George Henry Falkiner Nuttall and the origins of parasitology and Parasitology.

By the beginning of the twentieth century, most of the major discoveries concerning the nature and life cycles of parasites had been made and tropical medicine was beginning to establish itself as a discipline but parasitology still lacked any real cohesion or focus. This focus arrived in 1908 when George Nuttall founded a new journal, Parasitology, as a Supplement to the Journal of Hygiene in order to cater for increasing numbers of papers on protozoological, helminthological and entomological topics that were being submitted for publication to that journal; thus bringing these three subjects together under one heading and, in doing so, established the discipline of parasitology. The events leading up to and the subsequent development of the discipline are discussed.

Malaria vaccines--progress and problems.

Developing a vaccine against malaria is a major priority of the WHO. A decade of research exploiting the techniques of molecular biology has yielded a series of potentially protective vaccines. However, progress has been frustrated by the complexity of the parasite's life cycle and the antigenic diversity exhibited by each stage. Although candidate vaccines are now entering human trials, questions still arise concerning the nature of a successful malaria vaccine and who will benefit from it.

The evolutionary expansion of the Sporozoa.

The sporozoans comprise a coherent group of protozoans, with characteristic and complex life cycles, containing 4-5000 species parasitic in invertebrates, particularly annelids and arthropods, and vertebrates. The group is a very successful one but neither its origins nor evolution are well understood. Considerations of traditional life cycles combined with newer methodologies have thrown some light on the evolutionary expansions of the main groups of sporozoans, the gregarines, coccidia, haemosporidians and piroplasms. The sporozoans of economic importance such as the coccidia, malaria parasites and piroplasms have received most attention but the data obtained have also thrown new light on the possible evolution of less well studied groups and it is concluded that conclusions based on simple comparisons of life cycles will have to be modified. It is also clear that humans have played a major part in affecting the distribution and present abundance of many sporozoans of economic significance and probably also those of less importance, and that the rates of evolutionary expansion are much more rapid than previously thought.

Designer vaccines for parasitic diseases.

Conventional ways of developing vaccines against infections, either on pragmatic grounds or by identifying protective antigens and attempting to mimic natural immune responses, have largely been unsuccessful for parasitic-infections, mainly because of the complexity of the immunological processes involved. It is clear that a new approach is required and it is now known that the "immunological environment" in which the immune response is initiated is as, or more, important than the actual antigens used. CD4+ and CD8+ T1 cells, through the agency of IL-2 and IFN-gamma, direct the response towards cell-mediated immunity involving cytotoxicity and macrophage activation, whereas T2 cells, through the agency of IL-4 and IL-10, direct the response towards antibody production. The two poles are counter-regulatory in that IFN-gamma inhibits antibody formation and IL-4 and IL-10 inhibit macrophage activation. However, immune responses are not immutable and can be artificially driven towards one or other pole, for example IFN-gamma, IL-2 and IL-12 favour T1 responses, whereas IL-4 and IL-10 favour the T2 type. With this knowledge, it is possible to design recombinant or nucleic acid vaccines that include gene products or genes for desirable cytokines as well as the appropriate antigen. For example, in experimental leishmaniasis, protective immune responses can be induced by the incorporation of genes for IL-2 and IFN-gamma into recombinant Salmonella typhimurium vectors and nucleic acid vaccines. A similar approach might be appropriate in experimental schistosomiasis, in which exogenous IL-12 drives the immune response towards the T1 pole and ameliorates T2-mediated pathology. These approaches require novel delivery systems and these have already begun to produce encouraging results. However, simply modifying the nature and route of administration of the vaccine is not enough and attention has now turned to the effector molecules involved, for example nitric oxide, and the signaling systems that are modified by the presence of particular cytokines.

Control of coccidiosis: lessons from other sporozoa.

Coccidiosis is the most important parasitic infection in poultry worldwide and also causes problems in cattle, sheep and goats. Control is largely limited to good husbandry and prophylactic chemotherapy using a range of drugs against which resistance is rapidly acquired. Attempts at vaccination using conventional vaccines have been disappointing and there is now a need for a new approach. Research into the immunology of coccidiosis has lagged behind that of other sporozoans and there are useful lessons that might be learned from studies on toxoplasmosis, cryptosporidiosis, theileriosis and malaria. In these infections the emphasis has turned to the cytokine network that drives the response towards protection. Central to these studies are the roles of interferon-gamma, interleukin-12 and activated macrophages with the involvement of nitric oxide in parasite killing. Cytotoxic T cells have also increasingly been implicated. Research has shown that different immune responses can be elicited by manipulating the cytokine system and these new concepts can be applied to the design of peptide or recombinant vaccines, and the possibilities of developing such vaccines against coccidiosis will be discussed.

