the mice were exposed to three 2-Gy doses of gamma irradiation. After 30 days, mice were fasted for 18 hours and then sacrificed to observe the lifespan of EAC-bearing hosts. Malondialdehyde (MDA), catalase activity, glutathione content, and total protein in serum, liver tissue, and ascitic fluid were determined. Iron, total iron-binding capacity, transferrin, and ferritin were also evaluated in serum. The data showed the presence of different types of compounds in FSME, such as flavonoids, terpenoids, alkaloids, phenols, and sterols; estragole (71.099%) was the predominant alcohol, gallic acid was the phenolic compound (18.895%), and L-limonene was the most prevalent monoterpene hydrocarbon (11.967%). The mean±standard deviation 50% inhibitory concentrations were 50±0.03 μg/mL for the MCF7 breast cancer cell line and 48±022 μg/mL for the Hepg-2 liver cancer cell line. The significant increase in MDA levels and the significant decrease in catalase activity and glutathione content in liver and tumor tissue in mice bearing EAC were ameliorated after FSME administration. In contrast, total protein content was increased in ascitic fluid. Serum iron was inversely proportional to the levels of ferritin and transferrin and total iron-binding capacity. Administration of FSME before irradiation exerted a cytoprotective effect against gamma irradiation, as manifested by a restoration of the MDA level, catalase activity, and GSH content to near-normal levels. In conclusion, FSME may have remarkable anticancer potential against a breast cancer cell line (MCF7) and liver cancer cell line (Hepg-2). It also showed strong free radical-scavenging activity (100%). Thus, FSME may reduce oxidative stress and protect mouse cells from damage caused by reactive oxygen species. In addition, it could be used as a safe, effective, and easily accessible source of natural antioxidants to improve the oxidative stability of fatty foods during storage. FSME also exhibited an antitumor effect by modulating lipid peroxidation and augmenting the antioxidant defense system in EAC-bearing mice with or without exposure to radiation.

Evaluation of probiotic characteristics of newly isolated Lactobacillus spp.: Immune modulation and longevity

In the current study, the probiotic potential of approximately 350 strains of lactic acid bacteria isolated from Korean infant feces and Kimchi was investigated. Common probiotic properties of the bacterial strains, such as acid tolerance, bile tolerance and adhesion to human intestinal epithelial cells (HT-29 cells), were examined. Some strains were found to have immune modulatory and antimicrobial properties. Antagonistic activity against a panel of pathogenic bacteria was found to be strain dependent. To evaluate the immune modulatory activity of the strains, lymphocyte interferon (IFN)-γ secretion was determined in conjunction with cell proliferation. Some strains of Lactobacillus gasseri, L. fermentum and L. plantarum exhibited increased IFN-γ levels and lymphocyte proliferation. To evaluate the effects of these immune modulating lactobacilli on host life span, Caenorhabditis elegans was used as an in vivo model. Nematodes that were supplied heat-killed lactobacilli as a food source exhibited obvious differences in life span compared with those fed Escherichia coli OP50. The mean life span (determined as mean percent survival) of worms fed L. plantarum CJLP133 and L. fermentum LA12 was 13.89% and 13.69% greater, respectively, than that of control nematodes after 21 days (P=0.036 and 0.043, respectively). In addition, some of safety profiles, including hemolytic type, gelatin hydration and degradation of urea, were found to be positive. These newly identified lactobacilli hold promise for use as probiotic agents, feed additives and/or in food applications.

Modeling routes of chronic wasting disease transmission: environmental prion persistence promotes deer population decline and extinction.

Chronic wasting disease (CWD) is a fatal disease of deer, elk, and moose transmitted through direct, animal-to-animal contact, and indirectly, via environmental contamination. Considerable attention has been paid to modeling direct transmission, but despite the fact that CWD prions can remain infectious in the environment for years, relatively little information exists about the potential effects of indirect transmission on CWD dynamics. In the present study, we use simulation models to demonstrate how indirect transmission and the duration of environmental prion persistence may affect epidemics of CWD and populations of North American deer. Existing data from Colorado, Wyoming, and Wisconsin's CWD epidemics were used to define plausible short-term outcomes and associated parameter spaces. Resulting long-term outcomes range from relatively low disease prevalence and limited host-population decline to host-population collapse and extinction. Our models suggest that disease prevalence and the severity of population decline is driven by the duration that prions remain infectious in the environment. Despite relatively low epidemic growth rates, the basic reproductive number, R 0, may be much larger than expected under the direct-transmission paradigm because the infectious period can vastly exceed the host's life span. High prion persistence is expected to lead to an increasing environmental pool of prions during the early phases (i.e. approximately during the first 50 years) of the epidemic. As a consequence, over this period of time, disease dynamics will become more heavily influenced by indirect transmission, which may explain some of the observed regional differences in age and sex-specific disease patterns. This suggests management interventions, such as culling or vaccination, will become increasingly less effective as CWD epidemics progress.