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Bovine trypanotolerance: A natural ability to prevent severe anaemia and haemophagocytic syndrome?

Bovine trypanotolerance: A natural ability to prevent severe anaemia and haemophagocytic syndrome?
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  Invited review Bovine trypanotolerance: A natural ability to prevent severe anaemiaand haemophagocytic syndrome? J. Naessens  *  International Livestock Research Institute, P.O. Box 30709, 00100 Nairobi, Kenya Received 10 November 2005; received in revised form 8 February 2006; accepted 15 February 2006 Abstract Trypanotolerance is the capacity of certain West-African, taurine breeds of cattle to remain productive and gain weight after trypanosomeinfection. Laboratory studies, comparing  Trypanosoma congolense  infections in trypanotolerant N’Dama cattle (  Bos taurus ) and in moresusceptible Boran cattle (  Bos indicus ), confirmed the field observations. Experiments using haemopoietic chimeric twins, composed of a tolerantand a susceptible co-twin, and T cell depletion studies suggested that trypanotolerance is composed of two independent traits. The first is a bettercapacity to control parasitaemia and is not mediated by haemopoietic cells, T lymphocytes or antibodies. The second is a better capacity to limitanaemia development and is mediated by haemopoietic cells, but not by T lymphocytes or antibodies. Weight gain was linked to the lattermechanism, implying that anaemia control is more important for survival and productivity than parasite control. Anemia is a marker for a morecomplex pathology which resembles human haemophagocytic syndrome: hepatosplenomegaly, pancytopenia and a large number of hyperactivated phagocytosing macrophages in bone marrow, liver and other tissues. Thus, mortality and morbidity in trypanosome-infectedcattle are primarily due to self-inflicted damage by disproportionate immune and/or innate responses. These features of bovine trypanotolerancediffer greatly from those in murine models. In mice, resistance is a matter of trypanosome control dependent on acquired immunity. However, amodel of anaemia development can be established using C57BL/6J mice. As in cattle, the induction of anaemia was independent of T cells but itsdevelopment differed with different trypanosome strains. Identification of the molecular pathways that lead to anaemia and haemophagocytosisshould allow us to design new strategies to control disease. q 2006 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved. Keywords:  Trypanosomiasis; Trypanotolerance; Anemia; Haemophagocytic syndrome; Cattle; Murine models; Tumor necrosis factor alpha 1. African trypanosomes While other pathogens evade innate and adaptive responsesin the plasma by hiding in a host cell, African trypanosomes areunique for being able to multiply and survive in the blood of their mammalian host. Trypanosomes elude antibody attack bysporadically varying their surface glycoprotein, forcing thehost to mount a new cycle of antibody production each time anew variant appears. In this way, the parasite manages tosurvive and increase its chances of transmission by tsetse orbiting flies. Unfortunately for the host, the disease often leadsto a fatal outcome.Not all mammalian hosts are equally susceptible. Forexample,  Trypanosoma brucei brucei  is known to infect cattleand mice, but not humans. A trypanolytic factor in humanserum, apoL-I in high density lipoprotein (Vanhamme andPays, 2004), is lethal for  T. b. brucei , but not for the relatedparasite  Trypanosoma brucei rhodesiense  which has adapted toa life in the blood of its human host. Further, not alltrypanosome strains living in the host’s blood are invariablylethal, and the disease severity is strain dependent. In Europeand North America, the parasite  Trypanosoma theileri  occursin a high percentage of otherwise healthy cattle and appears inblood cell cultures, but as it does not cause pathology (Verlooet al., 2000) is not the object of control.There exists a variety of disease patterns associated withdifferent host–trypanosome combinations. Patterns of suscep-tibility to infection and disease between trypanosome strainsand different mammalian hosts may help us identifymechanisms that lead to higher resistance and potentiallyallow the design of new control measures. International Journal for Parasitology 36 (2006) 521–528www.elsevier.com/locate/ijpara0020-7519/$30.00 q 2006 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.doi:10.1016/j.ijpara.2006.02.012 *  Tel.: C 254 20 422 3000; fax: C 254 20 422 3001. E-mail address:  j.naessens@cgiar.org  2. Bovine trypanosomosis African trypanosomosis in livestock is a serious hindranceto development and reduction of poverty. Estimates of the costto consumers and producers on the African continent reachUS$ 1 billion (Kristjanson et al., 1999). The main parasites thatcause disease in livestock are tsetse-transmitted  Trypanosomacongolense  and  Trypanosoma vivax  and to a minor extent T. brucei . Their distribution is restricted to Africa, although T. vivax  has crossed the Atlantic and spreads in South Americavia mechanical transmission by biting flies.  