Mechanisms of Pathogenesis, Infective Dose and Virulence in Human Parasites

The number of pathogens that are required to infect a host, termed infective dose, varies dramatically across pathogen species. It has recently been predicted that infective dose will depend upon the mode of action of the molecules that pathogens use to facilitate their infection. Specifically, pathogens which use locally acting molecules will require a lower infective dose than pathogens that use distantly acting molecules. Furthermore, it has also been predicted that pathogens with distantly acting immune modulators may be more virulent because they have a large number of cells in the inoculums, which will cause more harm to host cells. We formally test these predictions for the first time using data on 43 different human pathogens from a range of taxonomic groups with diverse life-histories. We found that pathogens using local action do have lower infective doses, but are not less virulent than those using distant action. Instead, we found that virulence was negatively correlated with infective dose, and higher in pathogens infecting wounded skin, compared with those ingested or inhaled. More generally, our results show that broad-scale comparative analyses can explain variation in parasite traits such as infective dose and virulence, whilst highlighting the importance of mechanistic details.     

Intensive Farming: Evolutionary Implications for Parasites and Pathogens

An increasing number of scientists have recently raised concerns about the threat posed by human intervention on the evolution of parasites and disease agents. New parasites (including pathogens) keep emerging and parasites which previously were considered to be 'under control' are re-emerging, sometimes in highly virulent forms. This re-emergence may be parasite evolution, driven by human activity, including ecological changes related to modern agricultural practices. Intensive farming creates conditions for parasite growth and transmission drastically different from what parasites experience in wild host populations and may therefore alter selection on various traits, such as life-history traits and virulence. Although recent epidemic outbreaks highlight the risks associated with intensive farming practices, most work has focused on reducing the short-term economic losses imposed by parasites, such as application of chemotherapy. Most of the research on parasite evolution has been conducted using laboratory model systems, often unrelated to economically important systems. Here, we review the possible evolutionary consequences of intensive farming by relating current knowledge of the evolution of parasite life-history and virulence with specific conditions experienced by parasites on farms. We show that intensive farming practices are likely to select for fast-growing, early-transmitted, and hence probably more virulent parasites. As an illustration, we consider the case of the fish farming industry, a branch of intensive farming which has dramatically expanded recently and present evidence that supports the idea that intensive farming conditions increase parasite virulence. We suggest that more studies should focus on the impact of intensive farming on parasite evolution in order to build currently lacking, but necessary bridges between academia and decision-makers.     

Parasitism as a constraint on the rate of life-history evolution

There are a number of ways in which a host can respond in evolutionary time to reductions in survival and reproduction due to a virulent parasite. These include evolving physiological morphological, or behavioural mechanisms of resistance to infection (or to proliferation, once infection has occurred). But a more unexpected tactic is also possible. This is for hosts to reproduce (slightly) sooner when in the presence of a virulent parasite as compared to when the parasite is less virulent or absent. As such, hosts which reproduce younger may be at a selective advantage, since they can both evade parasitism in time and, even when parasitised, can reduce the likely impact of the parasite on survival and reproductive success. We employ a simple mathematical model to propose that parasites and pathogens can act as important agents in the evolution of the timing of reproduction and associated life-history characters (e.g. body size). Once established in a semelparous host population, evolutionary increases in parasite virulence should result in the evolution of shorter lived hosts; whereas the evolution of less virulent forms of the parasite should be accompanied by the evolution of longer lived hosts. We argue that in the presence of a sufficiently virulent parasite the evolution of longer pre-reproductive life-spans should require the previous or concomitant evolution of morphological, behavioural or physiological resistance to parasitic infection and proliferation.     

Evolution of airborne infectious diseases according to changes in characteristics of the host population

The authors predicted evolutionary changes in airborne infectious diseases according to changes in the characteristics of the host population. The predictions were based upon a mathematical model of infectious diseases and the validity of the predictions was verified against the history of man and pathogens. The feature of this model is that it involves a density of pathogens in the environment as an additional variable which can be regarded as more suitable to airborne infectious diseases. In spite of this modification, this study reached a similar conclusion to the threshold density theory: that is, susceptible host density in the absence of the pathogen must be larger than that in the presence of the pathogen, for the pathogen to be persistent. Moreover the authors concluded that one type of pathogen cannot be replaced by another type of pathogen as long as the susceptible host density of the former type is the mininum one. The predictions were considered to be valid for a wide range of infectous diseases. Making use of these principles, the authors predicted that the variety of infectious diseases should increase as host density increases and that pathogens should evolve to be less virulent as the host life-span increases. The finalidea discussed is whether or nor the history of man and pathogen can be verified by the predictions.     

