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The role of the spleen and immunization against malaria
Update
356
TRENDS in Parasitology
Vol.21 No.8 August 2005
Letters
The role of the spleen and immunization against malaria Geoffrey A. Butcher Department of Biological Sciences, Sir Alexander Fleming Building, Imperial College London, Imperial College Road, London, UK, SW7 2AZ
The article by Engwerda et al. [1] about the importance of the spleen in malaria is a welcome contribution to an aspect of malarial immunity that has recently been somewhat neglected. However, the situation is, perhaps, even more complicated than the authors have portrayed. Although it is generally assumed that the spleen is essential for resistance to Plasmodium, this is not always the case. For example, Wyler et al. [2] reported that splenectomy in some host species causes a normally chronic infection to be eliminated, indicating that the spleen might occasionally provide an environment that is favourable to the parasite rather than to the host. Similarly, although something of a curiosity, the marmoset (Callithrix jacchus) can control infection by Plasmodium knowlesi after splenectomy [3] and in the absence of anti-merozoite antibody [4]. A more complex situation was observed in rhesus monkeys immunized against P. knowlesi with merozoites and Freund’s complete adjuvant (FCA) [3,5]. These animals were shown to be highly immune to challenge by homologous and heterologous isolates. But, if splenectomized and challenged immediately, some monkeys died and some survived; the same result was observed if they were challenged 4–6 weeks after splenectomy [3,5]. Clearly, the spleen was not crucial for maintaining immunity induced by this form of successful vaccination; however, the spleen was necessary for its induction [5] but there was preliminary evidence for non-antibody-mediated killing of parasites by spleen cells in vitro [3]. Attempts to replace FCA with other adjuvants in this system were unsuccessful [3,5]. FCA might be effective because of its high content of mycobacterial unmethylated CpG [6]. FCA generates a variety of effects on the immune system that is now well understood and proving to be of value in the detailed study of cellular events in autoimmune disease [7]. However, its once frequent use in malaria immunization has received less attention as other, more acceptable adjuvants for human use have been developed. The current lack of interest in FCA and malaria vaccination might be a mistake because recent successful immunization of volunteers with low-dose infections of Plasmodium falciparum [8] might mimic some of the features of earlier experiments with FCA in that cell-mediated immunity seems to be the main means of controlling parasite replication in both situations. Corresponding author: Butcher, G.A. ([email protected]). Available online 17 June 2005 www.sciencedirect.com
By way of example of FCA-mediated immunity, Billau and Matthys [7] suggest that the mycobacterial component of FCA causes ‘remodelling of the haemopoietic system.over several weeks characterised by a drastic expansion of immature Mac 1 positive immature myeloid cells’. Differences in the timing of similar remodelling and expansion of lymphoid cells might explain the variation in responses of the challenged splenectomized rhesus monkeys mentioned earlier. Furthermore, there is increasing realization that nonspecific innate immune mechanisms, particularly natural killer cells, might initiate the T-helper 1 cells of the acquired response [9] through interactions with myeloid dendritic cells; because many different leukocyte subtypes can exist outside the spleen [10–13], the latter might be important in initial immunization but might not be essential thereafter. As with the cytokines and lymphokines that have overlapping compensatory functions, evidence from murine malaria suggests that T-cell subsets in the liver might compensate for the absence of a spleen [14]. If so, this could explain the continued resistance to malaria of semi-immune splenectomized humans [15]. Although Good’s suggested use of attenuated parasites or mixtures of different parasite proteins for malaria immunization [8] might sound impractical for large-scale use, understanding the sequence of immunological events following low-dose immunizations in comparison with FCA, and the role of the spleen and liver might help the design of better malaria vaccines than those tested to date. Finally, one of the most intriguing aspects of the role of the spleen in malaria that might be worth re-examining in the light of modern knowledge [16] is the old data relating to its modulation of the surface expression of parasite antigens [17].