Killing of blood stage Plasmodium vinckei petteri by spleen macrophages through L-arginine dependent mechanism.

A series of experiments was carried out to investigate the involvement of the L-arginine-dependent effector mechanism (LADEM) in the killing of the blood stages of the rodent malaria parasite, Plasmodium vinckei petteri, by activated spleen macrophages in vitro. P.v.petteri-infected red blood cells were co-incubated with spleen macrophages from normal mice which had previously received 10(8) Mycobacterium bovis (BCG) 5 days earlier, in the presence of 0.1 microgram/ml LPS with and without 0.1 mM L-NMMA, an L-arginine analogue which inhibits LADEM, for 16 hours. The viability of the parasites was assessed according to their infectivity following inoculation into experimental mice. Incubation of parasites with spleen macrophages in the presence of LPS without L-NMMA reduced the parasite viability to about 3%. When L-NMMA was included in the culture, inhibition of parasite killing was observed, resulting in an increase of parasite viability to about 21%. These data provide evidence to suggest that spleen macrophages play an important role as effector cells in the immune mechanisms against P.v.petteri infection, and that the parasite killing of these cells, at least in part, was mediated by LADEM.

Interactions between chemotherapy and immunity in bovine theileriosis.

In bovine theileriosis the use of chemotherapy to control an infection sufficiently long to permit the establishment of a solid protective immune response has been developed as a routine vaccination procedure. Infections with Theileria parva and T. annulata can be prevented by the administration of carefully controlled numbers of sporozoites simultaneously with a long acting tetracycline and this form of immunization has been widely used for the control of East Coast fever in Africa with considerable success. In this review, the nature of the chemotherapy, the immune response and the interactions between chemotherapy and immunity in the development of infection-and-treatment immunization procedures are discussed.

Concomitant infections, parasites and immune responses.

Concomitant infections are common in nature and often involve parasites. A number of examples of the interactions between protozoa and viruses, protozoa and bacteria, protozoa and other protozoa, protozoa and helminths, helminths and viruses, helminths and bacteria, and helminths and other helminths are described. In mixed infections the burden of one or both the infectious agents may be increased, one or both may be suppressed or one may be increased and the other suppressed. It is now possible to explain many of these interactions in terms of the effects parasites have on the immune system, particularly parasite-induced immunodepression, and the effects of cytokines controlling polarization to the Th1 or Th2 arms of the immune response. In addition, parasites may be affected, directly or indirectly, by cytokines and other immune effector molecules and parasites may themselves produce factors that affect the cells of the immune system. Parasites are, therefore, affected when they themselves, or other organisms, interact with the immune response and, in particular, the cytokine network. The importance of such interactions is discussed in relation to clinical disease and the development and use of vaccines.

Differential susceptibility of rodent malaria parasites to nonspecific immunity.

Nonspecific immunity to rodent malaria parasites can be produced by immunising mice with heterologous parasites or pretreating them with BCG, Corynebacterium parvum or Brucella abortus. Nonspecific immunity is easily produced against Plasmodium vinckei but not P. berghei. This is due to the difference between the cells occupied by the parasites, young red blood cells in the case of P. berghei and mature red blood cells in the case of P. vinckei.

Heterologous immunity between piroplasms and malaria parasites: the simultaneous elimination of Plasmodium vinckei and Babesia microti from the blood of doubly infected mice.

Mice which have recovered from infections with the avirulent piroplasm Babesia microti are also resistant to challenge with the virulent malaria parasite Plasmodium vinckei. In mice infected with P. vinckei before the peak of the B. microti infection the numbers of malaria parasites in the blood increase until that peak and are then eliminated at the same time as the piroplasms. In mice infected with P. vinckei at or after the peak there is no apparent multiplication and the malaria parasites begin to disappear from the blood immediately. The malaria parasites in doubly infected mice show signs of degeneration similar to those seen in mice pre-treated with Corynebacterium parvum and it is suggested that a common mechanism exists in homologous and heterologous immunity and in immunity following pre-treatment with C. parvum or BCG.

Specific and nonspecific immunisation against parasitic infections.

Parasitic diseases present major problems to man and his domesticated animals but do not respond easily to conventional vaccination procedures. Vaccines including attenuated stains, killed parasites, homogenates and soluble extracts all produce varying degrees of protection but controlled infections and immunisation with heterologous species or nonspecific antigens also induce protective immunity.

