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Endogenous and exogenous transplacental infection in Neospora caninum and Toxoplasma gondii
Opinion
TRENDS in Parasitology
Vol.21 No.12 December 2005
Endogenous and exogenous transplacental infection in Neospora caninum and Toxoplasma gondii Alexander J. Trees and Diana J.L. Williams Veterinary Parasitology, Liverpool School of Tropical Medicine and Faculty of Veterinary Science, University of Liverpool, Liverpool, UK, L3 5QA
It is clear from researching the vertical transmission of Neospora caninum in cattle that the terms ‘vertical’, ‘congenital’ and, indeed, ‘transplacental’ are inadequate for describing two extremely different situations that have fundamentally different immunological, epidemiological and control implications. A similar situation pertains to Toxoplasma gondii in different hosts. We advocate the use of the terms ‘endogenous transplacental infection (TPI)’ to define foetal infection from a recrudescent maternal infection acquired before pregnancy (and probably prenatally) and ‘exogenous TPI’ to define foetal infection that occurs as a result of an infection of the dam during pregnancy. Transmission modes ‘Vertical’ (see Glossary), ‘congenital’ and ‘transplacental’ are adjectives that are variously used to describe the transmission of an infection from one generation to the next. With the relatively recent discovery of Neospora caninum and the elucidation of its transmission modes in cattle, together with a consideration of the transmission characteristics of the related apicomplexan parasite Toxoplasma gondii, it is apparent that none of the above terms is precise enough to distinguish two extremely different transmission scenarios. We advocate the use of the terms ‘endogenous transplacental infection (TPI)’ and ‘exogenous TPI’ to describe respectively the TPI of an agent from a pre-existing chronic infection of the dam (which, itself, was probably infected in utero) and a TPI that results from infection of the dam when pregnant (Figure 1). Although both of these transmission modes are embraced by all of the terms in the Glossary, the consequences – epidemiological, immunological and for control – are so different that it is crucial for the modes to be adequately defined and distinguished.
Transplacental transmission The issues under discussion are exemplified by the two closely related parasites T. gondii and N. caninum. Both endogenous and exogenous TPI occur in each parasite but the predominance of each mode can vary, not only with host species but also with intraspecific host genotype. Corresponding author: Trees, A.J. ([email protected]). Available online 11 October 2005
In T. gondii infections, the term ‘congenital toxoplasmosis’ has been used to describe both transmission in outbred mice – which Beverley et al. [1] demonstrated could occur repeatedly through successive generations (endogenous TPI) – and human foetal infection and disease, which are generally thought to occur only if de novo infection occurs during pregnancy (i.e. exogenous TPI) [2]. In mice, the situation is complex and host genotype seems to be a major influence on the potential nature of TPI. Thus, in outbred wild species Mus musculus and Apodemus sylvaticus, endogenous TPI occurs and is extremely efficient [3], yet only exogenous TPI occurs in inbred Balb/c mice [4]. In ovine toxoplasmosis, the accepted paradigm since the classic work by Beverley et al. has been that only exogenous TPI can occur [5,6], and this view has generally been supported by epidemiological studies showing increasing prevalence of infection with age, which indicates that the majority of infection is acquired postnatally [7]. However, recent work in sheep suggests that this might not always be the case [8], although the interpretation of field-study data is difficult when only foetal infection is detected because it could result from either endogenous or exogenous TPI. This emphasizes the crucial need to distinguish these situations. It is clear that the situation in ovine toxoplasmosis is more complex than hitherto thought and merits reappraisal. In humans, too, there have been reports of congenital toxoplasmosis from chronic infection (i.e. endogenous TPI), most recently by Silveira et al. and Kodjikian et al. [9,10]. Such instances seem to be extremely rare [2] but, clearly, the possibility of endogenous TPI in human toxoplasmosis has profound consequences. N. caninum is closely related to T. gondii and, similarly, is a facultative heteroxenous parasite. Its veterinary importance is primarily in cattle and dogs, although direct (parasite identification) or indirect (antibody responses) evidence of infections has been described in a range of other species [11]. The dog is a definitive host [12], Glossary Congenital: present at birth, acquired in utero or in ovo. Transplacental: acquired in utero. Vertical: transmitted from one generation to the next.
