Helminths as vectors of pathogens in vertebrate hosts: a theoretical approach.

Pathogens frequently use vectors to facilitate transmission between hosts and, for vertebrate hosts, the vectors are typically ectoparasitic arthropods. However, other parasites that are intimately associated with their hosts may also be ideal candidate vectors; namely the parasitic helminths. Here, we present empirical evidence that helminth vectoring of pathogens occurs in a range of vertebrate systems by a variety of helminth taxa. Using a novel theoretical framework we explore the dynamics of helminth vectoring and determine which host-helminth-pathogen characteristics may favour the evolution of helminth vectoring. We use two theoretical models: the first is a population dynamic model amalgamated from standard macro- and microparasite models, which serves as a framework for investigation of within-host interactions between co-infecting pathogens and helminths. The second is an evolutionary model, which we use to predict the ecological conditions under which we would expect helminth vectoring to evolve. We show that, like arthropod vectors, helminth vectors increase pathogen fitness. However, unlike arthropod vectors, helminth vectoring increases the pathogenic impact on the host and may allow the evolution of high pathogen virulence. We show that concomitant infection of a host with a helminth and pathogen are not necessarily independent of one another, due to helminth vectoring of microparasites, with profound consequences for pathogen persistence and the impact of disease on the host population.

The infectivity of spongiform encephalopathies: does a modified membrane hypothesis account for lack of immune response?

Scrapie, the prototype of a group of diseases which have the unique property of being both hereditary and infectious, is also exceptional in that it fails to evoke an immune response. Purification of crude scrapie preparations revealed a strong association of infectivity with a membrane protein ('PrPsc'); but a protein with the same amino acid sequence ('PrPc') was subsequently also found in normal mammalian nervous tissue. It is postulated by some investigators that 'PrPsc' is itself the infectious agent, or the most important part thereof, but in papers making that proposal immunological aspects have not been addressed. Experimental evidence supporting the hypothesis of a membrane fragment as agent has likewise lately not been taken into account. A modified form of the membrane hypothesis could account for immunological as well as genetic aspects of these diseases.

Sub-acute, transmissible spongiform encephalopathies: current concepts and future needs.

The first diagnosis of bovine spongiform encephalopathy (BSE) in the United Kingdom in 1986 was to stimulate the most intensive epidemiological study of any animal disease of all time in that country. It led also to the initiation of a broad-based research programme with an international flavour. This principally involved scientists and veterinarians in Europe (especially the United Kingdom) and the United States of America, especially those with experience of slow infections in general and experimental scrapie in particular. This final chapter highlights some of the significant discoveries made in the study of BSE and related diseases of this group but also emphasises the deficits in knowledge which need to be corrected before such diseases as scrapie in sheep and goats can be brought under control. The benefits resultant upon effective disease control will be manifest as improvement in animal production, welfare and, importantly, the removal of trading barriers currently in place to protect countries in which diseases such as BSE and scrapie do not exist. Of key importance is the development of a simple, cheap and effective diagnostic test for use in the live animal before the onset of clinical signs. This will be difficult since the nature of the causal agents is uncertain and none provokes either a detectable immune response or inflammatory reaction in the host. The earlier chapters, written by acknowledged specialists from around the world, deal with the specific diseases in detail and all present some of the most recent knowledge available. Here the authors emphasise the important role that major national and international agencies have in effecting the highest level of control possible in the absence of key information. International collaboration with countries in which these diseases exist, and as well as those where they are absent, is of paramount importance. It is essential that the BSE epidemic which has severely affected the cattle industry of the United Kingdom is not allowed to happen in developing countries. Whereas the former has implemented stringent control measures based on scientific knowledge and is well on the way to eradicating the disease, the latter could have much greater difficulty in establishing control. The answer is clear. BSE must be prevented from occurring elsewhere. To do that, knowledge of BSE and other members of the group should be widely dispersed and it is the purpose of this issue to do just that.

From slow virus to prion: a review of transmissible spongiform encephalopathies.