How parasites evade the immune response.

Infections caused by parasitic protozoa and worms are characteristically longlasting, 40-60 years in some forms of malaria and Chagas' disease for example. For years many parasitologists believed that there was no effective immunity against most parasites, but the prevalence of exacerbated or disseminated infections in immunosuppressed patients altered this viewpoint. It is now widely accepted that acquired immunity is the rule but that the parasites escape its consequences by actively evading the immune response. This evasion has important consequences because on one hand it is the cause of the immunopathology that does the real damage in most infections and on the other it places a major constraint on the development of vaccines. It was against this background that a recent symposium considered the immunological basis of the evasion of the immune response(∗).

History of human parasitology.

Humans are hosts to nearly 300 species of parasitic worms and over 70 species of protozoa, some derived from our primate ancestors and some acquired from the animals we have domesticated or come in contact with during our relatively short history on Earth. Our knowledge of parasitic infections extends into antiquity, and descriptions of parasites and parasitic infections are found in the earliest writings and have been confirmed by the finding of parasites in archaeological material. The systematic study of parasites began with the rejection of the theory of spontaneous generation and the promulgation of the germ theory. Thereafter, the history of human parasitology proceeded along two lines, the discovery of a parasite and its subsequent association with disease and the recognition of a disease and the subsequent discovery that it was caused by a parasite. This review is concerned with the major helminth and protozoan infections of humans: ascariasis, trichinosis, strongyloidiasis, dracunculiasis, lymphatic filariasis, loasis, onchocerciasis, schistosomiasis, cestodiasis, paragonimiasis, clonorchiasis, opisthorchiasis, amoebiasis, giardiasis, African trypanosomiasis, South American trypanosomiasis, leishmaniasis, malaria, toxoplasmosis, cryptosporidiosis, cyclosporiasis, and microsporidiosis.

Interactions between Trypanosoma brucei and Babesia spp. and Plasmodium spp. in mice.

Swiss mice with chronic Trypanosoma brucei infections become refractory to subsequent infection with Babesia microti and B. rodhaini. Infection with B. microti 7 days after T. brucei resulted in an obvious inhibition of the babesia parasitaemias and this inhibition became more profound as the time interval between the infections increased, until at 17-20 days the parasitaemias were totally abolished. Even after intravenous injection of large numbers of parasites parasitaemias were inhibited. Similar inhibition was obtained in BALB/c mice but not in C57BL/6 mice. Mice with established T. brucei infections also showed reduced susceptibility to B. rodhaini. In mice similarly infected with T. brucei and the malaria parasites Plasmodium chabaudi chabaudi and P. c. adami the pre-patent periods were noticeably prolonged but the subsequent parasitaemias were unaffected. Infections with P. yoelii were unaffected. Trypanosoma brucei infections were not affected by the intracellular parasites. Among the mechanisms investigated to explain these findings were changes in red blood cell populations, cross-reacting antigens, the release of toxic factors and the generation of activated oxygen species. None of these could account for the inhibition observed.

Nonspecific defence mechanism: the role of nitric oxide.

There is a marked contrast between the extraordinary complexity and specificity of the adaptive immune response and the limited number of effector mechanisms that it can direct. Recently, a great deal of interest has focused on the possible role of nitric oxide (NO) in one of these mechanisms. Here F.Y. Liew and Frank Cox examine the evidence supporting a role for NO in parasitic disease and suggest possible mechanism of NO-mediated parasite damage.

Interactions between the intestinal flagellates Giardia muris and Spironucleus muris and the blood parasites Babesia microti, Plasmodium yoelii and Plasmodium berghei in mice.

In mice infected with the intestinal flagellates Giardia muris or Spironucleus muris, together with the blood parasites Babesia microti or Plasmodium yoelii, there is a temporary decrease of flagellate cyst output coincident with the peak of the blood parasite infections, followed by a rapid return to normal levels. This decrease in cyst output is correlated with decreased numbers of trophozoites in the small intestine. The effect on S. muris is more marked than that on G. muris. Neither blood parasites has any effect on the total duration of the flagellate infection and the flagellates do not affect the blood parasites. In mice infected with G. muris or S. muris and P. berghei there is also a decrease in cyst output but this is less apparent than in infections with B. microti or P. yoelii because of the fatal nature of the P. berghei infection. It is suggested that the decrease in cyst output is probably due to changes in the contents of the small intestine or to non-specific immunological factors rather than to specific immunological changes.