www.sciencedirect.com 1471-4922/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.pt.2005.09.005
Opinion
(a) Endogenous
TRENDS in Parasitology
(b) Exogenous
Host + parasite
Host
Pregnancy
Pregnancy
Neonate + parasite
Neonate + parasite
Parasite
TRENDS in Parasitology
Figure 1. Host–parasite relationship and pregnancy. Image shows the difference between (a) endogenous and (b) exogenous TPI, as defined in the main text.
producing oocysts that can infect cattle, but systemic infection also occurs in dogs. Transplacental infection is associated with disease in neonatal dogs and it is generally assumed – although, in naturally occurring clinical cases, usually not proven – that this is from a chronic maternal infection, but such transmission is inefficient [13]. Much more is known about TPI in cattle, in which N. caninum is now recognized to be a major cause of abortion worldwide (Figure 2). TPI is extremely efficient in cattle; on-farm studies relating the precolostral antibody status of calves to the seropositivity of their dams have shown a probability of such transmission to be 0.95 [14]. These studies, like most field studies, could not rule out the possibility that primary infection had occurred during some pregnancies, but when persistently infected cows were housed throughout pregnancy to preclude exogenous infection the probability of TPI, undoubtedly of endogen-
Figure 2. Neospora caninum in the bovine placenta. Placentation in ruminants is cotyledonary and synepitheliochorial, and is the least intimate of all mammalian placentation. Foetal blood and maternal blood are separated by several cell layers: the endothelial cells of the maternal blood vessel, connective tissue and the endometrial epithelium on the maternal side, and the chorionic epithelium, connective tissue and endothelium on the foetal side. Micrograph shows a cotyledonary villus (F) embedded within a maternal caruncular crypt (M), with brown-staining tachyzoites visible within foetal chorionic epithelial cells (T). A foetal-derived binucleate trophoblast cell (B) can be seen in proximity to the maternal epithelium. Scale bar Z 10 mm. Structures are shown using peroxidase– antiperoxidase immunostaining with polyclonal antibody specific for N. caninum. Image courtesy of Helen Gibney. www.sciencedirect.com
Vol.21 No.12 December 2005
559
ous origin, was still high [15]. Further evidence that endogenous TPI is extremely important in cattle is provided by the infection distribution in dairy herds in which female offspring might be retained over several generations. Cross-sectional studies of such herds have revealed a nonrandom distribution of infection (as determined by antibody detection), with aggregation in family lines, providing powerful evidence of endogenous TPI [16–19]. Furthermore, repeated TPI transmission in successive pregnancies has been shown in individual cows in many studies (e.g. Ref. [20]). The final epidemiological evidence indicating that, in at least some situations, endogenous TPI is the major mode of transmission comes from within-herd age–prevalence studies in which no increase in prevalence with age has been described [17,21]. Exogenous TPI can also occur in cattle, and this has been shown experimentally by tachyzoite inoculation (e.g. Refs [22–24]) and, importantly, oocyst infection [25]. What is not yet clear is the relative importance to abortion incidence of endogenous versus exogenous TPI. Implication of different modes of TPI If, in a given host–parasite relationship, endogenous TPI can occur and is efficient (e.g. a transmission probability of 0.95, as for N. caninum in cattle [14]), and there is no postnatal mortality associated with the infection, this route of infection might contribute to the majority of the total prevalence of infection in a population. This seems to be the case in N. caninum infections in cattle, where modelling reveals that only extremely low rates of postnatal infection are needed to establish a stable and high infection prevalence over time in