Parasitology Today, vol, 9, no. 8, 1993
Benzimidazole (BZ) resistance was also addressed in a number of reports. Roger Prichard (McGill University, Montreal, Canada) described a decrease in the extent of high-affinity binding, without a change in binding constant, in BZ resistant H. contortus and the evidence for a change in ~-tubulin in resistant nematodes. Two ~-tubulin gene families have been described in H. contortus and B. pahangi. Benzimidazole resistance was associated with a reduction in the number of alleles in each of these [}-tubulin gene families, with only one allele appearing to be present in one of the ~-tubulin gene families in BZ resistant nematodes. Leo Le Jambre (CSIRO, Armidale, New South Wales, Australia) showed a similar loss of 13-tubulin diversity in BZ-resistant Trichostrongylus colubnformis. Marleen Roos and Marcel Kwa (University of Utrecht, The Netherlands) presented
evidence that intensive selection for BZ resistance in H. contortus may result in the selection for the complete loss of one of the J3-tubulin gene families as identified by restriction fragment length polymorphism (RFLP) analysis with a specific probe. However, there is still the possibility that other ~-tubulin genes/alleles not detected with the probe used may exist.
Conclusion Much other exciting research on free-living and parasitic helminths, including RNA-splicing mechanisms in nematodes and S. mansoni, and cultivation of cells of the latter trematode, in wtro, were presented in this symposium, but space constraints prevent further examples of the immense crossfertilization that occurred between C. elegans addicts and parasite
proselytes. Great advances are being made in understanding the molecular biology of helminths which will help unravel physiological processes in animals, and offer targets for chemotherapeutic and immunotherapeutic control of parasites. This symposium must be repeated in a couple of years.
Acknowledgements The Keystone Symposium, Molecular Helminthology: An Integrated Approach, held at Tamarron, Colorado, USA, I0 17 February 1993, was organized by James Bennett, Timothy Geary, Roger Prichard, Phil Lo Verde and Fritz Rottman with support from the Upjohn Co. and the MacArthur Foundation. Symposium abstracts were published in the Journal of Cellular Biochemistry (Supplement 17C, 1993). The responsibility for these comments on the Symposium rests entirely with RP. Roger Prichard is at the Institute of Parasitology, McGill University, Montreal, Canada.
Host-Parasite Diplomacy G.A. Butcher Liverpool, UK April 1993 Whatever the behaviour patterns of parasites, the behaviour of parasitologists attending meetings on the immunology of parasites has for many years been quite predictable: as soon as 'Immunity to Protozoa' appears on the programme the helminthologists get up to leave, and of course vice versa. There was some justification for this, as the immunological mechanisms involved in resistance to these very different organisms seemed to have only limited features in common. At the recent one-day parasite immunology meeting, the traditional pattern was, to a great extent, forsaken. As the day progressed, the theme of immunological outcomes being determined by the balance between THI and TH2 lymphocyte-subset responses became gradually more apparent. However, the final sequel to any parasite infection is also determined by the peculiarities of the life cycle of a parasite within its host. These two aspects of parasitism clearly contribute significantly to the dynamic interplay between parasites and their hosts that determines their eventual relationships. © 1993 ElsevierScLencePublishe~Ltd /UK)
Peculiarities of Plasmodium A notable characteristic of Plasmodium falciparum is the relatively high mortality it causes compared with other parasites, in association with high levels of tumour necrosis factor alpha (-I-NF-ec) in severely infected subjects. The work of Adrian Hill and colleagues (Institute of Molecular Medicine, Oxford, UK), particularly on Class I responses determined by HLA B53 to the P. falciparum liver-stage antigen I (a probable vaccine candidate), has demonstrated that this allele is virtually confined to Africa, and supports the concept that P. falciparum is a relatively new cause of malaria in man and probably arose in this continent. That the parasite may be ~ill evolving was further emphasized by another Oxford contribution (Dominic Kwiaktowski) who presented evidence that toxin extracts (see below) of different isolates and even different clones from a single isolate vary widely in their capacity to stimulate the production of TNF-cc, in vitro. Thus, it appears likely that there is phenotypic variation with respect to TNF-cc induction. Similarly, patients with malaria also cam/ parasites that vary in their ability to adhere
to autologous macrophages (Marcel Hommel, University of Liverpool, UK). Those with severe malaria cam/ parasites with a high adherence, although this declines following treatment. Coming this close to a macrophage would appear to be a suicidal tendency and may indicate that most isolates from patients are going to be ones with low adherent properties. In view of the prolonged period required for gametocytes of P. falciparum to mature, it is clearly disadvantageous for the parasite to kill its host quickly, and it is not surprising that only a low percentage of infections are fatal in Africa. It would be interesting to compare P. falciparum with P. malariae (a parasite causing no mortality in the short term) in regard to TNF-ec induction. The latter induces fever at much lower parasitaemias ~, suggesting it is a good TNF-cc generator, in contrast to some (possibly most) isolates of P. falciparum, but the activation of macrophages that results may also prevent parasitaemias reaching critical levels. The P. falciparum story is obviously further complicated by the ability of its schizonts to sequester in the small blood vessels, and the increased expression of endothelial cell receptors for parasites that may follow TNF-ec induction. High TNF-cc in itself