Trypanosomaevansi  is also transmitted by biting flies and infects a widerange of livestock, including camels and buffalo in parts of Asia. Cattle are also an epidemiologically important reservoirfor the human-infective parasite  T. b. rhodesiense  (Hide et al.,1996; Welburn et al., 2001; Njiru et al., 2004). During the bite of an infected tsetse fly, metacyclictrypanosome forms are deposited in the skin of the mammalianhost. An immune reaction to the metacyclic parasites causes ahuge swelling in the skin, known as a chancre, and triggers theenlargement of the local draining lymph node. Metacyclicsdifferentiate into bloodstream forms, migrate to the blood andcause a systemic infection. The most consistent clinicalfeatures in livestock are intermittent fever and anaemia.There is a general leukopenia, enlarged spleen and liver, andloss of weight. Chronically infected animals lose appetite,become lethargic and emaciated, and die usually of congestiveheart failure. 3. Cerebral infections in cattle Both  T. congolense  and  T. vivax  are intravascular parasites,while the  T. brucei  ssp. and  T. evansi  can leave the bloodvessels and invade solid tissues (Losos and Ikede, 1972). Trypanosoma congolense  show a preference for microvascularsites, where they will occur in higher densities and may evenbind to endothelial cells (Banks, 1978). They contribute topathology by provoking dilation of the microvasculature,compromising capillary circulation and impairing nutrient andmetabolite exchange. Because  T. congolense  and  T. vivax  donot leave the circulation, cerebral infection is not a majorclinical feature in cattle infections, but it has been reported with T. brucei . About half of all cattle infected with  T. b.rhodesiense  developed fatal CNS disease, which is comparablewith that found in man (Wellde et al., 1989). Further  T. b.brucei  has been reported to cause CNS abnormalities and canbe found in CSF (Losos and Ikede, 1972; Morrison et al.,1983). Although figures are not available, the frequency of CNS involvement seems to be lower for  T. b. brucei  than for T. b. rhodesiense , and may depend on the particular strain. Nocerebral infections have been observed with monospecificinfections with  T. congolense  or  T. vivax  in cattle (Losos andIkede, 1972; Masake et al., 1984) but a high frequency of CNSinvolvement was observed in concurrent infections (Masakeet al., 1984). These authors suggested that  T. congolense ,because of its potential to bind microvascular walls (Banks,1978), may partially damage the endothelial barrier eithermechanically or through inflammatory responses, allowing T. brucei  to cross into the CNS. Most isolates from the CSF of multiply-infected cattle were  T. brucei , but in one case T. congolense  was recovered. The isolation of   T. congolense from brain tissue of a multiply infected cow, was probably theresultofasimilarmixedinfection(Haaseetal.,1981). T.vivax isabletocrossthebloodbarrieringoatsandhasalsobeenfoundinthe eye of infected goats and cattle, causing corneal cloudiness(Ilemobade and Schilhorn van Veen, 1974; Whitelaw et al., 1988). More recently, clear evidence for cerebral infections incattle has been observed in an outbreak of surra, caused by T. evansi  (Tuntasuvan et al., 1997). Even  T. theileri , which isconsidered a non-pathogenic parasite, was reported in the CSFof a cow with encephalitis (Braun et al., 2002).The evidence available so far suggests that  T. brucei  strains,and in particular the subspecies  T. b. rhodesiense,  constitutedthe major cerebral infections in cattle. The presence of trypanosomes in immunoprotected tissues such as brain andeyes presents a problem for therapy since they are protectedfrom drugs that do not cross the blood–brain barrier (Jenningset al., 1979; Whitelaw et al., 1988), and potentially developreactive encephalitis (Jennings et al., 1993). The relativefrequencies of cerebral infections in tolerant and susceptiblecattle has not been investigated. 