closed breeding populations such as dairy herds [26]. In this circumstance, an infected dam will, with a high probability, infect every foetus in every pregnancy. By contrast, exogenous TPI results from the random exposure of naı¨ve individuals. Depending on the frequency and length of gestation, the longevity of a given host and the force of environmental transmission, there is a statistically variable, but relatively low, probability of foetal infection occurring in any pregnancy. This probability is further reduced because population infection prevalence and herd immunity increase if a prior infection outwith pregnancy confers immunity to exogenous TPI – which it does in the case of N. caninum and T. gondii (see later). Thus, the incidence of foetal infection and foetopathy in the population might be positively related to infection prevalence where endogenous TPI is dominant, and negatively related to infection prevalence where only exogenous TPI occurs. Immunological implications We have reviewed the immunological implications elsewhere with respect to bovine neosporosis [27], so they will be discussed only briefly here. In bovine N. caninum infections, there is strong evidence from experimental studies that cattle can be protected from exogenous TPI by prior infection [24,28] and there is some epidemiological evidence that this also happens in the field [29]. However,
560
Opinion
TRENDS in Parasitology
there is no evidence, to our knowledge, that protective immunity to endogenous TPI in N. caninum can occur. Particularly striking are experimental results in which maternal infection in persistently infected cows recrudesced and infected foetuses in cattle that had resisted a lethal exogenous foetopathic challenge earlier in the same pregnancy [28]. Similarly, there is evidence that protection against exogenous TPI in T. gondii is conferred either by natural infection or by immunization in sheep [6,30,31] and mice [32]. Such evidence has led to the development of a successful vaccine against Toxoplasma-induced abortion in sheep [33]. However, we are not aware of any evidence that immunity can be induced against endogenous TPI of T. gondii. Implications for control Implications for control are starkly exemplified by N. caninum in cattle, in which both endogenous and exogenous TPI can cause infection and foetopathy but in which the relative contribution of endogenous and exogenous TPI to the total abortion rate is unclear. Control strategies where endogenous TPI is dominant should concentrate on the identification of carrier animals, and their culling or selective breeding (i.e. not breeding for herd replacements): ultimately, to achieve zero prevalence in a herd (e.g. Refs [18,26,34]). In these circumstances, a conventional vaccine is unlikely to be effective against endogenous TPI but could provide protection against exogenous infection. By contrast, if exogenous TPI is predominant, control should focus on reducing environmental infection from oocysts. It might be preferable to retain infected animals that will resist challenge, and a vaccine could prove beneficial. Future perspectives Emerging understanding of the nature of TPI in N. caninum in cattle has highlighted the markedly different consequences and implications of what we call here endogenous and exogenous TPI. The consequences and implications provide a strong argument for using these terms as a more precise alternative to such inadequate terms as ‘vertical’ or ‘congenital’. In the ubiquitous and zoonotic parasite T. gondii, examples of endogenous and exogenous TPI also occur and emphasize the need for greater precision in describing field or experimental research that describes infection passing from mother to foetus. Acknowledgements We thank the BBSRC, DEFRA, the Wellcome Trust and Novartis for supporting our research on bovine neosporosis. We thank colleagues researching Neospora caninum worldwide, especially the EU COST 854 programme, for fruitful collaborations, and the referees for their helpful comments.
