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Rodent malaria
476 TRANSACTIONS OP THE ROYAL SOCIKW OP TROPICAL MEDICINE
AND
HYGIENE, VOL. 73, No. 4,1979
Book Reviews
R. Killick-Kendrick and W. Rodent Malaria. Peters (Editors). 1978. London: Academic Press. xxv + 406 pp. (illus.). ISBN 0 12 407150 3. Price gl9.20. The brief title of this book does nothing to advertise the richness of its contents. The book is based on four particular species of rodent malaria, Plasmodium berghei, P. yoelii, P. vinckei, P. chabaudi
and their subspecies, discovered during the past 30 years in African thicket rats, especially Thamnomys rutilans. Such elusive protozoa might well have been left in academic obscurity, were it not for their capacity to be maintained cyclically in laboratory rodents and mosquitoes, making them the most convenient models of mammalian malaria. During the 194Os, Ignace Vincke purposefully tracked down the first strains of these parasites in Katanga after having detected sporozoites in Anopheles dureni millec~mpsi, a forest mosquito that breeds in streams. Not until 1964 did Meir Yoeli overcome the difficulties of transmitting these malarias via laboratory anophelines. Research on rodent malaria has now become so prolific and diversified as to have been reported in well over 1,000 publications. This book therefore summarizes a burgeoning subject, the frontiers of which are expanding most rapidly in the areas of malaria genetics, pathology, biochemistry, physiology, chemotherapy and immunology. Professor L. J. Bruce-Chwatt provides an ample introduction drawing on his broad knowledge of malariology, but glossing over his personal discovery in Nigeria of the parasite later to be called P. vinckei brucechwatti. History is well served by this record of the events whereby rodent malarias and their vectors were first found and identified (see Mosquito Systematics 7: 313, for additional notes on mosquito names), and of how these parasites have become such important subjects for laboratory experimentation. The opening chapter by R. Killick-Kendrick on taxonomy, zoogeography and evolution of rodent malaria is an erudite exposition of some rather baffling biological problems. Special attention is given to the general questions of Plasmodium classification, speciation and nomenclature before dwelling on the distributions and complexities of the four main species at issue. Animal behaviour, vegetation and even palaeoclimatology are brought into this analysis of the imperfectly known patterns of rodent malaria ecology and distribution in Africa. Admitting that some of his ideas are sneculative. Killick-Kendrick points out some interesting topics to follow UD in the field and in the laboratorv. He also regrets how little is known about the various other malaria species currently grouped in the subgenus Vinckeiu.
Life cycles and morphology of the four murine parasites are covered by I. Landau and Y. Boulard in a chapter translated from French by W. Peters. They stress the vital point, originally deduced by Yoeli, that relatively low temperatures are required for sporogony of P. berghei (18 to 21°C) because its natural vectors tend to rest in cool situations. Attention is also drawn to the occurrence of relapses that may be due to a special kind of chronic liver schizont. If this relapse mechanism of rodent malaria could be exnlained it might helu to solve the problem of relapsing human m:laria (cf. SHUTE et al., 1976; Trans. R. Sot. trop. Med. Hyg., 70, 474-481). A painstaking account of the cell biology of malaria is provided by R. E. Sinden. Here for the first time in the book we seeproof of the importance of studies on these amenable rodent parasites. Much of what is known about the ultrastructure and intracellular activities of Plasmodium is described in detail and illustrated in more than 60 electronmicrographs, mostly of P. yoeZii nigeriensis. This chapter gives the book a hard core, not simply by presenting an informative pictorial atlas of malaria parasites and their organelles at successive stages of development, but also because the explanatory text is so well interpreted. C. A. Homewood then makes a brave attempt to as investigated