4. Trypanotolerance Cattle of taurine origin were first introduced in Africaaround 6000 BC. From their srcin of domestication in theNear East, taurine cattle spread through Egypt and the NorthAfrican coast and expanded westward until they encounteredthe tsetse belt, which prevented further migration. Millennia of selection in tsetse-infested areas allowed some of these cattlebreeds to develop a certain degree of ‘reduced susceptibility’ totrypanosomosis. It is possible that genes conferring thistolerance entered the population through cross breeding withan ancient population of African cattle, whose existence couldbe traced by DNA analysis in breeds from the continent(Hanotte et al., 2002). The term trypanotolerance was definedas the trait that confers the capacity to survive and remainproductive after trypanosome infection (Murray et al., 1982).Despite the rapid and wide distribution of zebu cattle (  Bosindicus ) over the African continent since their first introductionaround 700 AD, taurine breeds predominate in areas of thetsetse belt. Early studies described that certain taurine breeds inWest Africa could cope better in tsetse-infested areas(reviewed in Murray et al., 1982; Murray and Dexter, 1988).Under natural conditions of tsetse challenge, trypanotolerantcattle had lower mortality, lower trypanosome levels, lesssevere anaemia, superior weight gain and better reproductiveperformance than more susceptible indicine breeds. The breedswere tolerant to both  T. vivax  and  T. congolense , with a higherdegree of resistance to  T. vivax  (Murray et al., 1981, 1982;Mattioli et al., 1999). Field studies suggested that control of anaemia, but not parasitaemia, had a major effect on overallproductivity (Trail et al., 1991a) and had a significant degree of heritability (Trail et al., 1991b).  J. Naessens / International Journal for Parasitology 36 (2006) 521–528 522  Comparison of infections with  T. congolense  in laboratoryconditions between trypanotolerant N’Dama calves (  Bostaurus ) with more susceptible Boran calves (  B. indicus ),confirmed observations in the field that N’Dama remainedproductive, continued to gain weight at the same rate as theuninfected controls, and females continued their oestrous cyclecompared with the infected Boran cattle (Paling et al., 1991).Furthermore, N’Dama were better at controlling parasitaemiaand the associated anaemia. No correlation between the degreeof anaemia and parasitaemia was found in individual N’Dama,suggesting that the two processes were not linked to each other,despite earlier views to the contrary (Dargie et al., 1979).Previous exposure with heterologous trypanosome strains didnot affect the course of infection, although it did reduce theseverity of anaemia in N’Dama, but not Boran cattle (Williamset al., 1991).Several efforts have been made to identify genes thatcontribute to trypanotolerance and this understanding couldhelp to discover the processes that confer resistance. In onetype of approach, differential gene expression betweentolerant and susceptible cattle allows the detection of geneswhose up- or down-regulation is correlated with a tolerantphenotype. Using serial analysis of gene expression (SAGE),187 genes that changed their expression were identified inN’Dama leukocytes after infection by  T. congolense (Berthier et al., 2003; Maillard et al., 2004, 2005).Unfortunately, this technology has not been used to comparetolerant and susceptible animals. Gene expression in bloodleukocytes was compared between N’Dama and Boran calvesusing gene array technology at different time points afterinfection (Hill et al., 2005). Thirty differentially expressedgenes were described, including three members of the proteinkinase C family. Confirmation of these observations is nowneeded, including data on purified cell populations and othertissues.A different, genomic approach aimed at identifying locicorrelated with a trypanotolerant phenotype uses genotypicanalysis of F2 calves derived from N’Dama and Borangrandparents (Hanotte et al., 2003). This approach had beensuccessfully undertaken in a murine trypanotolerance modelpreviously(Kemp etal.,1997;Kemp andTeale,1998).Incattle16 phenotypes, including anaemia, body weight and para-sitaemia were used in the analysis of the bovine data and 18quantitative trait loci (QTL) were identified (Hanotte et al.,2003). Trypanotolerance is thus highly polygenic, with eachgene or locus explaining no more than 10–12% of thephenotypic variance of the trait. Most QTLs were linked tocontrol of anaemia and only a few to parasitaemia, suggestingthat anaemia control is complex and of major significance. Aninteresting observation was that five resistance alleles in theQTL originated from the susceptible Boran grandparent,suggesting that trypanotolerance as observed in N’Dama,could be improved upon by further crossbreeding (Hanotteet al., 2003). Genes located in a QTL and differentiallyexpressed in tissues from trypanotolerant and susceptibleanimals should be particularly informative and are potential‘resistance genes’. 