References 1 Beverley, J.K.A. et al. (1959) Congenital transmission of toxoplasmosis through successive generations of mice. Nature 183, 1348–1349 2 Montoya, J.G. and Liesenfeld, O. (2004) Toxoplasmosis. Lancet 363, 1965–1976 www.sciencedirect.com
Vol.21 No.12 December 2005
3 Owen, M.R. and Trees, A.J. (1998) Vertical transmission of Toxoplasma gondii from chronically infected house (Mus musculus) and field (Apodemus sylvaticus) mice determined by polymerase chain reaction. Parasitology 116, 299–304 4 Roberts, C.W. and Alexander, J. (1992) Studies on a murine model of congenital toxoplasmosis: vertical disease transmission only occurs in BALB/c mice infected for the first time during pregnancy. Parasitology 104, 19–23 5 Watson, W.A. and Beverley, J.K.A. (1971) Ovine abortion due to experimental toxoplasmosis. Vet. Rec. 88, 42–45 6 Beverley, J.K.A. and Watson, W.A. (1971) Prevention of experimental and of naturally occurring ovine abortion due to toxoplasmosis. Vet. Rec. 88, 39–41 7 Blewett, D.A. (1983) The epidemiology of ovine toxoplasmosis. I. The interpretation of data for the prevalence of antibody in sheep and other host species. Br. Vet. J. 139, 537–545 8 Duncanson, P. et al. (2001) High levels of congenital transmission of Toxoplasma gondii in a commercial sheep flock. Int. J. Parasitol. 31, 1699–1703 9 Silveira, C. et al. (2003) Toxoplasmosis transmitted to a newborn from the mother infected 20 years earlier. Am. J. Opthalmol. 136, 370–371 10 Kodjikian, L. et al. (2004) Vertical transmission of toxoplasmosis from a chronically infected immunocompetent woman. Ped. Inf. Dis. J. 23, 272–274 11 Dubey, J.P. and Thulliez, P. Prevalence of antibodies to Neospora caninum in wild animals. J. Parasitol. (in press) 12 McAllister, M.M. et al. (1998) Dogs are definitive hosts of Neospora caninum. Int. J. Parasitol. 28, 1473–1478 13 Barber, J.S. and Trees, A.J. (1998) Naturally occurring vertical transmission of Neospora caninum in dogs. Int. J. Parasitol. 28, 57–64 14 Davison, H.C. et al. (1999) Estimation of vertical and horizontal transmission parameters of Neospora caninum infections in dairy cattle. Int. J. Parasitol. 29, 1683–1689 15 Guy, C.S. et al. (2001) Neospora caninum in persistently infected pregnant cows: spontaneous transplacental infection is associated with an acute increase in maternal antibody. Vet. Rec. 149, 443–449 16 Bjorkman, C. et al. (1996) Neospora species infection in a herd of dairy cattle. J. Am. Vet. Med. Assoc. 208, 1441–1444 17 Schares, G. et al. (1998) The efficiency of vertical transmission of Neospora caninum in dairy cattle analysed by serological techniques. Vet. Parasitol. 80, 87–98 18 Anderson, M.L. et al. (1997) Evidence of vertical transmission of Neospora sp. infection in dairy cattle. J. Am. Vet. Med. Assoc. 210, 1169–1172 19 Pare´, J. et al. (1996) Congenital Neospora caninum infection in dairy cattle and associated calfhood mortality. Can. J. Vet. Res. 60, 133–139 20 Barr, B.C. et al. (1993) Congenital Neospora infection in calves born from cows that had previously aborted Neospora-infected foetuses: four cases (1990–1992). J. Am. Vet. Med. Assoc. 202, 113–117 21 Davison, H.C. et al. (1999) Herd-specific and age-specific seroprevalence of Neospora caninum in 14 British dairy herds. Vet. Rec. 144, 547–550 22 Barr, B.C. et al. (1994) Experimental reproduction of bovine fetal Neospora infection and death with a bovine Neospora isolate. J. Vet. Diag. Invest. 6, 207–215 23 Williams, D.J.L. et al. (2000) Neospora caninum-associated abortion in cattle: the time of experimentally-induced parasitaemia during gestation determines foetal survival. Parasitology 121, 347–358 24 Innes, E.A. et al. (2001) Protection against vertical transmission in bovine neosporosis. Int. J. Parasitol. 31, 1523–1534 25 Gondim, L.F.P. et al. (2004) Transplacental transmission and abortion in cows administered Neospora caninum oocysts. J. Parasitol. 90, 1394–1400 26 French, N.P. et al. (1999) Mathematical models of Neospora caninum infection in dairy cattle: transmission and options for control. Int. J. Parasitol. 29, 1691–1704 27 Trees, A.J. and Williams, D.J.L. (2003) Vaccination against bovine neosporosis – the challenge is the challenge. J. Parasitol. 89, S198– S201