References 1 Engwerda, C.R. et al. (2005) The importance of the spleen in malaria. Trends Parasitol. 21, 75–80 2 Wyler, D.J. et al. (1978) The role of the spleen in malaria infections. In Role of the Spleen in the Immunology of Parasitic Diseases. (Tropical Disease Research Series 1), pp. 183–204, Schwabe 3 Langhorne, J. et al. (1979) Preliminary investigations on the role of the spleen in immunity to Plasmodium knowlesi malaria. In Role of the Spleen in the Immunology of Parasitic Diseases. (Tropical Disease Research Series 1), pp. 205–225, Schwabe 4 Butcher, G.A. and Cohen, S. (1972) Antigenic variation and protective immunity in Plasmodium knowlesi malaria. Immunology 23, 503–521 5 Butcher, G.A. et al. (1978) Antibody-mediated mechanisms of immunity to malaria induced by vaccination with Plasmodium knowlesi merozoites. Immunology 34, 77–86
Update
TRENDS in Parasitology
6 Tokunaga, T. et al. (1999) How BCG led to the discovery of immunostimulatory DNA. Jpn. J. Infect. Dis. 52, 1–11 7 Billiau, A. and Matthys, P. (2001) Modes of action of Freund’s adjuvants in experimental models of autoimmune diseases. J. Leukoc. Biol. 70, 849–860 8 Good, M.F. (2005) Vaccine-induced immunity to malaria parasites and the need for novel strategies. Trends Parasitol. 21, 29–34 9 Gerosa, F. et al. (2005) The reciprocal interaction of NK cells with plasmacytoid or myeloid dendritic cells profoundly affects innate resistance functions. J. Immunol. 174, 727–734 10 Ikuta, S. et al. (2004) Enhanced interferon-g production and bacterial clearance in the liver of splenectomised mice in the models of Escherichia coli injection or intestinal obstruction. Shock 21, 452–457 11 Kawamura, T. et al. (2002) Association of CD8C natural killer T cells in the liver with neonatal tolerance phenomenon. Transplantation 73, 978–992 12 Klonz, A. et al. (1996) The marginal blood pool of the rat contains not only granulocytes, but also lymphocytes, NK-cells and monocytes: a second intravascular compartment, its cellular composition, adhesion
Vol.21 No.8 August 2005
13
14
15 16 17
357
molecule expression and interaction with the peripheral blood pool. Scand. J. Immunol. 44, 461–449 Passlick, B. et al. (1991) Post-traumatic splenectomy does not influence human peripheral blood mononuclear cell subsets. J. Clin. Lab. Immunol. 34, 157–161 Weerasinghe, A. et al. (2001) Association of intermediate T cell receptor cells, mainly their NK1.1(K) subset, with protection from malaria. Cell. Immunol. 207, 28–35 Looareesuwan, S. et al. (1993) Malaria in splenectomised patients: report of four cases and review. Clin. Infect. Dis. 16, 361–366 Recker, M. et al. (2004) Transient cross-reactive immune responses can orchestrate antigenic variation in malaria. Nature 429, 555–558 David, P.H. et al. (1983) Parasite sequestration in Plasmodium falciparum malaria: spleen and antibody modulation of cytoadherence of infected erythrocytes. Proc. Natl. Acad. Sci. U. S. A. 80, 5075–5079
1471-4922/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.pt.2005.06.001
What distinguishes malaria parasites from other pigmented haemosporidians? Gediminas Valkiu¯nas1, Ali M. Anwar 2, Carter T. Atkinson3, Ellis C. Greiner 4, Ilan Paperna5 and Michael A. Peirce6 1
Institute of Ecology, Vilnius University, Akademijos 2, Vilnius 21, LT-08412, Lithuania Department of Zoology, Oxford University, South Parks Road, Oxford, UK, OX1 3PS 3 US Geological Survey, Biological Resources Discipline, Pacific Island Ecosystems Research Center, PO Box 44, Hawaii National Park, HI 96718, USA 4 Department of Pathobiology, College of Veterinary Medicine, PO Box 110880, University of Florida, Gainesville, FL 32610, USA 5 Department of Animal Science, Faculty of Agriculture, Hebrew University of Jerusalem, PO Box 12, Rehovot 76-100, Israel 6 MP International Consultancy, 6 Normandale House, Normandale, Bexhill-on-Sea, East Sussex, UK, TN39 3NZ 2
