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Australian society for parasitology presidential address
International Journal for Parasitology Vol. 15, No. Pergamon Press Ltd. Printed in Great Britain.
6, pp.
597400,
1985
AUSTRALIAN SOCIETY FOR PARASITOLOGY PRESIDENTIAL ADDRESS* GENE EXCHANGE
BETWEEN M.
Department
J. HOWELL
of Zoology, Australian National Canberra, ACT 2601, Australia
PARASITES and their hosts represent intimate, interactive genetic systems. Given the respective obligatory and nonobligatory nature of the relationship to each of the organisms involved parasites would seemingly have had to make particularly significant genetic adjustments in adapting to their hosts. But such adjustments have not been the sole prerogative of parasites; the elaboration of defence mechanisms by hosts and the generation of biochemical diversities among them are considered to have arisen in response to the selection pressures imposed by parasitic infection (Hamilton, 1982). The spectrum of biochemical characteristics of red cells selected for by malarial infection are especially well known examples of adaptive changes that can take place in infected animals. Most biologists would explain the evolution of hostparasite relationships in terms of neo-Darwinism-random mutation and recombination generating variation with natural selection acting on the variation so produced. However, there is at least one additional mechanism that can be invoked to account for some variation as this address will attempt to show. The facts are not new, but the ideas they suggest have not, to my knowledge, been proposed before in a parasitological context; the ideas derive from a recent controversial text on evolution (Steele, 1979) and some astonishing findings in molecular biology over the past few years. It is difficult to generalise about a phenomenon as diverse as parasitism. One possible outcome of the relationship between a host and parasite is the development of a state of tolerance, where there is an apparent failure of the host to recognise the parasite as foreign and to respond in such a way that is detrimental to the parasite’s survival. This idea was originally developed by Sprent (1962) and termed ‘adaptation tolerance’. It was envisaged as a dual modification of host and parasite-a deletion of antigen combining sites in the former paralleled by stabilization of parasite antigens towards conformity with related substances in the host. The concept of a reduction in the antigenic disparity between parasite and host, especially in what has been termed the parasite’s “fitness” antigens (Dineen, 1963), is consistent with Sprent’s hypothesis. The discovery of “host antigens” in or on parasites (Capron, Biguet, Vernes & Afchain, 1968; Smithers, Terry & Hockley, 1969) lent support to the hypothesis; parasites appeared to have the genetic capacity to produce hostlike substances. Perhaps the most convincing evidence of
*Annual
General
Meeting,
Sydney,
HOSTS AND PARASITES
28 August
University,
this is the demonstration of a “mouse” protein, a2-macroglobulin, on the body surface of schistosomes (Damian, 1967). Other notable examples are the close similarity between human and Ascaris collagens (Michaeli, Senyk, Maoz & Fuchs, 1975) and the ability of liver fluke to synthesise human blood group substances (Ben-Ismail, Mulet-Clamagirand, Carme & Gentilini, 1982). There are additional recorded instances of antigen sharing by hosts and parasite (Capron el al., 1968; Damian, 1979), but in these cases the possibility that host-like molecules in parasites were passively acquired rather than synthesised de now or indeed synthesised from messenger RNA captured from hosts (Smyth, 1973) has not been excluded. If parasites have the genetic capacity to synthesise macromolecules either identical to or closely resembling those produced by their hosts, it can be assumed that their genomes contain DNA sequences that are identical, or closely related, to those of their hosts (DNA homology). Such homology represents either conservation over the long periods of time that have elapsed during the evolution of metazoan animals, or more recent adaptive change for which neo-Darwinism would generally be invoked as an explanation. However, it is argued here that DNA homologies between parasites and their hosts may have arisen by the direct incorporation of host genetic material into the parasite genome. Indeed, this type of event is not without precedent; it underlies the presence of the gene for superoxide dismutase in a bacterium which inhabits the light-producing organs of some fish. This gene, which is part of the bacterial chromosome, has clearly been captured from the genome of the fish (Lewin, 1985). In the present discussion this notion of interspecies gene transfer is taken further to suggest that that there has been a two way flow of DNA-from host to parasite and vice versa. Such exchange rather than the slower processes of mutation and recombination opens up the possibility of more rapid evolution, a desirable prospect for an organism endeavouring to bridge the gap between a free-living and parasitic mode of life or indeed to a host adapting to a parasitic infection. From the parasite’s point of view this two-way gene exchange can be seen to offer the following, but not necessarily the only, advantages: incorporation of parasite genetic material into the host genome may lead to tolerance towards the parasite if the information is expressed and recognised by the host as self during its development. Incorporation of host DNA into the parasite genome may lead to the expression of certain host macromolecules by the parasite which facilitate the avoidance of immune
1985 597
598
M. J. HOWELL
