We have examined genetic variability in parasites in the context of ecological interactions with the host. Recent research on Echinococcus, Giardia and Cryptosporidium has been used to illustrate: (i) the problems that parasite variability and species recognition pose for understanding the complex and often controversial relationship between parasite and host occurrence; (ii) the need for accurate parasite characterization and the application of appropriate molecular techniques to studies on parasite transmission if fundamental questions about zoonotic relationships and risk factors are to be answered; (iii) our lack of understanding about within-host interactions between genetically heterogeneous parasites at the inter-and intraspecific levels, and the significance of such interactions with respect to evolutionary considerations and the clinical outcome of parasite infections. If advances in molecular biology and mathematical ecology are to be realized, we need to give serious consideration to the development of appropriate species concepts and in vivo systems for testing the predictions and assumptions of theoretical models.

Recent work on the inheritance of susceptibility to malaria suggests that, over what may have been a relatively short evolutionary period, a remarkably diverse series of gene families have been modified in response to the selective drive of this single infection. The phenotype consequences are not confined to the red cell, but involve the immune system, cytokines and many other systems. It seems likely that the mechanisms of variation in genetic susceptibility to other infective agents will reflect at least a similar degree of complexity and, if the selective pressures have been present for longer periods of our evolutionary history, may be even more diverse. This may have important implications for work directed at trying to define susceptibility loci for current infectious and non-infectious diseases.

Infection by a variety of species of intestinal nematode infection gives rise to a wide variation in parasite load within a host population. There has been much investigation into the basis of this variation and is thought to involve several factors. Studies of infections of gut dwelling nematodes in laboratory rodents has clearly demonstrated that this variation may be due to the production of cytokines produced as part of the host immune response to infection. More specifically, activation of distinct T helper cell subsets leads to the generation of effective or ineffective responses resulting in clearance of the parasite load or maintenance of chronic infection. The induction of differential responses remains to be determined but is likely to be influenced at a number of levels including involvement of accessory cells and activation of co-stimulatory molecules on antigen presenting cells. Moreover, it appears that these parasites may actively interfere with the host cytokine response to promote their own survival. This review concentrates on recent findings of cytokine mediated control of intestinal nematodes highlighting a central role for the immune system in regulating both acute and chronic infection by these parasites.

Individual susceptibility to malaria infection, disease and death is influenced by host genotype, parasite virulence and a number of environmental factors including malaria-specific immunity. Immune responses are themselves determined by a combination of host genes and environmental effects. The extent to which host genotype limits the spectrum of possible immune responses may influence the outcome of infection and has consequences for vaccine design. Associations have been observed between human major histocompatibility complex (MHC) genotype and susceptibility to severe malaria, but no similar associations have been observed for mild malarial disease or for specific antibody responses to defined malaria antigens. Epidemiological studies have shown that, in practice, neither T helper cell nor antibody responses to malaria parasites are limited by host MHC genotype, but have revealed that genes lying outside the MHC may influence T cell proliferative responses. These genes have yet to be identified, but possible candidates include T cell receptor (TcR) genes, and genes involved in TcR gene rearrangements. More importantly, perhaps, longitudinal epidemiological studies have shown that the anti-malarial antibody repertoire is selective and becomes fixed in malaria-immune individuals, but is independent of host genotype. These findings suggest that the antibody repertoire may be determined, at least in part, by stochastic events. The first of these is the generation of the T and B cell repertoire, which results from random gene recombinations and somatic mutation and is thus partially independent of germline genes. Secondly, of the profusion of immunogenic peptides which are processed and presented by antigen presenting cells, a few will, by chance, interact with T and B cell surface antigen receptors of particularly high affinity. These T and B cell clones will be selected, will expand and may come to dominate the immune response, preventing the recognition of variant epitopes presented by subsequent infections - a process known as original antigenic sin or clonal imprinting. The immune response of an individual thus reflects the balance between genetic and stochastic effects. This may have important consequences for subunit vaccine development.