Parasitology Today, vol. 9, no. 8, 1993
is not too dangerous as it occurs dramatically in P. vivax infections, but here there is no sequestration. The malaria toxins responsible for much of the pathology of malaria (first identified by Professor John Playfair's group 2) induce TNF-~ generation and include the GPI anchors of two merozoite surface proteins (Louis Schofield, NIMR, Mill Hill, London, UK), although there is still debate about their precise nature. In addition to TNF-induction they also mimic insulin and cause hypoglycaemia. This suggests that their activities may depend on the target cell. However, GPI anchors from other parasite species, such as trypanosomes, lack TNF-inducing activity, perhaps reflecting different structural properties. An early host reponse to these toxins is the generation of T-cell-independent anti-phospholipid antibody, a response common to a wide range of infections. This antibody is a part of the process of inhibiting uncontrolled TNF-~ secretion, a necessary and primary function of TH2 lymphocytes that inhibit macrophage activation through the mediation of interleukins IL-4 and IL-6. Nitric Oxide - Killer and Controller
In mice, macrophages require activation by interferon gamma (IFN-7) before they can respond protectively to the presence of parasites such as Leishmania and Plasmodium and secrete toxic factors, amongst which nitric oxide is now thought to be prominent (Eddy Liew and Andrew Taylor-Robinson, University of Glasgow, UK). Interferon-~/ is generated by THI lymphocytes that in a P. chabaudi adami infection are responsible for protection. Nitric oxide is also generated by THI lymphocytes themselves and acts by feedback inhibition to cut off the synthesis of IFN-~/, thus preventing an escalating rise in TNF-~ with consequent pathology. This is in addition to the inhibitory influence Of TH2 cells via IL-4 and other cytokines.
larval moult (Richard Grencis, University of Manchester, UK). This raises the question as to whether the parasite makes an antigen that disrupts the development of a protective immune response, as mouse strains that make a strong T.2 reponse clear the infection through the mediation of antibody. Human onchocerciasis is an interesting example of a parasite that causes special problems for the host by the nature of its life cycle and the possession of a particular antigen (Ov 39) that has wicle crossreactivity (Nick Mckechnie, University of Cambridge, UK). This Onchocerca vulvulus antigen is present in other species of the same genus of parasites, but it is not involved in the generation of pathology in the respective hosts. However, in human onchocerciasis the presence of the microfilarae in the eye is thought to unmask a crossreactive host antigen that is not normally seen by the immune system. A damaging inflammatory response results which is extensive and may well include an autoimmune component. In mice immunized with irradiated cercariae of S. mansoni, and subsequently challenged, the larvae get no further than the lungs (Lesley Smythies, University of York, UK). If they are removed and transplanted into naive mice, their normal development continues, showing that a cytostatic but not cytotoxic effect is exerted in the lungs of the immunized hosts. This inhibition is caused by CD4+ lymphocytes generating IFN-~, as immunized
T h e m e s to C o m e
The factors that determine the course of some important parasitic infections are now becoming somewhat clearer: the nature of the T-helper response by the host, with or without the involvement of macrophages, acts in concurrence with the anatomical position and antigenic composition of parasites. It will be particularly interesting to discover more of the basic role of molecules with a long evolutionary history such as nitric oxide and TNF-~ early in immunoregulation, and their relationships to T-cell activities. Acknowledgements This seminar on Immunity to Parasites, organized by the British Society for Immunology, took place in Liverpool, UK, on 16 April 1993. References I Miller, M.j. (1958) Trans. R. Sac Trap Med. Hyg. 52, 152 168 2 Bate, C.A.W., Taveme, J. and Playfair,J.H.L (I 989) Immunology66, 600-605 Geoff Butcher is at the Impend College of Science Technology and Medicine, Department of Biology, Prince Consort Road, London, UK SW7 2BB.
Prospective Articles in Future Issues of
Antibody isotopes in human lymphatic fllariasis
Nemoglobins Parasitophorous ducts? Anergy and the adaptable lymphocyte hypothesis
Aikawa Grossman R6cken Mottram Vercruysse
In contrast to the situation in malaria, strains of mice that make a predominantly THI response to a natural murine parasite, Trichuns muris, remain susceptible to the infection, particularly if it persists beyond 20-21 days when some antigenic change occurs that appears to be associated with a new
mice receiving antibody to this cytokine are not protected. It was suggested that THI cells are responsible for generating pulmonary foci and physically block the migration of the worms, possibly through the increased expression of adhesins.
Holder Rondinelli Hirumi
Parasitic infections, T-cell tolerance and autoimmune disease CDC2-related protein kinases Cross-immunity between gastrointestinal nematodes in ruminants Role of merozoite surface protein in cell invasion Conservation and variation of heat shock proteins in T. cruzi Axenic cultivation of bloodstream forms of Trypanosoma
Don't miss these - subscribe to ParasitologyToday using the form bound in this issue.