responses. In effect, these exchanges of DNA offer an unconventional explanation for adaptation tolerance. It is possible to envisage selective advantages which may also accrue to the host if reciprocal gene exchange took place. If a host produced a parasite molecule which played a crucial role in the orderly development of that parasite at inappropriate times or at inappropriate concentrations it may be able to regulate the parasite population by nonimmunological means. There may be an analogy here between plants and herbivores; the production of oestrogen and juvenile hormone analogues by plants can have deleterious consequences for the breeding activities of the animals which consume them (Damian, 1979). In the case of the expression of host DNA by the parasite, certain physiological processes in the host may be amplified with desirable consequences for the host; it may grow faster and compete more effectively and enjoy greater reproductive success. In this respect, the genetic capacity of the cestode Spirometra mansonoides to produce a mammalian growth hormone-like substance that stimulates mice to grow to rat-like proportions (Mueller, 1974) may have some relevance. Thus far consideration has been given to gene exchange between hosts and parasites. However, the possibility of gene exchange between parasites that share the same host should not be discounted; does this underlie the phenomenon of cross-immunity? Non-reciprocal cross-immunity (Schad, 1966) could represent a situation where one species of parasite has acquired the DNA of another, expresses the antigens it codes for and generates immunity to the potentially competing parasite. How, then, could direct gene exchange occur? How could genetic information acquired in this way become fixed in the germ line, a prerequisite if such events are to have any impact on the evolution of parasites and their hosts? Likely candidates for effecting a two-way transfer of genetic information between hosts and parasites-and indeed between parasites-are the retroviruses. Retroviruses are RNA viruses; their mode of replication is considered briefly here but a more detailed account is given by Strayer &Gillespie (1980) and Muller & Verma (1984). On infecting a eukaryotic cell the viral RNA is copied into DNA by the enzyme reverse transcriptase; this DNA enters the cell nucleus where it integrates into the DNA of a host chromosome. Following transcription, some of the viral RNA is translated into protein which encloses additional copies of viral RNA. Mature viral particles bud from the cell membrane but the cell is not killed. Retroviruses possess a number of interesting properties which are worth reiterating here. Firstly, an RNA virus may remain in the host genome in a silent or latent form, replicating at each cell division but failing to produce viral particles (Strayer & Gillespie, 1980). The virus may even enter the genome of germ cells and become vertically transmitted through successive generations of the host species (Steffen, Taylor, & Weinberg, 1982; Mowat & Bernstein, 1983; Schieke, Harbers & Jaenisch, 1983). For example, all domestic cats and their closest relatives have a silent virus-RB114-in their genome which rarely produces viral particles. The virus is thought to have entered the germ line of the ancestors of domestic cats (probably from baboons) and has remained within their genome since that time. Neither the virus nor any part of its genome is present in other members of the cat family (Strayer & Gillespie, 1980). Secondly, retroviruses can transduce host DNA; that
I.J.P. VOL. 15. 1985
is they can, through their close association with the host genome, capture host DNA sequences (these are referred to as oncogenes) by way of RNA copies which then become a characteristic feature of their genomes (Bishop, 1983). Infection of other host species or other members of the same host species with such a virus can lead to the insertion of the transduced DNA into the genome of the new host cell, an event which may be followed by tumour growth. An example of an oncogenic retrovirus is FBJ-murine osteosarcoma virus which induces neoplastic tumours in new born mice. This virus carries an oncogene (v-fos) which is homologous with DNA in the genomes of a number of vertebrates (Curran, Peters, Van Beveren, Teich & Verma, 1982) and which has clearly been transduced from normal cellular DNA. Many other examples are also known (Strayer & Gillespie, 1980; Bishop, 1983; Muller & Verma, 1984). Oncogenes, which are part and parcel of the normal genome of all cells, appear to code for proteins involved in important developmental processes. When they are transduced by retro-viruses and inserted into aberrant locations within the genomes of other cells, they may escape from the normal regulatory processes which control their activity and precipitate uncontrolled growth. Oncogenes are present in both invertebrates and vertebrates. There is also homology between oncogenes in animals as widely separated as nematodes, insects, birds and mammals (Shilo & Weinberg, 1981). Thus, oncogenes appear to have been conserved throughout an extremely long period of evolution. On three grounds retroviruses have the potential to act as vehicles for the exchange of genetic material between hosts and parasites. They can (a) transduce DNA; (b) cross species boundaries; (c) enter the germ lines of their hosts. However, it should be noted that the ability of retroviruses to transduce cellular genes other than oncogenes has not yet been established (Bishop, 1983). The question that remains is what sort of evidence would be looked for in support of the occurrence of viral-mediated gene exchange between hosts and parasites (or indeed between parasites) by retroviruses. Two major areas of investigation could be considered: (a) the existence