Infections with Theileria parva in the African buffalo are invariably asymptomatic, whereas infections in cattle usually result in clinical disease, the severity of which varies in different populations of cattle. The parasite exhibits antigenic heterogeneity, which in cattle manifests as differences between parasite strains in their cross-protective properties. A series of studies on T cell responses to T. parva in cattle have demonstrated that class I MHC-restricted cytotoxic T lymphocytes (CTL), specific for parasitized lymphoblasts, are important mediators of immunity. Cytotoxic T cell responses frequently display parasite strain-restricted specificities which appear to correlate with the capacity of strains to cross-protect. The strain specificity of CTL responses varies in animals immunized with the same parasite strain and is influenced by both host and parasite genotype. Recent studies have provided evidence that there is competition between epitopes for induction of CTL responses, which can result in a bias to strain-specific epitopes. These properties of the CTL response have important implications for vaccination. Thus, in designing a vaccine, it may be possible, by selecting parasite proteins containing appropriate CTL epitopes, to generate CTL responses that protect against a wide range of parasite strains. Although there are no comparable data on CTL responses in the buffalo, it is considered that the features of the immune response described for cattle would be advantageous for survival of parasite populations in the buffalo. Specifically, a bias in the immune responses to strain-specific determinants should favour establishment of infection in buffalo already carrying the parasite and allow fluctuation in the levels of different parasite strains during the course of persistent infection.

Two important recent advances in Leishmania immunology are: (i) the demonstration of a dramatic dichotomy in T helper 1 versus T helper 2 subset expansion leading to protection versus disease exacerbation; and (ii) analysis of the macrophage activation pathways leading to enhanced intracellular killing of parasites, in particular the tumour necrosis factor α (TNFα)-dependent sustained induction of the inducible nitric oxide synthase gene (Nos2) leading to the generation of large amounts of nitric oxide (NO). Given the broad spectrum of disease phenotypes in human leishmaniasis, one might predict that a genetic defect at any key point in this macrophage activation pathway and/or in pathways leading to activation of different T cell subsets, and the latter may be a pleiotropic effect of the former, will contribute to disease susceptibility. By studying disease in genetically-defined inbred mouse strains, it has been possible to identify 5 regions of the murine genome carrying leishmanial susceptibility genes. The genes include: (i) Scl-2 (mouse chromosme 4/human chromosome 9p; candidate Janus tyrosine kinase 1) controlling a unique no lesion growth resistance phenotype to Leishmania mexicana; (ii) Scl-1 (distal mouse chromosome 11/human 17q; candidates Nos2, Sigje, MIP1α, MIP1β) controlling healing versus non-healing responses to L. major; (iii) the ‘T helper 2’ cytokine gene cluster (proximal murine chromosome 11/human 5p; candidates IL4,5,9) controlling later phases of L. major infection; (iv) the major histocompatibility complex (MHC: H-2 in mouse, HLA in man: mouse chromosome 17/human 6p; candidates class II and class III including TNFα/β genes); and (v) Nramp1, the positionally cloned candidate for the murine macrophage resistance gene Ity/Lsh/Bcg (mouse chromosome 1/human 2q35). This review examines these 5 regions and the candidate genes within them, reflecting on their current status as candidates for human disease susceptibility genes.

There is substantial evidence that host genetic factors play a major role in determining the outcome of infection with many pathogens. Detailed analysis of malaria has identified twelve genes that affect susceptibility in various human populations. However, less attention has been paid to other major infectious diseases where twin studies have identified an important host genetic component to susceptibility. Recent progress in the analysis of the human genome offers exciting prospects for the mapping and identification of new susceptibility and resistance genes for common infectious diseases. Screening of the whole genome in affected sibling pair studies is now feasible by employing highly informative microsatellite markers. In addition, many polymorphic candidate genes have become available for analysis in case-control studies. It is proposed that these new genetic tools offer a powerful approach to the epidemiological analysis of many infectious diseases in humans and supersede traditional genetic approaches to identifying susceptibility genes in mouse models. Progress in characterizing the role of major histocompatibility genes in susceptibility to malaria and other infectious diseases is reviewed before outlining the methodologies for and progress in identifying non-MHC susceptibility genes.

A condition with a weak genetic component, but a strong correlation with age, is the summarizing of conferences. It is an art form often resembling the expression of gratitude by a bride on the receipt of her sixth electric kettle. However, our gratefulness now is genuine, because we have been given a wonderfully interesting series of papers. Their authors were chosen with skill to show the manifold variety of genetic interactions between parasites and hosts. The range of these interactions would daunt even the strongest-hearted summarizer, and my task can only be managed by a ruthless subjectivity.