Opinion
TRENDS in Parasitology
28 Williams, D.J.L. et al. (2003) First demonstration of protective immunity against foetopathy in cattle with latent Neospora caninum infection. Int. J. Parasitol. 33, 1059–1065 29 McAllister, M.M. et al. (2000) Evidence of point-source exposure to Neospora caninum and protective immunity in a herd of beef cows. J. Am. Vet. Med. Assoc. 217, 881–887 30 Wilkins, M.F. et al. (1988) Toxoplasmosis in sheep III. Further evaluation of the ability of a live Toxoplasma gondii vaccine to prevent lamb losses and reduce congenital infection following experimental oral challenge. N.Z. Vet. J. 36, 86–89
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31 O’Connell, E. et al. (1988) Toxoplasmosis in sheep. II. The ability of a live vaccine to prevent lamb losses after an intravenous challenge with Toxoplasma gondii. N.Z. Vet. J. 36, 1–4 32 Letscher-Bru, V. et al. (2003) Vaccination with Toxoplasma gondii SAG-1 protein is protective against congenital toxoplasmosis in BALB/c mice but not in CBA/J mice. Infect. Immun. 71, 6615–6619 33 Buxton, D. (1993) Toxoplasmosis: the first commercial vaccine. Parasitol. Today 9, 335–337 34 Hall, C. et al. (2005) Neospora abortions in dairy cattle: diagnosis, mode of transmission and control. Vet. Parasitol. 128, 231–241
Articles of interest in other Trends journals ffrench-Constant, R.H. (2005) Something old, something transgenic, or something fungal for mosquito control? Trends Ecol. Evol.doi:10.1016/j.tree.2005.08.007 Mitreva, M. et al. (2005) Comparative genomics of nematodes. Trends Genet. doi:10.1016/j.tig.2005.08.003 Bezemer, T.M. and van Dam, N.M. (2005) Linking aboveground and belowground interactions via induced plant defenses. Trends Ecol. Evol. doi:10.1016/j.tree.2005.08.006 www.sciencedirect.com
561
TRENDS in Parasitology
Vol.21 No.12 December 2005
Endogenous and exogenous transplacental infection in Neospora caninum and Toxoplasma gondii Alexander J. Trees and Diana J.L. Williams Veterinary Parasitology, Liverpool School of Tropical Medicine and Faculty of Veterinary Science, University of Liverpool, Liverpool, UK, L3 5QA
It is clear from researching the vertical transmission of Neospora caninum in cattle that the terms ‘vertical’, ‘congenital’ and, indeed, ‘transplacental’ are inadequate for describing two extremely different situations that have fundamentally different immunological, epidemiological and control implications. A similar situation pertains to Toxoplasma gondii in different hosts. We advocate the use of the terms ‘endogenous transplacental infection (TPI)’ to define foetal infection from a recrudescent maternal infection acquired before pregnancy (and probably prenatally) and ‘exogenous TPI’ to define foetal infection that occurs as a result of an infection of the dam during pregnancy. Transmission modes ‘Vertical’ (see Glossary), ‘congenital’ and ‘transplacental’ are adjectives that are variously used to describe the transmission of an infection from one generation to the next. With the relatively recent discovery of Neospora caninum and the elucidation of its transmission modes in cattle, together with a consideration of the transmission characteristics of the related apicomplexan parasite Toxoplasma gondii, it is apparent that none of the above terms is precise enough to distinguish two extremely different transmission scenarios. We advocate the use of the terms ‘endogenous transplacental infection (TPI)’ and ‘exogenous TPI’ to describe respectively the TPI of an agent from a pre-existing chronic infection of the dam (which, itself, was probably infected in utero) and a TPI that results from infection of the dam when pregnant (Figure 1). Although both of these transmission modes are embraced by all of the terms in the Glossary, the consequences – epidemiological, immunological and for control – are so different that it is crucial for the modes to be adequately defined and distinguished.