of retroviruses common to both hosts and parasites; (b) DNA sequence homologies between host, parasite and virus genomes. Viruses (or virus-like particles) have been detected in protozoa (Terzakis, 1972; Gibbs, 1973), cestodes (Mueller & Strano, 1974a, b; Dougherty, Distefano, Feller&Mueller, 1975), trematodes (Byram, Ernst, Lumsden & SogandaresBernal, 1975), and nematodes (Harrison, 1973). In some cases the particles have similarities to C-type (RNA) viruses. More intensive work should uncover other examples. Of course the presence of viruses in the hosts of these parasitic groups has been well known for many years, and in insects, birds and mammals especially, RNA viruses are commonly encountered (Bellett, Fenner & Gibbs, 1973). Thus, one of the requirements for viral-mediated exchange of genetic material between hosts and parasites is probably met; but there is no guarantee that RNA viruses would be capable of crossing the broad phylogenetic gaps that exist between parasites and their hosts. Recent reports that major histocompatibihty complex (MHC) molecules of mammals act as virus receptors (Jacobson & Biddison, 1984) and that MHC antigens are present on schistosomes (Gitter, McCormick & Damian, 1982) means, however, that such exchanges are not entirely out of the question. More direct support for the idea of gene exchange
I.J.P. VOL. 15. 1985
Presidential
between hosts and parasites would come from the demonstration of homologous DNA sequences (other than evolutionarily conserved DNA sequences) in both partners in a relationship by, for example, the technique of Southern blotting; or by comparison of immunoprecipitation profiles obtained from translation products of messenger RNA of host and parasite origin. What is required for Southern blotting is a set of specific DNA sequences or probes which would enable host and parasite genomes to be compared. In order for the technique to provide evidence of comparatively recent gene exchange these probes would need to be DNA sequences which have not been evolutionarily conserved. The value of one such probe is exemplified by a study which has answered a fundamental question regarding the origin of certain host antigens in schistosomes. Adult schistosomes grown in mice carry mouse MHC antigens on their surfaces (Gitter et al., 1982). By probing the parasite genome with mouse MHC-specific DNA it was shown that there was no apparent DNA sequence homology between host and parasite and thus the MHC antigens on the worms would seem to be clearly of host origin (Simpson, Singer, McCutchan, Sacks & Sher, 1983). The immunoprecipitation procedure would be amenable to immediate investigation; messenger RNA could be isolated from host and parasite, translated in vitro and each set of proteins probed with antisera to either host or parasite antigens. In this way it could be determined whether host and parasite produced messenger RNA transcripts that gave rise to antigenically related molecules. A problem with this approach may be evolutionary conservatism; but, as with the Southern blotting technique, the burgeoning availability of specific probes in the form of monoclonal antibodies may provide a way around this potential obstacle. One of the consequences of host/parasite gene exchange mediated by retroviruses may be the induction of abnormal growth. Such transfer of genetic information may disturb the expression of growth regulatory substances in normal tissues and lead to neoplasia. What is envisaged here is something similar to the induction of tumours in vertebrates by the oncogenic retroviruses (Muller & Verma, 1984). In support of this idea it is noted that some parasites such as Echinococcus multilocularis (see Lubinsky & Desser, 1963) and Spirometra proliferum (see Mueller & Strano, 1974a) behave like cancerous growths. In the case of S. prohferum it was suggested that its unusual development may be the result of a virus infection. Additionally, neoplasia of host tissue has been associated with several protozoan and helminth infections (Cheng, 1973). In summary, this discussion has put forward the hypothesis that gene exchange mediated by retroviruses may give rise to some of the variation in parasites and hosts that natural selection has to work on. Benefits to both host and parasite that could accrue from these exchanges have been referred to. However, it should be noted that this source of variation may not be the only mechanism other than mutation and recombination that leads to evolutionary change in these organisms. Extrachromosomal genetic elements such as plasmids and phages occur widely in prokaryotes. Plasmids in particular can mobilise and transfer genetic information such as antibiotic resistance between distantly related bacterial species (Reanny, 1976) and between bacteria and higher plants as in the induction of crown gall tumours (Douglas, Staneloni, Rubin & Nester, 1985). A number of extrachromosomal genetic elements other than plasmids and viruses (eg. viroids, endosymbiotic
address
599
organims) also occur in eukaryotes. The existence of this mobile genetic material adds another dimension to the hypothesis put forward in this paper, and its possible contribution to the co-evolution of hosts and parasites cannot be overlooked (Guardiola, 1983). The recent demonstration of a red algal parasite’s ability to insert its nuclei into the cells of its red algal host (Goff & Coleman. 19841 is an additional and subtle way in which host and parasit; DNA can intimately interact; its consequences are probably far reaching. Molecular biology has the tools to investigate further all of these phenomena. It is certainly possible that the results of such studies may modify our views of parasitism and add to the fascination of this intriguing phenomenon.