Ranging patterns and parasitism in primates

Competing hypotheses exist concerning the influence of ranging patterns on parasitism. More intensive use of a home range could result in greater exposure to infectious agents that accumulate in the soil. Alternatively, when more intensive ranging is associated with territorial defence, this could decrease home range overlap and produce lower levels of parasitism. We tested these hypotheses using phylogenetic comparative methods and parasite richness data for 119 primate species. Helminth richness increased with the defensibility index, a quantitative measure of home range use that correlates with the degree of territoriality in primates. This association was independent of other host traits that influence parasite richness in primates. Results involving non-vector transmitted helminths produced the most significant results, suggesting that the relationship between territorial behaviour and parasitism is driven by accumulation of parasites in defended home ranges. In addition, costs associated with greater ranging could increase susceptibility to infectious agents.     

Depression of host population abundance by direct life cycle macroparasites

Simple population models are used to identify the factors which determine the degree to which direct life cycle macroparasites depress their host populations from disease free equilibrium levels. The impact of parasitic infection is shown to be related to a range of biological characteristics of the host and parasite. The most important theoretical predictions are as follows: (1) certain threshold conditions must be satisfied (concerning host density and the rates of host and parasite reproduction) to enable the pathogen to persist with the host population; (2) parasites of low to intermediate pathogenicity are the most effective suppressors of host population growth while highly pathogenic species are likely to cause their own extinction but not that of their host; (3) the statistical distribution of parasite numbers per host has a major influence on the degree of host population depression; (4) host population with high reproductive potential are better able to withstand the impact of pathogens; (5) density dependent constraints on parasite population growth within, or on the host, whether induced by competition for finite resources or immunological attack, restrict the regulatory influence of the parasites; (6) parasites with the ability to multiply directly within the host are the most effective suppressors of host population growth and may cause the extinction of the host and hence themselves.Theoretical predictions are discussed in light of (a) the use of pathogens as biological control agents of pest species and (b) the effects of disease control on host population growth.     

台湾的微生物防治

化学防治自1940年代后虽然为农业和医界害虫防治带来许多的经济效益。相对的。因其对非标的生物(有益生物,野生生物．家畜及农场操作人员)有毒害作用．及其残留量(residue)可在空气中．土壤,水中发现．又可经作物带给消费。也使我们得考虑其安全性．     

Influencing random transmission is a neutral character in hosts

This study introduces an individual-based model on a host-parasite assemblage to investigate whether hosts are necessarily selected for obstructing the transmission of virulent parasites to conspecifics. Contrary to the widespread notion, a host's ability to influence parasite transmission within the host population is a neutral character provided that parasite transmission routes are random, with no reference to genetic relatedness. Due to a lack of selection pressure under such circumstances, hosts may fail to evolve counteradaptations against manipulations by parasites to enhance transmission. However, vertically biased transmission (biased toward kin) selects hosts for a decrease of parasite transmission, while it is also known to select parasites to decrease virulence. Horizontally biased transmission routes (biased toward nonrelated conspecifics) select hosts to increase parasite transmission. In this case, their interests coincide with that of their virulent parasites in enhancing transmission to conspecifics. This finding yields the predictions that hosts infected by virulent pathogens, but unable to recover from disease, should be prone to emigrate from their natal territories and also to enhance transmission at a distance from their natal ranges. These results may considerably improve our understanding of the epidemiology of contagious pathogens and the evolution of social and sexual behavior in host species.     

Ecological and evolutionary principles in immunology

Experimental immunology has given rise to detailed insights into how immune cells react to infectious agents and fight pathogens. At the same time, however, the interplay between infectious agents and immune responses can be viewed as an ecological system in vivo . This is characterized by complex interactions between species of immune cells and populations of pathogens. This review discusses how an understanding of the immune system can be aided by the application of ecological and evolutionary principles: competition, predation, and the evolution of viruses in vivo . These concepts can shed light onto important immunological concepts such as the correlates of efficient virus control, immunodominance, the relationship between viral evolution and the development of pathology, as well as the ability of the immune system to control immunosuppressive infections.     