Transplacental transmission The issues under discussion are exemplified by the two closely related parasites T. gondii and N. caninum. Both endogenous and exogenous TPI occur in each parasite but the predominance of each mode can vary, not only with host species but also with intraspecific host genotype. Corresponding author: Trees, A.J. ([email protected]). Available online 11 October 2005
In T. gondii infections, the term ‘congenital toxoplasmosis’ has been used to describe both transmission in outbred mice – which Beverley et al. [1] demonstrated could occur repeatedly through successive generations (endogenous TPI) – and human foetal infection and disease, which are generally thought to occur only if de novo infection occurs during pregnancy (i.e. exogenous TPI) [2]. In mice, the situation is complex and host genotype seems to be a major influence on the potential nature of TPI. Thus, in outbred wild species Mus musculus and Apodemus sylvaticus, endogenous TPI occurs and is extremely efficient [3], yet only exogenous TPI occurs in inbred Balb/c mice [4]. In ovine toxoplasmosis, the accepted paradigm since the classic work by Beverley et al. has been that only exogenous TPI can occur [5,6], and this view has generally been supported by epidemiological studies showing increasing prevalence of infection with age, which indicates that the majority of infection is acquired postnatally [7]. However, recent work in sheep suggests that this might not always be the case [8], although the interpretation of field-study data is difficult when only foetal infection is detected because it could result from either endogenous or exogenous TPI. This emphasizes the crucial need to distinguish these situations. It is clear that the situation in ovine toxoplasmosis is more complex than hitherto thought and merits reappraisal. In humans, too, there have been reports of congenital toxoplasmosis from chronic infection (i.e. endogenous TPI), most recently by Silveira et al. and Kodjikian et al. [9,10]. Such instances seem to be extremely rare [2] but, clearly, the possibility of endogenous TPI in human toxoplasmosis has profound consequences. N. caninum is closely related to T. gondii and, similarly, is a facultative heteroxenous parasite. Its veterinary importance is primarily in cattle and dogs, although direct (parasite identification) or indirect (antibody responses) evidence of infections has been described in a range of other species [11]. The dog is a definitive host [12], Glossary Congenital: present at birth, acquired in utero or in ovo. Transplacental: acquired in utero. Vertical: transmitted from one generation to the next.
www.sciencedirect.com 1471-4922/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.pt.2005.09.005
Opinion
(a) Endogenous
TRENDS in Parasitology
(b) Exogenous
Host + parasite
Host
Pregnancy
Pregnancy
Neonate + parasite
Neonate + parasite
Parasite
TRENDS in Parasitology
Figure 1. Host–parasite relationship and pregnancy. Image shows the difference between (a) endogenous and (b) exogenous TPI, as defined in the main text.