REFERENCES BELLETT A. J. D., FENNER F. & GIBBS A. J. 1973. The viruses. In: Frontiers of Biology 31, Viruses and Invertebrates (Edited by GIBBS A. J.), pp. 41-88. North Holland, Amsterdam and London. BEN-ISMAIL R., MULET-CLAMAGIRAND C., CARME B. & GENTILINI M. 1982. Biosynthesis of A, H and Lewis blood group determinants in Fasciola hepatica. Journal of Parasitology 68: 402407. BISHOP J. M. iG83. Cellular oncogenes and retroviruses. Annual Review of Biochemistry 52: 301-354. BYRAM J. E., ERNST S. C., LUMSDEN R. D. & SOGANDARESBERNAL F. 1975. Virus like inclusions in the cecal epithelial cells of Parugonimus kellicotti (Digenea, Troglotrematidae). Journal ofParasitology 61: 253-264. CAPRON A., BIGUET J., VERNES A. & AFCHAIN D. 1968. Structure anti-genique des helminthes. Aspectes immunologiques des relations h&e-parasite. Puthologie et biologic, Paris 16: 121-138. CHENC T. C. 1973. General Parasitology. Academic Press, New York and London. CURRAN T., PETERS G., BEVEREN C. VAN, TEICH N. M. & VERMA 1. M. 1982. The FBJ murine osteosarcoma virus: identification and molecular cloning of biologically active proviral DNA. Journal of Virology 44: 674-682. DAMIAN R. T. 1967. Common antigens between Schistosoma mansoni and the laboratory mouse. Journal of Parasitology 53: 60-64. DAMIAN R. T. 1979. Molecular mimicry in biology adaptation. In: Host-Parasite Interfaces (Edited by NICKOL B. B.), pp. 103-126. Academic Press, New York and London. DINEEN J. K. 1963. Antigenic relationships between host and parasite. Nature, London 197: 471-472. DOUGHERTY R. M., DISTEFAN~ H., FELLER U. & MUELLER J. F. 1975. On the nature of particles lining the excretory ducts of pseuodphyllidean cestodes. Journal of Purasitology61: 1006-1015. DOUGLAS C. J., S~ANELONI R. J., RUFJIN R. A. & NESTER E. W. 1985. Identification and genetic analyses of an Agrobacterium tumefuciens chromosomal virulence region. Journal of Bacteriology 161: 850-860. GIBBS A. J. 1973. Other invertebrates. In: Frontiers of Biology 31, Viruses and Invertebrates (Edited by GIBBS A. J.), pp. 526-530. North-Holland, Amsterdam and London.
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GITTER B. D., MCCORMICK S. L. & DAMIAN R. T. 1982. Murine alloantigen acquisition by Schistosomn mansoni: presence of H-2K determinants on adult worms and failure of allogeneic lymphocytes to recognize acquired MHC gene products on schistosomula. Journal of Parasitology 68: 513-518. GOFF L. J. & COLEMAN A. W. 1984. Transfer of nuclei from a parasite to its host. Proceedings of the National Academy of Science, USA 81: 5420-5424. GUARDIOLA J. 1983. Extrachromosomal genetic elements and their relation to parasitism. In: Molecular Biology of Parasites (Edited by GUARDIOLA J., LUZZATTO L. and TRAGER W.), pp. 65-71. Raven Press, New York. HAMILTON W. D. 1982. Pathogens as causes of genetic diversity in their host populations. In: Population Biology of Infectious Disease (Edited by ANDERSON R. M. & MAY R. M.), pp. 269-296. Springer, Berlin, Heidelberg, New York. HARRISON B. D. 1973. Viruses and nematodes. In: Frontiers of Biology 31 Viruses and Invertebrates (Edited by GIBBS A. J.), pp. 513-525. North-Holland, Amsterdam and London. JACOBSON S. & BIDDISON W. E. 1984. MHC molecules as virus receptors. Immunology Today 5: 262-263. LEWIN R. 1985. Fish to bacterium gene transfer. Science 227: 1020. LUBINSKY G. & DESSER S. 1963. Growth of the vegetatively propagated strain of larval Echinococcus multilocularis in C57L/J, B6AF, and A/J mice. Canadian Journal of Zoology41: 1213-1216. MICHAELI D., SENYK G., MAOZ A. & FUCHS S. 1972. Ascaris cuticle collagen and mammalian collagens: Cell mediated and humoral immunity relationships. Journal of Immunology 109: 103-109. MOWAT M. & BERNSTEIN A. 1983. Linkage of the Fv-2 gene to a newly reinserted ecotropic retrovirus in Fv-2 congenic mice. Journal of Virology 47: 471-477. MUELLER J. F. 1974. The biology of Spirometra. Journal of Parasitology 60: 3-14. MUELLER J. F. & STRANO A. J. 1974a. Sparganum proliferum, a sparganum infected with a virus? Journal of Parasitology60: 15-19. MUELLER J. F. & STRANO A. J. 1974b. The ubiquity of type-C viruses in spargana of Spirometra spp. Journal of Parasitology 60: 398. MULLER R. & VERMA I. M. 1984. Expression of cellular oncogenes. Current Topics in Microbiology and Immunology 112: 73-l 15.
