Chromosomal mapping of the host resistance locus to rodent malaria (Plasmodium yoelii) infection in mice

The disease outcome in malaria caused by the protozoan parasite Plasmodium is influenced by host genetic factors. To identify host genes conferring resistance to infection with the malaria parasite, we undertook chromosomal mapping using a whole-genome scanning approach in cross-bred mice. NC/Jic mice all died with high parasitemia within 8 days of infection with 1 x 10(5) parasitized erythrocytes. In contrast, 129/SvJ mice all completely excluded malaria parasites from the circulation and remained alive 21 days after infection. We performed linkage analysis in backcross [(NC/Jic x 129/SvJ)xNC/Jic] mice. The Pymr ( Plasmodium yoelii malaria resistance) locus was mapped to the telomeric portion of mouse Chromosome (Chr) 9. This locus controls host survival and parasitemia after infection. The Char1 locus ( P. chabaudi resistance locus 1), controlling host survival and peak parasitemia in P. chabaudi infection, was previously mapped to the same region. This host resistance locus mapping to Chr 9 may represent a ubiquitous locus controlling susceptibility to rodent malaria. Elucidation of the function of this gene will provide valuable insights into the mechanism of host defense against malaria parasite infection.     

Plasmodium chabaudi chabaudi(AS): Inflammatory Cytokines and Pathology in an Erythrocytic-Stage Infection in Mice

Cross, C. E., and Longhorne J. 1998.Plasmodium chabaudi chabaudi(AS): Inflammatory cytokines and pathology in an erythrocytic-stage infection in mice.Experimental Parasitology90220–229. We have sought to characterizePlasmodium chabaudi chabaudiinfection in mice for use as a model for malaria pathology. Different mouse strains vary in their susceptibility to the erythrocytic stages of this parasite and this is manifested not only in the outcome of infection (survival versus death) but also by differences in the numbers of circulating parasites at the peak of infection. We have shown that regardless of final outcome, both resistant and susceptible mice exhibit other parameters of disease such as loss in body weight and anemia. By contrast, other parameters such as hypothermia appear more severe in susceptible mice. The severe symptoms coincide with high levels of inflammatory cytokines in the circulation of susceptible mice, not seen in H-2-matched resistant mice. However, levels of mRNA for the same cytokines, measured in the spleen of the same mice was not significantly different between the two strains. Neutralization of IFN-γin vivoled to an increase in parasitemia, in both susceptible and resistant mice, but did not affect the final outcome of disease. Indeed, symptoms were exacerbated in the absence of IFN-γ, presumably because of larger numbers of circulating parasites. These data suggest that IFN-γ does not directly contribute to the lethal outcome of infection in susceptible strains of mice.     

Vaccination with a Plasmodium chabaudi adami multivalent DNA vaccine cross-protects A/J mice against challenge with P. c. adami DK and virulent Plasmodium chabaudi chabaudi AS parasites

A current goal of malaria vaccine research is the development of vaccines that will cross-protect against multiple strains of malaria. In the present study, the breadth of cross-reactivity induced by a 30K multivalent DNA vaccine has been evaluated in susceptible A/J mice (H-2a) against infection with the Plasmodium chabaudi adami DK strain and a virulent parasite subspecies, Plasmodium chabaudi chabaudi AS. Immunized A/J mice were significantly protected against infection with both P. c. adami DK (31–40% reduction in cumulative parasitemia) and P. c. chabaudi AS parasites, where a 30–39% reduction in cumulative parasitemia as well as enhanced survival was observed. The 30K vaccine-induced specific IFN-γ production by splenocytes in response to native antigens from both P. c. chabaudi AS and P. c. adami DK. Specific antibodies reacting with surface antigens expressed on P. c. adami DS and P. c. chabaudi AS infected red blood cells, and with opsonizing properties, were detected. These results suggest that multivalent vaccines encoding conserved antigens can feasibly induce immune cross-reactivity that span Plasmodium strains and subspecies and can protect hosts of distinct major histocompatibility complex haplotypes.     