Entobdella soleae--pointers to the future

The biology of the monogenean skin parasite Entobdella soleae and its relationship with its host, the common sole (Solea solea), are probably better known than those of any other monogeneans. The author describes his early involvement with this parasite and the special features of parasite and host that make this relationship so suitable for parasitological studies. Aspects of the biology of E. soleae that have been investigated are briefly mentioned, but most of the paper is concerned with areas of the parasite's biology that remain a challenge to determine. Unresolved areas are as follows: (1) the identity of the factor (or factors) in host skin mucus that stimulates hatching of the parasite's eggs; (2) whether or not the larvae of the parasite are attracted to their host; (3) the nature of factors controlling the contrasting behaviour of adult parasites on the upper and lower surfaces of the host; (4) how nutrients are supplied to the remote regions of the haptor; (5) whether the host has any control via its immune system over parasite invasion success and survival; (6) how the parasite copes with the migratory habits of some sole populations, assuming that such populations are infested with the parasite. The intimacy of this parasite/host relationship is its most remarkable feature, the reflection of which, not surprisingly, is the greatly restricted host range of the parasite. E. soleae has been reported from only three host species, all highly specialised bottom-dwelling members of Solea. It is all the more surprising that relatives of E. soleae, such as Neobenedenia melleni, retain the ability to parasitise an enormous range of hosts. How this versatility is achieved remains to be seen.     

The spread of fecally transmitted parasites in socially-structured populations

Mammals are infected by a wide array of gastrointestinal parasites, including parasites that also infect humans and domesticated animals. Many of these parasites are acquired through contact with infectious stages present in soil, feces or vegetation, suggesting that ranging behavior will have a major impact on their spread. We developed an individual-based spatial simulation model to investigate how range use intensity, home range overlap, and defecation rate impact the spread of fecally transmitted parasites in a population composed of social groups (i.e., a socially structured population). We also investigated the effects of epidemiological parameters involving host and parasite mortality rates, transmissibility, disease-related mortality, and group size. The model was spatially explicit and involved the spillover of a gastrointestinal parasite from a reservoir population along the edge of a simulated reserve, which was designed to mimic the introduction pathogens into protected areas. Animals ranged randomly within a "core" area, with biased movement toward the range center when outside the core. We systematically varied model parameters using a Latin hypercube sampling design. Analyses of simulation output revealed a strong positive association between range use intensity and the prevalence of infection. Moreover, the effects of range use intensity were similar in magnitude to effects of group size, mortality rates, and the per-contact probability of transmission. Defecation rate covaried positively with gastrointestinal parasite prevalence. Greater home range overlap had no positive effects on prevalence, with a smaller core resulting in less range overlap yet more intensive use of the home range and higher prevalence. Collectively, our results reveal that parasites with fecal-oral transmission spread effectively in socially structured populations. Future application should focus on parameterizing the model with empirically derived ranging behavior for different species or populations and data on transmission characteristics of different infectious organisms.     

Vaccination against the major infectious diseases

The reputation of vaccination rests on a 200-year-old history of success against major infectious diseases. That success has led to the doctrine of 'for each disease, a vaccine'. Although some diseases have proved frustrating, this doctrine carries considerable truth. However, when one reviews the vaccines now available it is apparent that most successes have been obtained when the microbe has a bacteremic or viremic phase during which it is susceptible to the action of neutralizing antibodies, and before replication in the particular organ to which it is tropic. Poliomyelitis and infections by capsulated bacteria are examples where vaccination has worked efficiently. However, some success has also been achieved against agents replicating on respiratory or gastrointestinal mucosae. Influenza, pertussis and rotavirus vaccines are examples of such agents, against which it has been possible to induce immune responses acting locally as well as systemically. In addition, when bacteria produce disease through exotoxins, purification and chemical or genetic inactivation of those toxins has yielded highly efficacious vaccines. Control of intracellular pathogens has not been achieved, except partly with the BCG vaccine against tuberculosis, and modern efforts are directed towards pathogens against which cellular immune responses are critical. In general, two achievements have been crucial to the success of vaccines: the induction of long-lasting immunological memory in individuals and the stimulation of a herd immunity that enhances control of infectious diseases in populations.     