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REANNY D. 1976. Extrachromosomal elements as possible agents of adaptation and development. Bacteriological Reviews 40: 552-590. SCHAD G. 1966. Immunity, competition and natural regulation of helminth populations. The American Naturulist 100: 359-364. SCHNIEKE A., HARBERS K. & JAENISCH R. 1983. Embryonic lethal mutation in mice induced by retrovirus insertion into the al (1) collagen gene. Nature, London 304: 315-320. SHILG B-Z. & WEINBERG R. A. 1981. DNA sequences homologous to vertebrate oncogenes are conserved in Drosophila melanogaster. Proceedings of the National Academy of Sciences, USA 78: 6789-6792. SIMPSGN A. J. G., SINGER D., MCCUTCHAN T. F., SACKS D. L. & SHER A. 1983. Evidence that schistosome MHC antigens are not synthesized by the parasite but are acquired from the host as intact glycoproteins. Journal of Immunology 131: 962-965. SMITHERS S. R., TERRY R. J. & HOCKLEY D. J. 1969. Host antigens in schistosomiasis. Proceedings of the Royal Society Series B, 171: 483-494. SMYTH J. D. 1973. Some interface phenomena in parasitic protozoa and platyhelminths. Canadian Journal of Zoology 51: 367-377. SPRENT J. F. A. 1962. Parasitism, immunity and evolution. In: The Evolution of Living Organisms (Edited by LEEPER G. W.), pp. 149-165. Melbourne University Press, Melbourne. STEELE E. J. 1979. Somatic Selection and Adaptive Evolution: On the Inheritance of Acquired Characters. Williams and Wallace International. STEFFEN D. L., TAYLOR B. A. & WEINBERG R. A. 1982. Continuing germ line integration of AKV proviruses during the breeding of AKR mice and derivative recombinant inbred strains. Journal of Virology 42: 165-175. STRAYER D. R. & GILLESPIE D. H. 1980. The nature and organisation of retroviral genes in animal cells. Virology Monographs 17: l-117. TERZAKIS J. A. 1972. Virus-like particles and sporozoite budding. Proceedings of the Helminthological Society of Washington 39 (Special Issue Basic Research in Malaria): 129-137.
6, pp.
597400,
1985
AUSTRALIAN SOCIETY FOR PARASITOLOGY PRESIDENTIAL ADDRESS* GENE EXCHANGE
BETWEEN M.
Department
J. HOWELL
of Zoology, Australian National Canberra, ACT 2601, Australia
PARASITES and their hosts represent intimate, interactive genetic systems. Given the respective obligatory and nonobligatory nature of the relationship to each of the organisms involved parasites would seemingly have had to make particularly significant genetic adjustments in adapting to their hosts. But such adjustments have not been the sole prerogative of parasites; the elaboration of defence mechanisms by hosts and the generation of biochemical diversities among them are considered to have arisen in response to the selection pressures imposed by parasitic infection (Hamilton, 1982). The spectrum of biochemical characteristics of red cells selected for by malarial infection are especially well known examples of adaptive changes that can take place in infected animals. Most biologists would explain the evolution of hostparasite relationships in terms of neo-Darwinism-random mutation and recombination generating variation with natural selection acting on the variation so produced. However, there is at least one additional mechanism that can be invoked to account for some variation as this address will attempt to show. The facts are not new, but the ideas they suggest have not, to my knowledge, been proposed before in a parasitological context; the ideas derive from a recent controversial text on evolution (Steele, 1979) and some astonishing findings in molecular biology over the past few years. It is difficult to generalise about a phenomenon as diverse as parasitism. One possible outcome of the relationship between a host and parasite is the development of a state of tolerance, where there is an apparent failure of the host to recognise the parasite as foreign and to respond in such a way that is detrimental to the parasite’s survival. This idea was originally developed by Sprent (1962) and termed ‘adaptation tolerance’. It was envisaged as a dual modification of host and parasite-a deletion of antigen combining sites in the former paralleled by stabilization of parasite antigens towards conformity with related substances in the host. The concept of a reduction in the antigenic disparity between parasite and host, especially in what has been termed the parasite’s “fitness” antigens (Dineen, 1963), is consistent with Sprent’s hypothesis. The discovery of “host antigens” in or on parasites (Capron, Biguet, Vernes & Afchain, 1968; Smithers, Terry & Hockley, 1969) lent support to the hypothesis; parasites appeared to have the genetic capacity to produce hostlike substances. Perhaps the most convincing evidence of
*Annual
General
Meeting,
Sydney,
HOSTS AND PARASITES
28 August
University,
this is the demonstration of a “mouse” protein, a2-macroglobulin, on the body surface of schistosomes (Damian, 1967). Other notable examples are the close similarity between human and Ascaris collagens (Michaeli, Senyk, Maoz & Fuchs, 1975) and the ability of liver fluke to synthesise human blood group substances (Ben-Ismail, Mulet-Clamagirand, Carme & Gentilini, 1982). There are additional recorded instances of antigen sharing by hosts and parasite (Capron el al., 1968; Damian, 1979), but in these cases the possibility that host-like molecules in parasites were passively acquired rather than synthesised de now or indeed synthesised from messenger RNA captured from hosts (Smyth, 1973) has not been excluded. If parasites have the genetic capacity to synthesise macromolecules either identical to or closely resembling those produced by their hosts, it can be assumed that their genomes contain DNA sequences that are identical, or closely related, to those of their hosts (DNA homology). Such homology represents either conservation over the long periods of time that have elapsed during the evolution of metazoan animals, or more recent adaptive change for which neo-Darwinism would generally be invoked as an explanation. However, it is argued here that DNA homologies between parasites and their hosts may have arisen by the direct incorporation of host genetic material into the parasite genome. Indeed, this type of event is not without precedent; it underlies the presence of the gene for superoxide dismutase in a bacterium which inhabits the light-producing organs of some fish. This