Spongiform encephalopathies include seven neurodegenerative diseases: three in man (Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease and kuru) and four in animals (scrapie, mink encephalopathy, bovine spongiform encephalopathy and chronic wasting disease in deer and elks). They are all transmissible to a variety of species, and man-to-man propagation of the diseases in the form of iatrogenic transmission has been well-documented. The infectious agent is highly unusual and the pathogenesis of infection remains controversial. The term prion was introduced to describe the proteinaceous infectious agent. Purification of this agent yielded a unique sialoglycoprotein, associated with the neuronal cell membrane, which is all or part of the infectious agent. Molecular genetics revealed variations in the prion protein; these are linked to or associated with the inherited forms of spongiform encephalopathies: familial Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker disease. The histological triad of spongiform change, neuronal loss and astrocytosis dominate the histological picture of spongiform encephalopathies. A recent case which did not develop any of the histological hallmarks of disease, but did have genetic abnormalities typical of the disease, indicates that the true incidence of Creutzfeldt-Jakob disease may be considerably higher than previously accepted, and a combination of molecular screening and immunohistochemistry for prion protein should complement traditional neuropathology to establish the diagnosis. The descriptive term of spongiform encephalopathy may now have to be abandoned in favour of prion disease.

The transmissible amyloidoses: genetical control of spontaneous generation of infectious amyloid proteins by nucleation of configurational change in host precursors: kuru-CJD-GSS-scrapie-BSE.

Kuru, Creutzfeld-Jakob disease, Gerstmann-Sträussler syndrome, scrapie, and bovine spongiform encephalopathy are caused by so-called unconventional viruses which are really replicating proteins which induce by auto nucleation and autopatterning a configurational change in the precursor protein to produce an infectious amyloid form. Crystallography and NMR may eventually determine how amyloid precursor protein is converted to this infectious form by configurational changes in all tertiary and quaternary structure of the normal precursor. Most sporadic cases of CJD arise by de novo spontaneous conversion of the normal precursor to the infectious form, a rare event occurring at the frequency of one per million persons per year (the annual incidence of CJD throughout the world). In the familial forms of CJD and GSS, where the occurrence is an autosomal dominant trait, each family has one of five different mutations causing a single amino acid change or one of five insertions of 5, 6, 7, 8 or 9 octapeptide repeats. Each mutation causes a million-fold increased probability of the spontaneous configurational change to an infectious polypeptide, and appears as an autosomal dominant trait. Thus, the behavior of the transmissible brain amyloidosis parallels completely that of the transthyretin amyloidoses causing familial amyloidotic polyneuropathy, in which there are 19 different point mutations, each one of which increases enormously the likelihood of configurational change of transthyretin prealbumin to amyloid.

A 'unified theory' of prion propagation.

There is now very persuasive evidence that the transmissible agent for spongiform encephalopathies such as scrapie, consists of a modified form of the normal host protein PrPc, devoid of any nucleic acid. On the other hand, because there are many different strains of scrapie agent with distinct phenotypes which can be propagated in animals homozygous for the PrPc gene, it has been suggested that a nucleic acid must be a component of the agent. Can the two views be reconciled?

Inactivation of the unconventional agents of scrapie, bovine spongiform encephalopathy and Creutzfeldt-Jakob disease.

Scrapie, bovine spongiform encephalopathy (BSE) and Creutzfeldt-Jakob disease (CJD) are the best known of the transmissible degenerative encephalopathies (TDE) that affect animals and man. Among the unusual properties of the unconventional causal agents is their relative resistance to standard decontamination procedures, and this has resulted in accidental transmission. Scrapie in sheep is the most common of these diseases and, through laboratory studies, is the best understood. As the model for the group, scrapie agent has been used in experiments to devise general standards for decontamination of the agents of the TDE.

Bovine spongiform encephalopathy.

Two years after the introduction of a slaughter policy for BSE, the author summarizes the development of the epidemic and introduction of Government controls. In conclusion, the risk to humans is discussed.

Methodological aspects of the validation of purification procedures of human/animal-derived products to remove unconventional slow viruses.

This study describes what needs to be considered in order to make a proper risk estimate of a human/animal-derived biological product from the contamination with unconventional slow virus(es). Several factors are important for this estimate. The first points regard the source of raw material (whether of human or animal origin), the kind of tissue (brain and other neural tissues being a higher risk), and in which way the tissue is collected. Then, the possibility, although remote, is taken into consideration of performing a quality control on the raw material through the measurement of PrP27-30, which is considered a specific marker of these diseases. Unfortunately, the detection of PrP27-30 is not yet so sensitive compared to the measurement of infectivity. Finally, the design of the validation experiments on the extraction and purification procedures of human/animal-derived products which gives the best estimate of safety is described. The conclusion of this study is that each biological product needs to be individually evaluated and therefore, it will be difficult to give standard guidelines for the judgement of their safety.