Comparison of pathology in susceptible A/J and resistant C57BL/6J mice after infection with different sub-strains of Plasmodium chabaudi

Susceptible A/J and more resistant C57BL/6J mice were infected with Plasmodium chabaudi chabaudi 54X, P.c. chabaudi AS and Plasmodium chabaudi adami 408XZ. As expected, most C57BL/6J mice survived the infections with the different isolates. But in contrast to previous observations, not all A/J mice succumbed to infection: just over 50% of A/J mice survived infections with P.c. chabaudi 54X, while 80% survived P.c. chabaudi AS. The more virulent parasite, P.c. adami 408XZ, was able to kill all A/J mice and 20% of C57BL/6J mice after an intravenous infection with 10(5) pRBC. A detailed study of four parameters of pathology (body weight, body temperature, blood glucose and RBC counts) in both mouse strains after a P.c. adami 408XZ infection showed similar patterns to those previously reported after infection with P.c. chabaudi AS. These data suggest that environmental factors as well as parasite polymorphisms might influence the severity of malaria between susceptible and resistant mice.     

Genetics of resistance to the African trypanosomes. VI. Heredity of resistance and variable surface glycoprotein-specific immune responses

The question of genetic linkage of parasite-specific immune responses to resistance to infection in experimental African trypanosomiasis was addressed. For this purpose, major histocompatibility complex-compatible resistant and susceptible inbred mouse strains and their F1 hybrid, F2 hybrid, and backcross offspring were infected with Trypanosoma brucei rhodesiense LouTat 1. Immunologic control of the first peak of parasitemia and survival times were the parameters measured. As we have reported previously (R. F. Levine and J. M. Mansfield, J. Immunol. 133:1564, 1984), B10.BR/SgSnJ mice are relatively resistant and controlled the growth of the infecting variant antigenic type (VAT) by mounting an antibody response to exposed epitopes of the variable surface glycoprotein (VSG). Fluctuating parasitemias resulting from sequential growth of different variable antigenic types occurred subsequently, and these mice died with a median survival time of 48 days. C3HeB/FeJ mice, relatively susceptible, did not control the infecting VAT and did not exhibit VSG-specific antibodies. These mice died with a median survival time of 22 days. The (B10.BR X C3H)F1 hybrids derived from crosses between resistant and susceptible mice all exhibited VSG-specific antibody responses and controlled the infecting VAT population. However, the median survival time of the F1 hybrids (24 days) was not significantly different from the survival time of the susceptible C3H parent. These findings demonstrate for the first time that antibody-mediated control of parasitemia is inherited as a dominant trait; that overall resistance, as measured by survival time, is inherited as a recessive trait (e.g., susceptibility is dominant); and that the two events segregate independently of one another. Further analyses of the inheritance of immunity and resistance (survival time) were made in which the F2 hybrid and backcross studies revealed that there are multiple genes controlling the VSG-specific antibody response as well as determining susceptibility. An extension of the present studies to a similar but non-major histocompatibility complex-mouse model system of resistance and susceptibility (C57BL/6J and C3H/HeJ mice, F1 hybrids, and 11 recombinant inbred B X H strains derived from them) was made in order to link the strain distribution patterns of known genetic markers with control of VSG-specific antibody responses or with control of susceptibility. Results of this study showed that resistance varied independently of the ability to control parasitemia with VSG-specific B cell responses.(ABSTRACT TRUNCATED AT 400 WORDS)     

Plasmodium chabaudi AS: erythropoietic responses during infection in resistant and susceptible mice.