gene, which is part of the bacterial chromosome, has clearly been captured from the genome of the fish (Lewin, 1985). In the present discussion this notion of interspecies gene transfer is taken further to suggest that that there has been a two way flow of DNA-from host to parasite and vice versa. Such exchange rather than the slower processes of mutation and recombination opens up the possibility of more rapid evolution, a desirable prospect for an organism endeavouring to bridge the gap between a free-living and parasitic mode of life or indeed to a host adapting to a parasitic infection. From the parasite’s point of view this two-way gene exchange can be seen to offer the following, but not necessarily the only, advantages: incorporation of parasite genetic material into the host genome may lead to tolerance towards the parasite if the information is expressed and recognised by the host as self during its development. Incorporation of host DNA into the parasite genome may lead to the expression of certain host macromolecules by the parasite which facilitate the avoidance of immune
1985 597
598
M. J. HOWELL
responses. In effect, these exchanges of DNA offer an unconventional explanation for adaptation tolerance. It is possible to envisage selective advantages which may also accrue to the host if reciprocal gene exchange took place. If a host produced a parasite molecule which played a crucial role in the orderly development of that parasite at inappropriate times or at inappropriate concentrations it may be able to regulate the parasite population by nonimmunological means. There may be an analogy here between plants and herbivores; the production of oestrogen and juvenile hormone analogues by plants can have deleterious consequences for the breeding activities of the animals which consume them (Damian, 1979). In the case of the expression of host DNA by the parasite, certain physiological processes in the host may be amplified with desirable consequences for the host; it may grow faster and compete more effectively and enjoy greater reproductive success. In this respect, the genetic capacity of the cestode Spirometra mansonoides to produce a mammalian growth hormone-like substance that stimulates mice to grow to rat-like proportions (Mueller, 1974) may have some relevance. Thus far consideration has been given to gene exchange between hosts and parasites. However, the possibility of gene exchange between parasites that share the same host should not be discounted; does this underlie the phenomenon of cross-immunity? Non-reciprocal cross-immunity (Schad, 1966) could represent a situation where one species of parasite has acquired the DNA of another, expresses the antigens it codes for and generates immunity to the potentially competing parasite. How, then, could direct gene exchange occur? How could genetic information acquired in this way become fixed in the germ line, a prerequisite if such events are to have any impact on the evolution of parasites and their hosts? Likely candidates for effecting a two-way transfer of genetic information between hosts and parasites-and indeed between parasites-are the retroviruses. Retroviruses are RNA viruses; their mode of replication is considered briefly here but a more detailed account is given by Strayer &Gillespie (1980) and Muller & Verma (1984). On infecting a eukaryotic cell the viral RNA is copied into DNA by the enzyme reverse transcriptase; this DNA enters the cell nucleus where it integrates into the DNA of a host chromosome. Following transcription, some of the viral RNA is translated into protein which encloses additional copies of viral RNA. Mature viral particles bud from the cell membrane but the cell is not killed. Retroviruses possess a number of interesting properties which are worth reiterating here. Firstly, an RNA virus may remain in the host genome in a silent or latent form, replicating at each cell division but failing to produce viral particles (Strayer & Gillespie, 1980). The virus may even enter the genome of germ cells and become vertically transmitted through successive generations of the host species (Steffen, Taylor, & Weinberg, 1982; Mowat & Bernstein, 1983; Schieke, Harbers & Jaenisch, 1983). For example, all domestic cats and their closest relatives have a silent virus-RB114-in their genome which rarely produces viral particles. The virus is thought to have entered the germ line of the ancestors of domestic cats (probably from baboons) and has remained within their genome since that time. Neither the virus nor any part of its genome is present in other members of the cat family (Strayer & Gillespie, 1980). Secondly, retroviruses can transduce host DNA; that
I.J.P. VOL. 15. 1985
is they can, through their close association with the host genome, capture host DNA sequences (these are referred to as oncogenes) by way of RNA copies which then become a characteristic feature of their genomes (Bishop, 1983). Infection of other host species or other members of the same host species with such a virus can lead to the insertion of the transduced DNA into the genome of the new host cell, an event which may be followed by tumour growth. An example of an oncogenic retrovirus is FBJ-murine osteosarcoma virus which induces neoplastic tumours in new born mice. This virus carries an oncogene (v-fos) which is homologous with DNA in the genomes of a number of vertebrates (Curran, Peters, Van Beveren, Teich & Verma, 1982) and which has clearly been transduced from normal cellular DNA. Many other examples are also known (Strayer & Gillespie, 1980; Bishop, 1983; Muller & Verma, 1984). Oncogenes, which are part and parcel of the normal genome of all cells, appear to code for proteins involved in important developmental processes. When they are transduced by retro-viruses and inserted into aberrant locations within the genomes of other cells, they may escape from the normal regulatory processes which control their activity and precipitate uncontrolled growth. Oncogenes are present in both invertebrates and vertebrates. There is also homology between oncogenes in animals as widely separated as nematodes, insects, birds and mammals (Shilo & Weinberg, 1981). Thus, oncogenes appear to have been conserved throughout an extremely long period of evolution. On three grounds retroviruses have the potential to act as vehicles for the exchange of genetic material