in review malaria biochemistry, three of the murine malaria species. Due to the technical difficulty of such studies, many workers have evidently mistaken results from host tissues for data pertaining to the parasites. Many plasmodial enzymes have now been identified, but the functions of few have been properly investigated and virtually nothing is yet known about the control of metabolism in malaria. Even so, the known contrasts between enzymes of rodent red cells and those of intra-erythrocytic parasites (notably the enzymes involved in producing nucleic acids and folate cofactors) give good indications of which biochemical targets might be most vulnerable to chemotherapeutic attack with blood schizontocides. The distinctive biochemical processes in other parasite stages are less well known, except that citric acid cycle enzymes appear only during sporogony in the vector. Homewood makes it clear that rodent malarias are fruitful materials for further biochemical research, provided that appropriate caution is exercised in the execution of the work and the interpretation of results. Genetics is covered by G. H. Beale, R. Carter and D. Walliker, largely from their own work with five isolates of P. bewhei. 24 of P. chabaudi (two subspp.), 12 of P. v&kei’(four subspp.) and 23 of P. yoelii (three subspp.). This unprecedented range of testable genotypes has permitted Plasmodium
477
BOOK REVIEWS
genetics to open up rapidly during the past decade; the inheritance of isozymes, virulence, antigenicity and drug resistance are the main lines of interest. Various polymorphisms have been found and particular genotypes have been selected or cloned. Since the chromosomes of malaria never condense discretely, the number of linkage groups is still in doubt (Sinden suggests 10 from cytological evidence). Genetic markers follow normal Mendelian rules of inheritance and genetic recombination occurs at some stage. There appears to be a regular eukaryotic life-cycle, blood stages of the parasites being haploid. Since clones from individual blood parasites can produce both micro- and macrogametes, it is inferred that gametic differentiation must be non-genetic. No attempt is made here to explain this apparent contradiction. Hybridization studies show that intraspecific crosses succeed, even between subspecies, whereas interspecific crosses fail. These findings have, of course, been taken into account in the prevailing taxonomy. R. S. Nussenzweig, A. H. Cochrane and H. J. responses to Lustwig deal with immunological malaria, perhaps the most important area of developing research where “the rodent malaria model appears to provide optimal conditions for experimental manipulation and investigation”. Consideration is given to innate resistance, cell-mediated immunity and humoral immunity. Attention is focussed on the antibody-mediated protective mechanisms so effective against extracellular parasite stages (merozoites and sporozoites) in the blood. As in man, rodent malaria antibodies may be passivelv transferred in serum or congenitally: The precise identity of the immunoglobulins involved has not yet been determined. Th
infections.
He discusses interactions in mice between malaria and various viruses (Influenza A, Moloney, Newcastle, Rowson-Parr, Semliki forest, Urethane leukaemia, West Nile), bacteria (Bordetella pertussis, Borrelia duttoni, Corynebacterium parvum, Escherichia coli, Mycoplasma neurolyticum, Mycobacterium bovis, Salmonella typhimurium), rickettsiae (Eperythrozoon coccoides, Haemobartonella muris), piroplasms (Anthemosoma garnhami, Babesia spp.), trypanosomes (T. lewisi, T. musculi), Giardia muris, Leishmania infanturn, Toxoplasma gondii, psittacosis and certain helminths (Nippostrongylus brasiliensis, Trichuris muris, Schistosoma mansoni). Professor Cox
has gathered together a surprising amount of significant data on this nebulous subject, including information on some comparable interactions between plasmodia and other parasites in mosquitoes. He concludes that the mutual interference of concomitant infections is usually disadvantageous to mammals. Since multiple infections are common in nature, he argues, these effects should be studied much more.