Opportunities for biological weed control in Europe

The development and application of biological weed control offer greatopportunities not only for farmers, nature conservationists and othervegetation managers but also for institutions and companies that wish tosell plant protection services and products, and for the general publicthat demands safe food and a visually attractive and diverseenvironment. Despite the obvious opportunities for biological weedcontrol, few control agents are actually being used in Europe. Potentialagent organisms have features that make them particularly strong anduseful for biological control, but they also have weaknesses. Weaknessesinclude a too narrow or too wide host specificity, lack of virulence, orsensitivity to unfavourable environmental conditions.Developing specific knowledge on the interaction between weeds andpotential biological control agents, as well as expertise to increasethe effect of control agents and so achieve sufficient weed control in acost-effective manner, should have the highest priority in researchprogrammes. From 1994 to 2000 most ongoing research on biological weedcontrol in Europe was combined in a cooperative programme. This COSTAction concentrated on the interactions between five target crop weedsand their antagonists (pathogens and insects), on furthercharacterisation of the specific blems and potential control agents andon the most suitable biological control approach.The next major challenge will be to apply the findings provided byCOST-816 to the development of practical control solutions. The leadingobjective of a new concerted research programme with European dimensionswill be to stabilise or even promote biodiversity in the most importantEuropean ecosystems by integrating biological weed control in themanagement of these systems.     

Revisiting the extracellular lifestyle

In microbiology textbooks infectious agents are traditionally classified as intracellular or extracellular pathogens depending on whether they multiply inside or outside host cells. In recent literature an increasing number of extracellular pathogens are described in close apposition with the host cell surface embedded in plasma membrane folds, making it difficult to classify them as strictly extracellular pathogens. This review further explores this emerging new lifestyle category tentatively named 'epicellular' in reference to earlier work describing the location of the parasite Cryptosporidium parvum. The lifestyles of three diverse such pathogens were examined: the parasite Cryptosporidium parvum, the Gram-negative bacterium Neisseria meningitidis and the human T cell leukaemia virus type 1 (HTLV-1). The specific cellular location, the mechanisms of adhesion, the induction of plasma membrane folds and the subsequent functional consequences will be compared. Although current knowledge suggests different underlying mechanisms, a concept that emerges is that the particular location of these pathogens has important functional consequences for the pathogens in terms of nutrient acquisition, immune escape, resistance to mechanical stress and transmission. Re-examining the lifestyle of other classically extracellular pathogens might thus shed a new light on the way pathogens interact with cells and point to new areas of investigation.     

Biotechnological approaches to develop bacterial chitinases as a bioshield against fungal diseases of plants

Fungal diseases of plants continue to contribute to heavy crop losses in spite of the best control efforts of plant pathologists. Breeding for disease-resistant varieties and the application of synthetic chemical fungicides are the most widely accepted approaches in plant disease management. An alternative approach to avoid the undesired effects of chemical control could be biological control using antifungal bacteria that exhibit a direct action against fungal pathogens. Several biocontrol agents, with specific fungal targets, have been registered and released in the commercial market with different fungal pathogens as targets. However, these have not yet achieved their full commercial potential due to the inherent limitations in the use of living organisms, such as relatively short shelf life of the products and inconsistent performance in the field. Different mechanisms of action have been identified in microbial biocontrol of fungal plant diseases including competition for space or nutrients, production of antifungal metabolites, and secretion of hydrolytic enzymes such as chitinases and glucanases. This review focuses on the bacterial chitinases that hydrolyze the chitinous fungal cell wall, which is the most important targeted structural component of fungal pathogens. The application of the hydrolytic enzyme preparations, devoid of live bacteria, could be more efficacious in fungal control strategies. This approach, however, is still in its infancy, due to prohibitive production costs. Here, we critically examine available sources of bacterial chitinases and the approaches to improve enzymatic properties using biotechnological tools. We project that the combination of microbial and recombinant DNA technologies will yield more effective environment-friendly products of bacterial chitinases to control fungal diseases of crops.     

Coexpression of the simian immunodeficiency virus Env and Rev proteins by a recombinant human adenovirus host range mutant.

Recombinant human adenoviruses (Ads) that replicate in the intestinal tract offer a novel, yet practical, means of immunoprophylaxis against a wide variety of viral and bacterial pathogens. For some infectious agents such as human immunodeficiency virus (HIV), the potential for residual infectious material in vaccine preparations must be eliminated. Therefore, recombinant human Ads that express noninfectious HIV or other microbial proteins are attractive vaccine candidates. To test such an approach for HIV, we chose an experimental model of AIDS based on simian immunodeficiency virus (SIV) infection of macaques. Our data demonstrate that the SIV Env gene products are expressed in cultured cells after infection with a recombinant Ad containing both SIV env and rev genes. An E3 deletion vector derived from a mutant of human Ad serotype 5 that efficiently replicates in both human and monkey cells was used to bypass the usual host range restriction of Ad infection. In addition, we show that the SIV rev gene is properly spliced from a single SIV subgenomic DNA fragment and that the Rev protein is expressed in recombinant Ad-SIV-infected human as well as monkey cells. The expression of SIV gene products in suitable live Ad vectors provides an excellent system for studying the regulation of SIV gene expression in cultured cells and evaluating the immunogenicity and protective efficacy of SIV proteins in macaques.     