5. The role of haemopoietic cells in trypanotolerance Once trypanotolerance was able to be measured underlaboratory conditions, a question that arose was whether it wasdue to an improved acquired response, to a better acute innateresponse or to an innate disposition that confers a degree of resistance. Studies in mice infected with  T. brucei  parasiteshave repeatedly shown that antibodies, particularly thosereacting with surface epitopes, were a major player in thecontrol of parasitaemia and survival (Campbell et al., 1977;Reinitz and Mansfield, 1990). In contrast, mice with a defect inT cell maturation or depleted of T cells were not moresusceptible to African trypanosomiasis and continued toproduce antibodies, again correlating antibodies with trypano-tolerance (Campbell et al., 1978; Rottenberg et al., 1993).Consequently, a lot of research effort has gone into findingdifferences in immune responses between tolerant andsusceptible mouse strains. In contrast, studies on the resistanceof African ruminant wildlife suggested a role for better innateresponses. Control of parasitaemia in African buffalo wascorrelated with a decline in catalase activity and an increase inperoxide in the plasma capable of reducing trypanosomenumbers (Wang et al., 2002). Human resistance to  T. b. brucei is neither the result of a better acquired response nor of a betterinnate response, but is carried by apoL-I in human serum that islytic to this trypanosome strain, but not to  T. b. rhodesiense (Vanhamme and Pays, 2004). Bovine trypanotolerance mightinclude any combination of such mechanisms.An elegant solution to check the involvement of cells of thehaemopoietic system in bovine trypanotolerance, was to makeuse of the fact that cattle twins are haemopoietic chimeras.Twins composed of a male and female both carry male andfemale haemopoietic cells in the blood. This is because bloodvessels in the placentas of bovine twin fetuses are known tofuse, allowing haemopoietic precursor cells to migrate intoboth siblings and populate their bone marrow. The proportionof haemopoietic cells from each co-twin is identical in bothoffspring, but is not necessarily 50%.Boran/N’Dama chimeric twins were created by putting aBoran and an N’Dama embryo in the same recipient mother(Naessens et al., 2003a). Analysis of the composition of Tlymphocytes confirmed that all twins were chimeras, but thateach pair of twins contained proportionately more cells of Boran srcin (ranging from almost 100 to 70%) than N’Damasrcin. We assumed that migration of haemopoietic precursorcells to the bone marrow occurred earlier in Boran foetuses,thus leading to a higher ratio of Boran haemopoietic cells inboth twin calves. As expected, the ratio of Boran vs N’Damacells was identical in each set of twin calves. Overall, the Boranchimeras were like normal Boran calves, except that they hadsome haemopoietic cells of N’Dama srcin, while the N’Damachimeras were like N’Dama calves, but had acquired themajority of their haemopoietic system from the susceptibleBoran background.The responses of the twin chimeras were compared afterinfection with  T. congolense  with those of Boran and N’Damasingletons (Table 1). The Boran chimeras had similar levels of   J. Naessens / International Journal for Parasitology 36 (2006) 521–528  523  parasitaemia and anaemia as the Boran singletons, suggestingthat the few haemopoietic cells that they had ‘inherited’ fromtheir N’Dama co-twins were not capable of bestowingtrypanotolerant traits on them. The N’Dama chimeras wereable to control parasitaemia as well as the N’Dama singletoncalves, but they developed severe anaemia, to the same extentas the susceptible Boran. Thus the two traits, better parasitecontrol and better anaemia control, were not linked. Thecorrelation between severe anaemia and absence of haemo-poietic cells of trypanotolerant origin indicated a role forN’Dama haemopoietic cells in anaemia control. Importantly,the N’Dama chimeras also lost the capacity to gain weightcompared with the singletons.This experiment thus confirmed that trypanotolerance ismediated by two independent mechanisms. The first is a bettercapacity to control parasitaemia and is not carried by cells froma haemopoietic lineage. This further suggested that thissuperior parasite control in N’Dama calves was not due todifferences in their immune responses. The second mechanismis a better capacity to control the associated anaemia and ismediated by cells from the haemopoietic system. At this stage,we can only speculate about the exact mechanism: it couldinclude an improved erythropoietic response in N’Dama or areduced contribution of lymphoid and phagocytic cells in thedevelopment of anaemia.Since productivity, or the capacity to gain weight, was notassociated with parasitaemia control but with anaemia control,further research focused primarily on the identification of thelatter mechanism. 