The fmal chapter, by Professor W. Peters and It tells R. E. Howells, concerns chemotherapy. first of the way that P. berghei was used for screening more than 250,000 chemical compounds to find a dozen new antimalarial drugs of continuing promise. The main American screening- _programme, using methods devised by Leo Rane and his wife, was based on survival time of infected mice treated with a single dose of the candidate compound. This berghei system proved economical and successful for detecting blood schizontocides. Other screening procedures employ P. berghei or P. yoelii to detect tissue schizontocides, sporontocides or causal prophylactic drugs. In general, results obtained with rodent malaria are comparable with what occurs when the drug concerned is used against P. falciparum or P. vivax in man. Resistant strains of P. berghei have been selected in relation to all antimalarial drugs, enabling early research on how to circumvent the problems of resistance and crossresistance. Chloroquine-resistant strains of P. berahei and P. voelii were found to vield zametocvtes wirh enhanced infectivity to mosquitoes; unfortunately similar effects occur in P. falciparum and may have contributed to the spread of chloroquineresistant human malaria. On the other hand, chemotherapeutic research on rodent malaria has sometimes been complicated by the occurrence in Anopheles stephensi of a cytotoxic virus or of microsporidia having deleterious effects on plasmodia in the vector. The book ends promisingly, with examples of how antimalarial drugs with known modes of action are being employed as biological probes for revealing more about the biochemistry of malaria. Multi-authored specialist books are seldom so well balanced and coherent, with a fully factual text that non-specialists can assimilate. For each topic, the context and conceptual background are explained enough to give the impression of a more general textbook; principles of parasitology as revealed through case studies on rodent malaria! The index, references and cross-referencing are generously done; the design and presentation on glossy paper give extra satisfaction. Gver 100 graphs, diagrams and half-tone plates (including portraits of some dramatis personae) are nicely reproduced, but a helpful colour plate portraying parasite blood stages(18 photomicrographs @ 25 x 38 mm) suffers from over-reduction. Editors, authors, publishers and printers have kept errors and misprints to a minimum: the product seems to be fair market value, but at a price that few individuals can afford. By giving such a lengthy review of this festschrift for a few favourite protozoa, I may have helped to justify the visionarv auest of Vincke and his followers; at least I have summarized its outcome for the benefit of readers who cannot see the book itself. Such books should inspire others to develoo and apply new techniques^ to the study of further organisms that may serve as raw materials or models in paramedical research. In addition to its academic merit, therefore, this book symbolizes how some .of the spirits that support the WHO Special Programme for Research on Tropical Diseases are working wonders with rodent malaria. I
GRAHAM WHITE
AND
HYGIENE, VOL. 73, No. 4,1979
Book Reviews
R. Killick-Kendrick and W. Rodent Malaria. Peters (Editors). 1978. London: Academic Press. xxv + 406 pp. (illus.). ISBN 0 12 407150 3. Price gl9.20. The brief title of this book does nothing to advertise the richness of its contents. The book is based on four particular species of rodent malaria, Plasmodium berghei, P. yoelii, P. vinckei, P. chabaudi
and their subspecies, discovered during the past 30 years in African thicket rats, especially Thamnomys rutilans. Such elusive protozoa might well have been left in academic obscurity, were it not for their capacity to be maintained cyclically in laboratory rodents and mosquitoes, making them the most convenient models of mammalian malaria. During the 194Os, Ignace Vincke purposefully tracked down the first strains of these parasites in Katanga after having detected sporozoites in Anopheles dureni millec~mpsi, a forest mosquito that breeds in streams. Not until 1964 did Meir Yoeli overcome the difficulties of transmitting these malarias via laboratory anophelines. Research on rodent malaria has now become so prolific and diversified as to have been reported in well over 1,000 publications. This book therefore summarizes a burgeoning subject, the frontiers of which are expanding most rapidly in the areas of malaria genetics, pathology, biochemistry, physiology, chemotherapy and immunology. Professor L. J. Bruce-Chwatt provides an ample introduction drawing on his broad knowledge of malariology, but glossing over his personal discovery in Nigeria of the parasite later to be called P. vinckei brucechwatti. History is well served by this record of the events whereby rodent malarias and their vectors were first found and identified (see Mosquito Systematics 7: 313, for additional notes on mosquito names), and of how these parasites have become such important subjects for laboratory experimentation. The opening chapter by R. Killick-Kendrick on taxonomy, zoogeography and evolution of rodent malaria is an erudite exposition of some rather baffling biological problems. Special attention is given to the general questions of Plasmodium classification, speciation and nomenclature before dwelling on the distributions and complexities of the four main species at issue. Animal behaviour, vegetation and even palaeoclimatology are brought into this analysis of the imperfectly known patterns of rodent malaria ecology and distribution in Africa. Admitting that some of his ideas are sneculative. Killick-Kendrick points out some interesting topics to follow UD in the field and in the laboratorv. He also regrets how little is known about the various other malaria species currently grouped in the subgenus Vinckeiu.