The course of anemia and the erythropoietic response in the bone marrow, spleen, and blood were studied during Plasmodium chabaudi AS infection in resistant C57BL/6 (B6) and susceptible A/J (A) mice. Infections in B6 mice were characterized by moderate levels of both parasitemia and anemia and survival. In contrast, A mice experienced high parasitemia, severe anemia, and high mortality rates. During the period of anemia, erythropoiesis, as measured by in vivo 59Fe incorporation, was significantly more depressed in bone marrow and more increased in the spleen in resistant B6 mice. The increase in splenic 59Fe incorporation was a function of the size of the spleen. Bone marrow CFU-E were decreased to 50% of control in both strains, while splenic CFU-E were increased twofold greater in B6 mice compared to those in A mice. However, the absolute numbers of CFU-E per spleen in the two strains were not significantly different during peak parasitemia. Bone marrow BFU-E were transiently increased before peak parasitemia whereas splenic BFU-E peaked during peak parasitemia. A mice had significantly lower numbers of BFU-E per spleen on all days except at peak parasitemia. The frequency of blood-borne BFU-E and plasma erythropoietin titers was increased earlier and to a greater extent in A mice. These results suggest that an impaired amplification of late-stage splenic erythropoiesis may be an important determinant in the severity of anemia and lethality of infection with P. chabaudi AS in A mice. Moreover, these results demonstrate that the defective amplification of splenic erythropoiesis in A mice is neither caused by a defect in the mobilization of BFU-E from the bone marrow to the spleen nor caused by a defect in erythropoietin production.     

CD4+CD25+Foxp3hi细胞在夏氏疟原虫感染DBA/2小鼠作用研究

利用调节性T细胞消除的致死型夏氏疟原虫(Plasmodium chabaudi chabaudi AS,P.c chabaudi AS)感染鼠疟模型,探讨DBA/2小鼠对P.c chabaudi AS感染易感性的原因。DBA/2小鼠对P.c chabaudi AS易感,伴随原虫血症增加CD4+CD25+Foxp3+细胞数量明显增加,且以CD4+CD25+Foxp3hi增加更为明显。原虫血症达峰值时CD4+CD25+Foxp3hi细胞数量亦达到峰值。相比,Treg消除鼠的原虫出现时间和疟血症峰值时间均明显延迟,且在疟血症达峰值前(5～8 d)原虫血症水平明显低于对照组。与之相应,CD4+CD25+Foxp3hi细胞数量明显处于低水平。同时,Treg消除鼠生存期明显延长。由此提示,P.c chabaudi AS感染导致Foxp3表达增加,扩增的CD4+CD25+Foxp3hi细胞有利于疟原虫复制和逃避宿主免疫应答,进而影响疟疾感染的进程和最终结局。     

Trypanosoma congolense: Genetic control of resistance to infection in mice

Primary isolates of Trypanosoma congolense show a range of virulence in NMRI mice. Stabiliates derived from an isolate (Dinderesso/ 80/CRTA/3) which showed moderate virulence in most NMRI mice (moderate parasitemia and survival) were used in inbred mice. C57B1/6 were resistant with low parasitemia and survival. Parasitemias were higher in males than females. BALB/c were the most sensitive of the strains tested and died with fulminating parasitemia. Inheritance of resistance, defined as low parasitemia, was studied using these two strains. Male F1 showed high parasitemia; the backcrosses of F1 to the resistant parent had a ratio of one susceptible to one resistant product; the product of F1 to susceptible parent were all susceptible; and the F2 crosses showed a ratio of three susceptible to one resistant product. The results obtained with female F1, backcrosses, and F2 mice showed similar segregation to that found using males, but the range of parasitemia was always 1–2 log₁₀ lower, except for the F1 backcrossed to BALB/c, where female and male parasitemia were undistinguishable. The segregation ratios were identical whether resistant females were crossed with sensitive males or vice-versa. The results obtained are compatible with resistance being a recessive trait controlled by a single autosomal gene (or gene cluster). In addition, sex-associated factors appear to confer higher resistance in females.     