Local adaptation in the Linum marginale-Melampsora lini host-pathogen interaction

The potential for local adaptation between pathogens and their hosts has generated strong theoretical and empirical interest with evidence both for and against local adaptation reported for a range of systems. We use the Linum marginale-Melampsora lini plant-pathogen system and a hierarchical spatial structure to investigate patterns of local adaptation within a metapopulation characterised by epidemic dynamics and frequent extinction of pathogen populations. Based on large sample sizes and comprehensive cross-inoculation trials, our analyses demonstrate strong local adaptation by Melampsora to its host populations, with this effect being greatest at regional scales, as predicted from the broader spatial scales at which M. lini disperses relative to L. marginale. However, there was no consistent trend for more distant pathogen populations to perform more poorly. Our results further show how the coevolutionary interaction between hosts and pathogens can be influenced by local structure such that resistant hosts select for generally virulent pathogens, while susceptible hosts select for more avirulent pathogens. Empirically, local adaptation has generally been tested in two contrasting ways: (1) pathogen performance on sympatric versus allopatric hosts; and (2) sympatric versus allopatric pathogens on a given host population. In situations where no host population is more resistant or susceptible than others when averaged across pathogen populations (and likewise, no pathogen population is more virulent or avirulent than others), results from these tests should generally be congruent. We argue that this is unlikely to be the case in the metapopulation situations that predominate in natural host-pathogen interactions, thus requiring tests that control simultaneously for variation in plant and pathogen populations.     

Trends and challenges in the effective and sustainable control of Haemonchus contortus infection in sheep. Review

Haemonchosis, with its very wide distribution, has become a very important production constraint in sheep farms in tropical, subtropical and temperate regions worldwide. Various intrinsic and extrinsic factors determine the survival of Haemonchus contortus and hence the development of the disease in the animal. In general, control of gastrointestinal nematode infestation in sheep relies heavily on anthelmintic treatments. However, the indiscriminate use of these drugs has led to the widespread emergence of drug resistant strains of parasites, that has necessitated the development and use of various parasite control methods such as grazing management, biological agents and vaccines and the selection of resistant breeds of animals, with or without moderate use of anthelmintics. The ultimate goal of such control programs is to enhance productivity, while minimising risks regarding drug resistance and consumer and environmental concerns. This review attempts to highlight the different methods employed in the control of haemonchosis in sheep and the practical limitations associated with both control programs and the internal and external factors associated with the parasite and its microenvironment.     

Mixed infections and insect–pathogen interactions

Abstract Most studies of insect–pathogen interactions consider the direct interaction between one disease agent and one species of host. However, given that hosts are subject to challenge from many pathogen/parasite species, mixed infections are probably common. In this study, using the desert locust and two species of fungal entomopathogen, we show how mixed infection with a largely avirulent pathogen can alter the virulence and reproduction of a second, highly virulent pathogen. We find that two strains of the avirulent pathogen vary in their interaction with the virulent pathogen, depending on the order of infection and environmental conditions. We propose that avirulent pathogens, which have largely been overlooked to date, could play a significant role in host–pathogen dynamics, with implications for biological control and evolution of virulence.     

Resistance to antiparasitic drugs: the role of molecular diagnosis

Chemotherapy is central to the control of many parasite infections of both medical and veterinary importance. However, control has been compromised by the emergence of drug resistance in several important parasite species. Such parasites cover a broad phylogenetic range and include protozoa, helminths and arthropods. In order to achieve effective parasite control in the future, the recognition and diagnosis of resistance will be crucial. This demand for early, accurate diagnosis of resistance to specific drugs in different parasite species can potentially be met by modern molecular techniques. This paper summarises the resistance status of a range of important parasites and reviews the available molecular techniques for resistance diagnosis. Opportunities for applying successes in some species to other species where resistance is less well understood are explored. The practical application of molecular techniques and the impact of the technology on improving parasite control are discussed.