between hosts and parasites. They can (a) transduce DNA; (b) cross species boundaries; (c) enter the germ lines of their hosts. However, it should be noted that the ability of retroviruses to transduce cellular genes other than oncogenes has not yet been established (Bishop, 1983). The question that remains is what sort of evidence would be looked for in support of the occurrence of viral-mediated gene exchange between hosts and parasites (or indeed between parasites) by retroviruses. Two major areas of investigation could be considered: (a) the existence of retroviruses common to both hosts and parasites; (b) DNA sequence homologies between host, parasite and virus genomes. Viruses (or virus-like particles) have been detected in protozoa (Terzakis, 1972; Gibbs, 1973), cestodes (Mueller & Strano, 1974a, b; Dougherty, Distefano, Feller&Mueller, 1975), trematodes (Byram, Ernst, Lumsden & SogandaresBernal, 1975), and nematodes (Harrison, 1973). In some cases the particles have similarities to C-type (RNA) viruses. More intensive work should uncover other examples. Of course the presence of viruses in the hosts of these parasitic groups has been well known for many years, and in insects, birds and mammals especially, RNA viruses are commonly encountered (Bellett, Fenner & Gibbs, 1973). Thus, one of the requirements for viral-mediated exchange of genetic material between hosts and parasites is probably met; but there is no guarantee that RNA viruses would be capable of crossing the broad phylogenetic gaps that exist between parasites and their hosts. Recent reports that major histocompatibihty complex (MHC) molecules of mammals act as virus receptors (Jacobson & Biddison, 1984) and that MHC antigens are present on schistosomes (Gitter, McCormick & Damian, 1982) means, however, that such exchanges are not entirely out of the question. More direct support for the idea of gene exchange
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between hosts and parasites would come from the demonstration of homologous DNA sequences (other than evolutionarily conserved DNA sequences) in both partners in a relationship by, for example, the technique of Southern blotting; or by comparison of immunoprecipitation profiles obtained from translation products of messenger RNA of host and parasite origin. What is required for Southern blotting is a set of specific DNA sequences or probes which would enable host and parasite genomes to be compared. In order for the technique to provide evidence of comparatively recent gene exchange these probes would need to be DNA sequences which have not been evolutionarily conserved. The value of one such probe is exemplified by a study which has answered a fundamental question regarding the origin of certain host antigens in schistosomes. Adult schistosomes grown in mice carry mouse MHC antigens on their surfaces (Gitter et al., 1982). By probing the parasite genome with mouse MHC-specific DNA it was shown that there was no apparent DNA sequence homology between host and parasite and thus the MHC antigens on the worms would seem to be clearly of host origin (Simpson, Singer, McCutchan, Sacks & Sher, 1983). The immunoprecipitation procedure would be amenable to immediate investigation; messenger RNA could be isolated from host and parasite, translated in vitro and each set of proteins probed with antisera to either host or parasite antigens. In this way it could be determined whether host and parasite produced messenger RNA transcripts that gave rise to antigenically related molecules. A problem with this approach may be evolutionary conservatism; but, as with the Southern blotting technique, the burgeoning availability of specific probes in the form of monoclonal antibodies may provide a way around this potential obstacle. One of the consequences of host/parasite gene exchange mediated by retroviruses may be the induction of abnormal growth. Such transfer of genetic information may disturb the expression of growth regulatory substances in normal tissues and lead to neoplasia. What is envisaged here is something similar to the induction of tumours in vertebrates by the oncogenic retroviruses (Muller & Verma, 1984). In support of this idea it is noted that some parasites such as Echinococcus multilocularis (see Lubinsky & Desser, 1963) and Spirometra proliferum (see Mueller & Strano, 1974a) behave like cancerous growths. In the case of S. prohferum it was suggested that its unusual development may be the result of a virus infection. Additionally, neoplasia of host tissue has been associated with several protozoan and helminth infections (Cheng, 1973). In summary, this discussion has put forward the hypothesis that gene exchange mediated by retroviruses may give rise to some of the variation in parasites and hosts that natural selection has to work on. Benefits to both host and parasite that could accrue from these exchanges have been referred to. However, it should be noted that this source of variation may not be the only mechanism other than mutation and recombination that leads to evolutionary change in these organisms. Extrachromosomal genetic elements such as plasmids and phages occur widely in prokaryotes. Plasmids in particular can mobilise and transfer genetic information such as antibiotic resistance between distantly related bacterial species (Reanny, 1976) and between bacteria and higher plants as in the induction of crown gall tumours (Douglas, Staneloni, Rubin & Nester, 1985). A number of extrachromosomal genetic elements other than plasmids and viruses (eg. viroids, endosymbiotic
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organims) also occur in eukaryotes. The existence of this mobile genetic material adds another dimension to the hypothesis put forward in this paper, and its possible contribution to the co-evolution of hosts and parasites cannot be overlooked (Guardiola, 1983). The recent demonstration of a red algal parasite’s ability to insert its nuclei into the cells of its red algal host (Goff & Coleman. 19841 is an additional and subtle way in which host and parasit; DNA can intimately interact; its consequences are probably far reaching. Molecular biology has the tools to investigate further all of these phenomena. It is certainly possible that the results of such studies may modify our views of parasitism and add to the fascination of this intriguing phenomenon.