6. The role of T lymphocytes and antibodies intrypanotolerance To identify a potential role of lymphocytes in the inductionof anaemia, calves were in vivo depleted for different T cellsubpopulations using mouse monoclonal antibodies to bovineleukocyte antigens (Naessens et al., 1997), and the techniquewas refined to ensure that all cells of a particular phenotypewould be removed from all peripheral lymphoid tissues and not just the blood (Naessens et al., 1998). Depletion of all CD8 Tcells did not influence the progress of anaemia after T. congolense  infection as compared with non-depleted controlcalves (Sileghem and Naessens, 1995). Similarly, using acombination of monoclonal antibodies to CD8 and WC1 tocompletely deplete all CD8 and all  g  /  d -T cells from theperiphery did not influence anaemia development (DeBuysscher E.V., Naessens J., unpublished data).Complete depletion of CD4 T lymphocytes was successfullyobtained in Boran and N’Dama calves. In such depleted cattleno chancre formation was observed in the skin upon the bite of infective tsetse flies (Naessens et al., 2003b). The experimentssuggested that the local skin reaction was an inflammatoryresponse to metacyclic forms, specific for the metacyclicvariant antigenic types (VAT), and mediated by CD4 Tlymphocytes. However, the absence of a response in the skinhad no effect on the subsequent migration of trypanosomes tothe bloodstream and the progress of infection (Naessens et al.,2003b). After infection of CD4-depleted and non-depletedBoran and N’Dama calves with  T. congolense , the antibodyresponses were found to be markedly reduced and delayed inthe depleted animals (Naessens et al., 2002). This was the casefor IgG and IgM antibodies to surface-exposed and internaltrypanosome epitopes, as well for the natural IgM antibodiesthat react with non-trypanosome antigens (Buza and Naessens,1999). In contrast to murine infections (Reinitz and Mansfield,1990), the proportion of T-cell independent antibodies is verylow in infected cattle. The extent of anaemia in the CD4-depleted N’Dama and Boran calves did not differ from that inthe non-depleted calves. The anaemia in the two Boran groupswas more severe than that in the two N’Dama groups. Takentogether, these data suggested that neither T cells, norantibodies mediate the trypanosome-associated anaemia. Thepotential contribution of auto-antibodies (Kobayashi andTizard, 1976; Facer et al., 1982; Assoku and Gardiner, 1992)and anti-trypanosome antibodies (Woo and Kobayashi, 1975;Rifkin and Landsberger, 1990) to removal of erythrocytes istherefore negligible in  T. congolense  infections in cattle. 7. Haemophagocytic syndrome in bovine trypanosomosis Thus far, three parameters were systematically used tomonitor trypanotolerance: parasitaemia in blood, anaemia andweight gain, with the latter being the most indicative of overallproductivity in a field situation. However, there are a number of additional pathological features associated with bovine trypa-nosomosis, including hepatosplenomegaly, pancytopenia andmacrophage activation. A careful analysis reveals that thiscollection of features constitutes haemophagocytic syndrome Table 1Capacity (marked with a C sign) to gain weight and to better control parasitaemia and anaemia after infection with  Trypanosoma congolense , of Boran and N’Damasingleton and haemopoietic chimeric calvesCalves Origin of haemopoietictissueOrigin of all othertissuesControl of parasitaemia Control of anaemia Productivity(weight gain)Boran Boran Boran  K K K N’Dama N’Dama N’Dama  C C C Chimera Boran Mainly Boran a Boran  K K K Chimera N’Dama Mainly Boran a N’Dama  C K K The capacity to control anaemia and to gain weight are associated with an N’Dama srcin of haemopoietic tissues, while the capacity to control parasitaemia isassociated with a N’Dama srcin of non-haemopoietic tissues. a 70–98% of haemopoietic cells in chimeras were of Boran srcin (Naessens et al., 2003a).  J. Naessens / International Journal for Parasitology 36 (2006) 521–528 524  (HPS) (Table 2). This set of clinical and pathologicalmanifestations in humans occurs as a result of hyperactivationof the phagocytic system (Kumakura, 2005; Me´nasche´ et al.,2005). The condition is often fatal and is associated with aninfection, malignancy, autoimmune disorder or with a geneticimpairment in T and natural killer (NK) cells (Me´nasche´ et al.,2005). The fact that these pathological features occur togetherunder apparently very different circumstances, suggests thatthey occur as a result of the deregulation of the same responses.Although the underlying events are not fully understood, itseems clear that more than one stimulus can give rise tohyperactivated, proliferating