In several recent publications [1–4], the term ‘malaria parasites’ has been used loosely to include all pigmented (and even some non-pigmented) haemosporidian parasites (Sporozoa: Haemosporida) that inhabit red blood cells and sometimes white blood cells. This terminology was in common use during the first half of the 20th century when there was considerable debate about the host range and identity of many of these parasites, but was eventually abandoned because it obscured basic biological differences among these organisms. Based on recent molecular genetic studies, Pe´rez-Tris et al. [3] have reopened the debate. They have proposed that this terminology should once again be used broadly to group avian and possibly mammalian haemoproteids with the more traditional malaria parasites of the genus Plasmodium. We feel, however, that this would obscure important life history and epidemiological characteristics of these organisms that are crucial for understanding their evolutionary relationships with their vertebrate hosts and vectors. Differences in the vectors, life cycles and epidemiology of these organisms (e.g. Plasmodium, Haemoproteus, Parahaemoproteus, Hepatocystis and Nycteria spp.) were recognized by the middle of the 20th century. Close evolutionary Corresponding author: Valkiu¯nas, G. ([email protected]). Available online 20 June 2005 www.sciencedirect.com
relationships, diversity of life history strategies among these organisms, and widespread use of avian, mammalian and reptilian species of Plasmodium as models for human disease, led to confusion among malariologists as to what was considered a ‘malaria’ parasite. The report of a World Health Organization (http://www.who.int/en/) drafting committee composed of prominent malariologists [5] attempted to clarify this by restricting the term ‘malaria parasites’ to the haemosporidians belonging to the genus Plasmodium. Garnham followed this recommendation in his outstanding monograph Malaria Parasites and Other Haemosporidia [6]. Furthermore, subsequent studies and reviews of haemosporidians continued to apply the term ‘malaria parasites’ to those pigmented parasites that multiply in the blood stream (i.e. Plasmodium species) [7–11]. Let us remember that species of Haemoproteus, Hepatocystis and other haemoproteids do not multiply in the blood, even though they sometimes give rise to outward clinical signs and symptoms characteristic of malaria. Furthermore, malaria is characterized by recrudescence and is transmitted by mosquitoes, whereas species belonging to the genus Haemoproteus and closely related genera are not [7,9,11]. We agree with Pe´rez-Tris et al. [3] that there is ample evidence from traditional research and recent molecular genetic studies [1,2,4,6,7,11] that species of Plasmodium
356
TRENDS in Parasitology
Vol.21 No.8 August 2005
Letters
The role of the spleen and immunization against malaria Geoffrey A. Butcher Department of Biological Sciences, Sir Alexander Fleming Building, Imperial College London, Imperial College Road, London, UK, SW7 2AZ
The article by Engwerda et al. [1] about the importance of the spleen in malaria is a welcome contribution to an aspect of malarial immunity that has recently been somewhat neglected. However, the situation is, perhaps, even more complicated than the authors have portrayed. Although it is generally assumed that the spleen is essential for resistance to Plasmodium, this is not always the case. For example, Wyler et al. [2] reported that splenectomy in some host species causes a normally chronic infection to be eliminated, indicating that the spleen might occasionally provide an environment that is favourable to the parasite rather than to the host. Similarly, although something of a curiosity, the marmoset (Callithrix jacchus) can control infection by Plasmodium knowlesi after splenectomy [3] and in the absence of anti-merozoite antibody [4]. A more complex situation was observed in rhesus monkeys immunized against P. knowlesi with merozoites and Freund’s complete adjuvant (FCA) [3,5]. These animals were shown to be highly immune to challenge by homologous and heterologous isolates. But, if splenectomized and challenged immediately, some monkeys died and some survived; the same result was observed if they were challenged 4–6 weeks after splenectomy [3,5]. Clearly, the spleen was not crucial for maintaining immunity induced by this form of successful vaccination; however, the spleen was necessary for its induction [5] but there was preliminary evidence for non-antibody-mediated killing of parasites by spleen cells in vitro [3]. Attempts to replace FCA with other adjuvants in this system were unsuccessful [3,5]. FCA might be effective because of its high content of mycobacterial unmethylated CpG [6]. FCA generates a variety of effects on the immune system that is now well understood and proving to be of value in the detailed study of cellular events in autoimmune disease [7]. However, its once frequent use in malaria immunization has received less attention as other, more acceptable adjuvants for human use have been developed. The current lack of interest in FCA and malaria vaccination might be a mistake because recent successful immunization of volunteers with low-dose infections of Plasmodium falciparum [8] might mimic some of the features of earlier experiments with FCA in that cell-mediated immunity seems to be the main means of controlling parasite replication in both situations. Corresponding author: Butcher, G.A. ([email protected]). Available online 17 June 2005 www.sciencedirect.com