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GITTER B. D., MCCORMICK S. L. & DAMIAN R. T. 1982. Murine alloantigen acquisition by Schistosomn mansoni: presence of H-2K determinants on adult worms and failure of allogeneic lymphocytes to recognize acquired MHC gene products on schistosomula. Journal of Parasitology 68: 513-518. GOFF L. J. & COLEMAN A. W. 1984. Transfer of nuclei from a parasite to its host. Proceedings of the National Academy of Science, USA 81: 5420-5424. GUARDIOLA J. 1983. Extrachromosomal genetic elements and their relation to parasitism. In: Molecular Biology of Parasites (Edited by GUARDIOLA J., LUZZATTO L. and TRAGER W.), pp. 65-71. Raven Press, New York. HAMILTON W. D. 1982. Pathogens as causes of genetic diversity in their host populations. In: Population Biology of Infectious Disease (Edited by ANDERSON R. M. & MAY R. M.), pp. 269-296. Springer, Berlin, Heidelberg, New York. HARRISON B. D. 1973. Viruses and nematodes. In: Frontiers of Biology 31 Viruses and Invertebrates (Edited by GIBBS A. J.), pp. 513-525. North-Holland, Amsterdam and London. JACOBSON S. & BIDDISON W. E. 1984. MHC molecules as virus receptors. Immunology Today 5: 262-263. LEWIN R. 1985. Fish to bacterium gene transfer. Science 227: 1020. LUBINSKY G. & DESSER S. 1963. Growth of the vegetatively propagated strain of larval Echinococcus multilocularis in C57L/J, B6AF, and A/J mice. Canadian Journal of Zoology41: 1213-1216. MICHAELI D., SENYK G., MAOZ A. & FUCHS S. 1972. Ascaris cuticle collagen and mammalian collagens: Cell mediated and humoral immunity relationships. Journal of Immunology 109: 103-109. MOWAT M. & BERNSTEIN A. 1983. Linkage of the Fv-2 gene to a newly reinserted ecotropic retrovirus in Fv-2 congenic mice. Journal of Virology 47: 471-477. MUELLER J. F. 1974. The biology of Spirometra. Journal of Parasitology 60: 3-14. MUELLER J. F. & STRANO A. J. 1974a. Sparganum proliferum, a sparganum infected with a virus? Journal of Parasitology60: 15-19. MUELLER J. F. & STRANO A. J. 1974b. The ubiquity of type-C viruses in spargana of Spirometra spp. Journal of Parasitology 60: 398. MULLER R. & VERMA I. M. 1984. Expression of cellular oncogenes. Current Topics in Microbiology and Immunology 112: 73-l 15.
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REANNY D. 1976. Extrachromosomal elements as possible agents of adaptation and development. Bacteriological Reviews 40: 552-590. SCHAD G. 1966. Immunity, competition and natural regulation of helminth populations. The American Naturulist 100: 359-364. SCHNIEKE A., HARBERS K. & JAENISCH R. 1983. Embryonic lethal mutation in mice induced by retrovirus insertion into the al (1) collagen gene. Nature, London 304: 315-320. SHILG B-Z. & WEINBERG R. A. 1981. DNA sequences homologous to vertebrate oncogenes are conserved in Drosophila melanogaster. Proceedings of the National Academy of Sciences, USA 78: 6789-6792. SIMPSGN A. J. G., SINGER D., MCCUTCHAN T. F., SACKS D. L. & SHER A. 1983. Evidence that schistosome MHC antigens are not synthesized by the parasite but are acquired from the host as intact glycoproteins. Journal of Immunology 131: 962-965. SMITHERS S. R., TERRY R. J. & HOCKLEY D. J. 1969. Host antigens in schistosomiasis. Proceedings of the Royal Society Series B, 171: 483-494. SMYTH J. D. 1973. Some interface phenomena in parasitic protozoa and platyhelminths. Canadian Journal of Zoology 51: 367-377. SPRENT J. F. A. 1962. Parasitism, immunity and evolution. In: The Evolution of Living Organisms (Edited by LEEPER G. W.), pp. 149-165. Melbourne University Press, Melbourne. STEELE E. J. 1979. Somatic Selection and Adaptive Evolution: On the Inheritance of Acquired Characters. Williams and Wallace International. STEFFEN D. L., TAYLOR B. A. & WEINBERG R. A. 1982. Continuing germ line integration of AKV proviruses during the breeding of AKR mice and derivative recombinant inbred strains. Journal of Virology 42: 165-175. STRAYER D. R. & GILLESPIE D. H. 1980. The nature and organisation of retroviral genes in animal cells. Virology Monographs 17: l-117. TERZAKIS J. A. 1972. Virus-like particles and sporozoite budding. Proceedings of the Helminthological Society of Washington 39 (Special Issue Basic Research in Malaria): 129-137.