Life cycles and morphology of the four murine parasites are covered by I. Landau and Y. Boulard in a chapter translated from French by W. Peters. They stress the vital point, originally deduced by Yoeli, that relatively low temperatures are required for sporogony of P. berghei (18 to 21°C) because its natural vectors tend to rest in cool situations. Attention is also drawn to the occurrence of relapses that may be due to a special kind of chronic liver schizont. If this relapse mechanism of rodent malaria could be exnlained it might helu to solve the problem of relapsing human m:laria (cf. SHUTE et al., 1976; Trans. R. Sot. trop. Med. Hyg., 70, 474-481). A painstaking account of the cell biology of malaria is provided by R. E. Sinden. Here for the first time in the book we seeproof of the importance of studies on these amenable rodent parasites. Much of what is known about the ultrastructure and intracellular activities of Plasmodium is described in detail and illustrated in more than 60 electronmicrographs, mostly of P. yoeZii nigeriensis. This chapter gives the book a hard core, not simply by presenting an informative pictorial atlas of malaria parasites and their organelles at successive stages of development, but also because the explanatory text is so well interpreted. C. A. Homewood then makes a brave attempt to as investigated in review malaria biochemistry, three of the murine malaria species. Due to the technical difficulty of such studies, many workers have evidently mistaken results from host tissues for data pertaining to the parasites. Many plasmodial enzymes have now been identified, but the functions of few have been properly investigated and virtually nothing is yet known about the control of metabolism in malaria. Even so, the known contrasts between enzymes of rodent red cells and those of intra-erythrocytic parasites (notably the enzymes involved in producing nucleic acids and folate cofactors) give good indications of which biochemical targets might be most vulnerable to chemotherapeutic attack with blood schizontocides. The distinctive biochemical processes in other parasite stages are less well known, except that citric acid cycle enzymes appear only during sporogony in the vector. Homewood makes it clear that rodent malarias are fruitful materials for further biochemical research, provided that appropriate caution is exercised in the execution of the work and the interpretation of results. Genetics is covered by G. H. Beale, R. Carter and D. Walliker, largely from their own work with five isolates of P. bewhei. 24 of P. chabaudi (two subspp.), 12 of P. v&kei’(four subspp.) and 23 of P. yoelii (three subspp.). This unprecedented range of testable genotypes has permitted Plasmodium
477
BOOK REVIEWS
genetics to open up rapidly during the past decade; the inheritance of isozymes, virulence, antigenicity and drug resistance are the main lines of interest. Various polymorphisms have been found and particular genotypes have been selected or cloned. Since the chromosomes of malaria never condense discretely, the number of linkage groups is still in doubt (Sinden suggests 10 from cytological evidence). Genetic markers follow normal Mendelian rules of inheritance and genetic recombination occurs at some stage. There appears to be a regular eukaryotic life-cycle, blood stages of the parasites being haploid. Since clones from individual blood parasites can produce both micro- and macrogametes, it is inferred that gametic differentiation must be non-genetic. No attempt is made here to explain this apparent contradiction. Hybridization studies show that intraspecific crosses succeed, even between subspecies, whereas interspecific crosses fail. These findings have, of course, been taken into account in the prevailing taxonomy. R. S. Nussenzweig, A. H. Cochrane and H. J. responses to Lustwig deal with immunological malaria, perhaps the most important area of developing research where “the rodent malaria model appears to provide optimal conditions for experimental manipulation and investigation”. Consideration is given to innate resistance, cell-mediated immunity and humoral immunity. Attention is focussed on the antibody-mediated protective mechanisms so effective against extracellular parasite stages (merozoites and sporozoites) in the blood. As in man, rodent malaria antibodies may be passivelv transferred in serum or congenitally: The precise identity of the immunoglobulins involved has not yet been determined. Th
infections.