producing oocysts that can infect cattle, but systemic infection also occurs in dogs. Transplacental infection is associated with disease in neonatal dogs and it is generally assumed – although, in naturally occurring clinical cases, usually not proven – that this is from a chronic maternal infection, but such transmission is inefficient [13]. Much more is known about TPI in cattle, in which N. caninum is now recognized to be a major cause of abortion worldwide (Figure 2). TPI is extremely efficient in cattle; on-farm studies relating the precolostral antibody status of calves to the seropositivity of their dams have shown a probability of such transmission to be 0.95 [14]. These studies, like most field studies, could not rule out the possibility that primary infection had occurred during some pregnancies, but when persistently infected cows were housed throughout pregnancy to preclude exogenous infection the probability of TPI, undoubtedly of endogen-
Figure 2. Neospora caninum in the bovine placenta. Placentation in ruminants is cotyledonary and synepitheliochorial, and is the least intimate of all mammalian placentation. Foetal blood and maternal blood are separated by several cell layers: the endothelial cells of the maternal blood vessel, connective tissue and the endometrial epithelium on the maternal side, and the chorionic epithelium, connective tissue and endothelium on the foetal side. Micrograph shows a cotyledonary villus (F) embedded within a maternal caruncular crypt (M), with brown-staining tachyzoites visible within foetal chorionic epithelial cells (T). A foetal-derived binucleate trophoblast cell (B) can be seen in proximity to the maternal epithelium. Scale bar Z 10 mm. Structures are shown using peroxidase– antiperoxidase immunostaining with polyclonal antibody specific for N. caninum. Image courtesy of Helen Gibney. www.sciencedirect.com
Vol.21 No.12 December 2005
559
ous origin, was still high [15]. Further evidence that endogenous TPI is extremely important in cattle is provided by the infection distribution in dairy herds in which female offspring might be retained over several generations. Cross-sectional studies of such herds have revealed a nonrandom distribution of infection (as determined by antibody detection), with aggregation in family lines, providing powerful evidence of endogenous TPI [16–19]. Furthermore, repeated TPI transmission in successive pregnancies has been shown in individual cows in many studies (e.g. Ref. [20]). The final epidemiological evidence indicating that, in at least some situations, endogenous TPI is the major mode of transmission comes from within-herd age–prevalence studies in which no increase in prevalence with age has been described [17,21]. Exogenous TPI can also occur in cattle, and this has been shown experimentally by tachyzoite inoculation (e.g. Refs [22–24]) and, importantly, oocyst infection [25]. What is not yet clear is the relative importance to abortion incidence of endogenous versus exogenous TPI. Implication of different modes of TPI If, in a given host–parasite relationship, endogenous TPI can occur and is efficient (e.g. a transmission probability of 0.95, as for N. caninum in cattle [14]), and there is no postnatal mortality associated with the infection, this route of infection might contribute to the majority of the total prevalence of infection in a population. This seems to be the case in N. caninum infections in cattle, where modelling reveals that only extremely low rates of postnatal infection are needed to establish a stable and high infection prevalence over time in closed breeding populations such as dairy herds [26]. In this circumstance, an infected dam will, with a high probability, infect every foetus in every pregnancy. By contrast, exogenous TPI results from the random exposure of naı¨ve individuals. Depending on the frequency and length of gestation, the longevity of a given host and the force of environmental transmission, there is a statistically variable, but relatively low, probability of foetal infection occurring in any pregnancy. This probability is further reduced because population infection prevalence and herd immunity increase if a prior infection outwith pregnancy confers immunity to exogenous TPI – which it does in the case of N. caninum and T. gondii (see later). Thus, the incidence of foetal infection and foetopathy in the population might be positively related to infection prevalence where endogenous TPI is dominant, and negatively related to infection prevalence where only exogenous TPI occurs. Immunological implications We have reviewed the immunological implications elsewhere with respect to bovine neosporosis [27], so they will be discussed only briefly here. In bovine N. caninum infections, there is strong evidence from experimental studies that cattle can be protected from exogenous TPI by prior infection [24,28] and there is some epidemiological evidence that this also happens in the field [29]. However,