By way of example of FCA-mediated immunity, Billau and Matthys [7] suggest that the mycobacterial component of FCA causes ‘remodelling of the haemopoietic system.over several weeks characterised by a drastic expansion of immature Mac 1 positive immature myeloid cells’. Differences in the timing of similar remodelling and expansion of lymphoid cells might explain the variation in responses of the challenged splenectomized rhesus monkeys mentioned earlier. Furthermore, there is increasing realization that nonspecific innate immune mechanisms, particularly natural killer cells, might initiate the T-helper 1 cells of the acquired response [9] through interactions with myeloid dendritic cells; because many different leukocyte subtypes can exist outside the spleen [10–13], the latter might be important in initial immunization but might not be essential thereafter. As with the cytokines and lymphokines that have overlapping compensatory functions, evidence from murine malaria suggests that T-cell subsets in the liver might compensate for the absence of a spleen [14]. If so, this could explain the continued resistance to malaria of semi-immune splenectomized humans [15]. Although Good’s suggested use of attenuated parasites or mixtures of different parasite proteins for malaria immunization [8] might sound impractical for large-scale use, understanding the sequence of immunological events following low-dose immunizations in comparison with FCA, and the role of the spleen and liver might help the design of better malaria vaccines than those tested to date. Finally, one of the most intriguing aspects of the role of the spleen in malaria that might be worth re-examining in the light of modern knowledge [16] is the old data relating to its modulation of the surface expression of parasite antigens [17].
References 1 Engwerda, C.R. et al. (2005) The importance of the spleen in malaria. Trends Parasitol. 21, 75–80 2 Wyler, D.J. et al. (1978) The role of the spleen in malaria infections. In Role of the Spleen in the Immunology of Parasitic Diseases. (Tropical Disease Research Series 1), pp. 183–204, Schwabe 3 Langhorne, J. et al. (1979) Preliminary investigations on the role of the spleen in immunity to Plasmodium knowlesi malaria. In Role of the Spleen in the Immunology of Parasitic Diseases. (Tropical Disease Research Series 1), pp. 205–225, Schwabe 4 Butcher, G.A. and Cohen, S. (1972) Antigenic variation and protective immunity in Plasmodium knowlesi malaria. Immunology 23, 503–521 5 Butcher, G.A. et al. (1978) Antibody-mediated mechanisms of immunity to malaria induced by vaccination with Plasmodium knowlesi merozoites. Immunology 34, 77–86
Update
TRENDS in Parasitology
6 Tokunaga, T. et al. (1999) How BCG led to the discovery of immunostimulatory DNA. Jpn. J. Infect. Dis. 52, 1–11 7 Billiau, A. and Matthys, P. (2001) Modes of action of Freund’s adjuvants in experimental models of autoimmune diseases. J. Leukoc. Biol. 70, 849–860 8 Good, M.F. (2005) Vaccine-induced immunity to malaria parasites and the need for novel strategies. Trends Parasitol. 21, 29–34 9 Gerosa, F. et al. (2005) The reciprocal interaction of NK cells with plasmacytoid or myeloid dendritic cells profoundly affects innate resistance functions. J. Immunol. 174, 727–734 10 Ikuta, S. et al. (2004) Enhanced interferon-g production and bacterial clearance in the liver of splenectomised mice in the models of Escherichia coli injection or intestinal obstruction. Shock 21, 452–457 11 Kawamura, T. et al. (2002) Association of CD8C natural killer T cells in the liver with neonatal tolerance phenomenon. Transplantation 73, 978–992 12 Klonz, A. et al. (1996) The marginal blood pool of the rat contains not only granulocytes, but also lymphocytes, NK-cells and monocytes: a second intravascular compartment, its cellular composition, adhesion
Vol.21 No.8 August 2005
13
14
15 16 17
357