He discusses interactions in mice between malaria and various viruses (Influenza A, Moloney, Newcastle, Rowson-Parr, Semliki forest, Urethane leukaemia, West Nile), bacteria (Bordetella pertussis, Borrelia duttoni, Corynebacterium parvum, Escherichia coli, Mycoplasma neurolyticum, Mycobacterium bovis, Salmonella typhimurium), rickettsiae (Eperythrozoon coccoides, Haemobartonella muris), piroplasms (Anthemosoma garnhami, Babesia spp.), trypanosomes (T. lewisi, T. musculi), Giardia muris, Leishmania infanturn, Toxoplasma gondii, psittacosis and certain helminths (Nippostrongylus brasiliensis, Trichuris muris, Schistosoma mansoni). Professor Cox
has gathered together a surprising amount of significant data on this nebulous subject, including information on some comparable interactions between plasmodia and other parasites in mosquitoes. He concludes that the mutual interference of concomitant infections is usually disadvantageous to mammals. Since multiple infections are common in nature, he argues, these effects should be studied much more.
The fmal chapter, by Professor W. Peters and It tells R. E. Howells, concerns chemotherapy. first of the way that P. berghei was used for screening more than 250,000 chemical compounds to find a dozen new antimalarial drugs of continuing promise. The main American screening- _programme, using methods devised by Leo Rane and his wife, was based on survival time of infected mice treated with a single dose of the candidate compound. This berghei system proved economical and successful for detecting blood schizontocides. Other screening procedures employ P. berghei or P. yoelii to detect tissue schizontocides, sporontocides or causal prophylactic drugs. In general, results obtained with rodent malaria are comparable with what occurs when the drug concerned is used against P. falciparum or P. vivax in man. Resistant strains of P. berghei have been selected in relation to all antimalarial drugs, enabling early research on how to circumvent the problems of resistance and crossresistance. Chloroquine-resistant strains of P. berahei and P. voelii were found to vield zametocvtes wirh enhanced infectivity to mosquitoes; unfortunately similar effects occur in P. falciparum and may have contributed to the spread of chloroquineresistant human malaria. On the other hand, chemotherapeutic research on rodent malaria has sometimes been complicated by the occurrence in Anopheles stephensi of a cytotoxic virus or of microsporidia having deleterious effects on plasmodia in the vector. The book ends promisingly, with examples of how antimalarial drugs with known modes of action are being employed as biological probes for revealing more about the biochemistry of malaria. Multi-authored specialist books are seldom so well balanced and coherent, with a fully factual text that non-specialists can assimilate. For each topic, the context and conceptual background are explained enough to give the impression of a more general textbook; principles of parasitology as revealed through case studies on rodent malaria! The index, references and cross-referencing are generously done; the design and presentation on glossy paper give extra satisfaction. Gver 100 graphs, diagrams and half-tone plates (including portraits of some dramatis personae) are nicely reproduced, but a helpful colour plate portraying parasite blood stages(18 photomicrographs @ 25 x 38 mm) suffers from over-reduction. Editors, authors, publishers and printers have kept errors and misprints to a minimum: the product seems to be fair market value, but at a price that few individuals can afford. By giving such a lengthy review of this festschrift for a few favourite protozoa, I may have helped to justify the visionarv auest of Vincke and his followers; at least I have summarized its outcome for the benefit of readers who cannot see the book itself. Such books should inspire others to develoo and apply new techniques^ to the study of further organisms that may serve as raw materials or models in paramedical research. In addition to its academic merit, therefore, this book symbolizes how some .of the spirits that support the WHO Special Programme for Research on Tropical Diseases are working wonders with rodent malaria. I
GRAHAM WHITE