560
Opinion
TRENDS in Parasitology
there is no evidence, to our knowledge, that protective immunity to endogenous TPI in N. caninum can occur. Particularly striking are experimental results in which maternal infection in persistently infected cows recrudesced and infected foetuses in cattle that had resisted a lethal exogenous foetopathic challenge earlier in the same pregnancy [28]. Similarly, there is evidence that protection against exogenous TPI in T. gondii is conferred either by natural infection or by immunization in sheep [6,30,31] and mice [32]. Such evidence has led to the development of a successful vaccine against Toxoplasma-induced abortion in sheep [33]. However, we are not aware of any evidence that immunity can be induced against endogenous TPI of T. gondii. Implications for control Implications for control are starkly exemplified by N. caninum in cattle, in which both endogenous and exogenous TPI can cause infection and foetopathy but in which the relative contribution of endogenous and exogenous TPI to the total abortion rate is unclear. Control strategies where endogenous TPI is dominant should concentrate on the identification of carrier animals, and their culling or selective breeding (i.e. not breeding for herd replacements): ultimately, to achieve zero prevalence in a herd (e.g. Refs [18,26,34]). In these circumstances, a conventional vaccine is unlikely to be effective against endogenous TPI but could provide protection against exogenous infection. By contrast, if exogenous TPI is predominant, control should focus on reducing environmental infection from oocysts. It might be preferable to retain infected animals that will resist challenge, and a vaccine could prove beneficial. Future perspectives Emerging understanding of the nature of TPI in N. caninum in cattle has highlighted the markedly different consequences and implications of what we call here endogenous and exogenous TPI. The consequences and implications provide a strong argument for using these terms as a more precise alternative to such inadequate terms as ‘vertical’ or ‘congenital’. In the ubiquitous and zoonotic parasite T. gondii, examples of endogenous and exogenous TPI also occur and emphasize the need for greater precision in describing field or experimental research that describes infection passing from mother to foetus. Acknowledgements We thank the BBSRC, DEFRA, the Wellcome Trust and Novartis for supporting our research on bovine neosporosis. We thank colleagues researching Neospora caninum worldwide, especially the EU COST 854 programme, for fruitful collaborations, and the referees for their helpful comments.
References 1 Beverley, J.K.A. et al. (1959) Congenital transmission of toxoplasmosis through successive generations of mice. Nature 183, 1348–1349 2 Montoya, J.G. and Liesenfeld, O. (2004) Toxoplasmosis. Lancet 363, 1965–1976 www.sciencedirect.com
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28 Williams, D.J.L. et al. (2003) First demonstration of protective immunity against foetopathy in cattle with latent Neospora caninum infection. Int. J. Parasitol. 33, 1059–1065 29 McAllister, M.M. et al. (2000) Evidence of point-source exposure to Neospora caninum and protective immunity in a herd of beef cows. J. Am. Vet. Med. Assoc. 217, 881–887 30 Wilkins, M.F. et al. (1988) Toxoplasmosis in sheep III. Further evaluation of the ability of a live Toxoplasma gondii vaccine to prevent lamb losses and reduce congenital infection following experimental oral challenge. N.Z. Vet. J. 36, 86–89
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31 O’Connell, E. et al. (1988) Toxoplasmosis in sheep. II. The ability of a live vaccine to prevent lamb losses after an intravenous challenge with Toxoplasma gondii. N.Z. Vet. J. 36, 1–4 32 Letscher-Bru, V. et al. (2003) Vaccination with Toxoplasma gondii SAG-1 protein is protective against congenital toxoplasmosis in BALB/c mice but not in CBA/J mice. Infect. Immun. 71, 6615–6619 33 Buxton, D. (1993) Toxoplasmosis: the first commercial vaccine. Parasitol. Today 9, 335–337 34 Hall, C. et al. (2005) Neospora abortions in dairy cattle: diagnosis, mode of transmission and control. Vet. Parasitol. 128, 231–241
Articles of interest in other Trends journals ffrench-Constant, R.H. (2005) Something old, something transgenic, or something fungal for mosquito control? Trends Ecol. Evol.doi:10.1016/j.tree.2005.08.007 Mitreva, M. et al. (2005) Comparative genomics of nematodes. Trends Genet. doi:10.1016/j.tig.2005.08.003 Bezemer, T.M. and van Dam, N.M. (2005) Linking aboveground and belowground interactions via induced plant defenses. Trends Ecol. Evol. doi:10.1016/j.tree.2005.08.006 www.sciencedirect.com
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