macrophages (Larroche andMouthon, 2004).What causes the appearance of HPS in trypanosomeinfections is not known. But since infected calves quicklyrecover from anaemia and other pathologies after treatmentwith trypanocidal drugs (Murray and Dexter, 1988), thecondition must be dependent on the continuous presence of trypanosomes or trypanosome factors. Since T lymphocytesdid not seem to interfere with anaemia development, directstimulation of macrophages probably causes this disease state.It is not known which parasite molecules trigger this pathway.Membrane variable surface glycoprotein (VSG), and to someextent soluble VSG, can trigger the secretion of tumournecrosis factor (TNF)- a  in murine (Magez et al., 1998) andbovine macrophages (Sileghem et al., 2001) and could be themolecules that trigger anaemia. However, it is more likely thata number of trypanosome stimuli and host immune mediatorssynergise to produce anaemia and HPS. 8. Murine trypanotolerance Trypanosoma congolense -infected C57BL/6 mice (BL6) dielater than similarly infected A/J or BALB/c mice, providing uswith a potential model to study trypanotolerance (Kemp et al.,1996). Susceptible A/J mice developed much higher para-sitaemias than BL6, suggesting that mortality was correlatedwith high parasite numbers. However, the associated anaemiain A/J was mild and transient, in contrast to anaemia in thetrypanotolerant BL6 mice which continued to develop to asevere degree (Nakamura et al., 2003; Naessens, unpublisheddata). The same pattern held true in the two host strains forinfections with the human-infective trypanosome  T. b.rhodesiense  (Naessens, unpublished data) and in BL6 andBALB/c mice infected with  T. b. brucei  (Magez et al., 2004).Thus parasitaemia control and anaemia control in mice are notcorrelated, as they were in bovine trypanosomosis. However,the data suggest that trypanotolerance as defined by longersurvival in the mouse model, is very different fromtrypanotolerance in cattle, defined as higher productivityafter infection. In the murine model, tolerance is correlatedwith parasitaemia control, but not with anaemia control,whereas in the bovine model, tolerance is primarily correlatedwith anaemia control, and to a lesser extent with parasitaemiacontrol. Studies in tolerant mice have suggested that severalmechanisms contribute to restriction of parasite growth.Comparison between infections in a collection of gene-deficient C57BL/6 mice demonstrated that control of   T.congolense  parasites depended on at least two effector armsof the immune system: interferon (IFN)- g -dependent pro-duction of nitric oxide (NO) and TNF- a  and presence of functional IgG antibodies (Magez et al., in press). The criticalrole of antibodies in murine trypanotolerance (Campbell et al.,1977; Magez et al., in press) but to a much lesser degree inbovine tolerance (see above) is evidence that the control of parasitaemia is also mediated by different mechanisms in thetwo species. We conclude from this that mice do not offer agood model to study bovine mechanisms of parasite control. 9. A murine model for anaemia development Although mice may not provide good model systems toidentify the responses that lead to resistance in a natural host,they may still offer good models to identify the molecularpathways that mediate particular resistance traits or pathologi-cal features, such as the trypanosome-associated anaemia.Since infected BL6 mice survived for a reasonably longtime and developed severe anaemia after infection, we selected Table 2Summary of clinical and pathological signs of haemophagocytic syndrome (HPS) a with features observed in cattle with trypanosomosisFeatures associated with HPS Features associated with bovine trypanosomosis Clinical manifestations High fever ( O week) YES (many reports)Hepatosplenomegaly YES (many reports)CNS symptoms NO, except when trypanosomes can cross the BBB  Biological manifestations Pancytopenia YES: anaemia, thrombocytopenia, neutropenia (Logan-Henfrey et al., 1999; many older reports)Macrophage activation YES: in  Trypanosoma congolense  (Anosa et al., 1997, 1999)YES: in  Trypanosoma vivax  (Anosa et al., 1992)Tissue infiltration of macrophages YES (many reports)Liver dysfunction No data?Hyper-triglyceridemia YES in cattle (Valli et al., 1980), marginally in sheep (Katunguka, 1995, 1999), up in mouse and rabbit Hyper-ferritinemia YES in cattle (Mamo and Holmes, 1975), in sheep (Katunguka-Rwakishaya et al., 1992) Haemodilution YES, partial haemodilution (reviewed in Katunguka-Rwakishaya et al., 1992)Defective NK cytotoxicity No data a Me´nasche´ et al., 2005; Kumakura, 2005.  J. Naessens / International Journal for Parasitology 36 (2006) 521–528  525
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