molecule expression and interaction with the peripheral blood pool. Scand. J. Immunol. 44, 461–449 Passlick, B. et al. (1991) Post-traumatic splenectomy does not influence human peripheral blood mononuclear cell subsets. J. Clin. Lab. Immunol. 34, 157–161 Weerasinghe, A. et al. (2001) Association of intermediate T cell receptor cells, mainly their NK1.1(K) subset, with protection from malaria. Cell. Immunol. 207, 28–35 Looareesuwan, S. et al. (1993) Malaria in splenectomised patients: report of four cases and review. Clin. Infect. Dis. 16, 361–366 Recker, M. et al. (2004) Transient cross-reactive immune responses can orchestrate antigenic variation in malaria. Nature 429, 555–558 David, P.H. et al. (1983) Parasite sequestration in Plasmodium falciparum malaria: spleen and antibody modulation of cytoadherence of infected erythrocytes. Proc. Natl. Acad. Sci. U. S. A. 80, 5075–5079
1471-4922/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.pt.2005.06.001
What distinguishes malaria parasites from other pigmented haemosporidians? Gediminas Valkiu¯nas1, Ali M. Anwar 2, Carter T. Atkinson3, Ellis C. Greiner 4, Ilan Paperna5 and Michael A. Peirce6 1
Institute of Ecology, Vilnius University, Akademijos 2, Vilnius 21, LT-08412, Lithuania Department of Zoology, Oxford University, South Parks Road, Oxford, UK, OX1 3PS 3 US Geological Survey, Biological Resources Discipline, Pacific Island Ecosystems Research Center, PO Box 44, Hawaii National Park, HI 96718, USA 4 Department of Pathobiology, College of Veterinary Medicine, PO Box 110880, University of Florida, Gainesville, FL 32610, USA 5 Department of Animal Science, Faculty of Agriculture, Hebrew University of Jerusalem, PO Box 12, Rehovot 76-100, Israel 6 MP International Consultancy, 6 Normandale House, Normandale, Bexhill-on-Sea, East Sussex, UK, TN39 3NZ 2
In several recent publications [1–4], the term ‘malaria parasites’ has been used loosely to include all pigmented (and even some non-pigmented) haemosporidian parasites (Sporozoa: Haemosporida) that inhabit red blood cells and sometimes white blood cells. This terminology was in common use during the first half of the 20th century when there was considerable debate about the host range and identity of many of these parasites, but was eventually abandoned because it obscured basic biological differences among these organisms. Based on recent molecular genetic studies, Pe´rez-Tris et al. [3] have reopened the debate. They have proposed that this terminology should once again be used broadly to group avian and possibly mammalian haemoproteids with the more traditional malaria parasites of the genus Plasmodium. We feel, however, that this would obscure important life history and epidemiological characteristics of these organisms that are crucial for understanding their evolutionary relationships with their vertebrate hosts and vectors. Differences in the vectors, life cycles and epidemiology of these organisms (e.g. Plasmodium, Haemoproteus, Parahaemoproteus, Hepatocystis and Nycteria spp.) were recognized by the middle of the 20th century. Close evolutionary Corresponding author: Valkiu¯nas, G. ([email protected]). Available online 20 June 2005 www.sciencedirect.com
relationships, diversity of life history strategies among these organisms, and widespread use of avian, mammalian and reptilian species of Plasmodium as models for human disease, led to confusion among malariologists as to what was considered a ‘malaria’ parasite. The report of a World Health Organization (http://www.who.int/en/) drafting committee composed of prominent malariologists [5] attempted to clarify this by restricting the term ‘malaria parasites’ to the haemosporidians belonging to the genus Plasmodium. Garnham followed this recommendation in his outstanding monograph Malaria Parasites and Other Haemosporidia [6]. Furthermore, subsequent studies and reviews of haemosporidians continued to apply the term ‘malaria parasites’ to those pigmented parasites that multiply in the blood stream (i.e. Plasmodium species) [7–11]. Let us remember that species of Haemoproteus, Hepatocystis and other haemoproteids do not multiply in the blood, even though they sometimes give rise to outward clinical signs and symptoms characteristic of malaria. Furthermore, malaria is characterized by recrudescence and is transmitted by mosquitoes, whereas species belonging to the genus Haemoproteus and closely related genera are not [7,9,11]. We agree with Pe´rez-Tris et al. [3] that there is ample evidence from traditional research and recent molecular genetic studies [1,2,4,6,7,11] that species of Plasmodium