Trypanosoma congolense: inheritance of susceptibility to infection in inbred strains of mice

Inbred strains of mice have shown marked differences in susceptibility to infection with Trypanosoma congolense, as judged by survival and levels of parasitemia. The underlying genetic basis of the susceptibility was examined with F1 hybrids and backcrosses derived from mouse strains of high and low susceptibility. The influence of H-2 haplotype on susceptibility was studied using H-2 congenic resistant strains of mice. F1 hybrids between the most susceptible strain (A/J) and the least susceptible strain (C57Bl/6) showed similar survival to that of the C57Bl/6 parent. This was reflected in a similar undulating pattern of parasitemia, although the level of parasitemia was consistently higher in the F1 hybrids than in the C57Bl/6. Backcrosses of the F1 hybrids with C57Bl/6 also had a similar pattern of parasitemia although there was a greater scatter in survival times so that a few animals survived longer than either of the parental strains. Backcrosses of F1 hybrids with A/J showed a range of survival times; approximately 25% of these animals died during the period when the A/J mice died, approximately 25% had a similar survival to that of C57Bl/6, while the remaining animals showed an intermediate duration of survival. All these backcrosses had a high initial peak of parasitemia; in about 70% of the mice the early parasitemia showed a distinct undulating pattern. F1 hybrids of A/J and C57Bl/6 with C3H/He mice, which are known to be of intermediate susceptibility, were also examined. The degree of dominance for low susceptibility was much less pronounced in these hybrid combinations than in the A/J × C57Bl/6 hybrids. The H-2 congenic resistant strains, all of which were on a C57Bl/10 genetic background, showed a similar pattern of parasitemia and survival. However, although the majority of all these strains survived for more than 100 days, there was a significant difference in survival between the C57Bl/10 mice and the H-2 congenic resistant strains. It was concluded that susceptibility of mice to T. congolense infection is likely to be under complex genetic control and that, at least in C57Bl/mice, H-2 haplotype has little influence on susceptibility.     

Susceptibility to a mouse acquired immunodeficiency syndrome is influenced by theH-2

The development of a mouse acquired immunodeficiency syndrome (MAIDS) induced following LP-BM5 MuLV infection depends on host genetic factors. Susceptible mice, such as C57BL/6J mice, develop a profound impairment of lymphoproliferative response to mitogens and hyperplasia of lymphoid organs and succumb to infection within 6 months. These changes do not occur in resistant mice, such as A/J mice. Resistance to MAIDS is a dominant trait since (C57BL/6JxA/J)F₁ hybrid mice did not develop any immune dysfunctions following infection. Genetic regulation of the trait of resistance/susceptibility to MAIDS was determined in AXB/BXA recombinant inbred (RI) mouse strains (derived from resistant A/J and susceptible C57BL/6J progenitors). Two different criteria were used to determine their resistance or susceptibility to developing MAIDS: the gross pathologic evaluation of lymphoid organs at 13–15 weeks of infection, and survival. RI mouse strains segregated into two non-overlapping groups. The first group did not develop any significant pathology, and these mouse strains were considered as resistant to MAIDS. The second group showed the virus-induced pathological changes as well as an immunological dysfunction as seen in C57BL/6J progenitor mice, and these strains were thus considered as susceptible to MAIDS. This bimodal strain distribution pattern of resistance/susceptibility to MAIDS among the RI strains suggests that this phenotype is controlled by a single gene. Linkage analysis with other allelic markers showed a strong association between resistance/susceptibility to MAIDS and theH-2 complex. Possession of theH-2 ^b haplotype derived from C57BL/6J mice was associated with susceptibility to MAIDS, while theH-2 ^a haplotype conferred resistance to the disease. This finding was confirmed by demonstrating thatH-2 ^a congenics on the susceptible C57BL/10 background were as resistant to MAIDS as A/J mice which donated theH-2 ^a locus. Gene(s) within theH-2 complex thus represent the major regulatory mechanism of resistance/susceptibility to MAIDS.     

Malarial anaemia: mechanisms and implications of insufficient erythropoiesis during blood-stage malaria

It has been proposed that the basis of severe malarial anaemia, a major cause of morbidity and mortality in endemic areas, is multifactorial. Inappropriately low reticulocytosis is observed in malaria patients suggesting that insufficient erythropoiesis is a major factor. Clinical studies provide conflicting data concerning the production of adequate levels of erythropoietin (EPO) during malaria. Plasmodium chabaudi AS causes non-lethal infection in resistant C57BL/6 mice, and lethal infection in susceptible A/J mice. In P. chabaudi AS infected C57BL/6 and A/J mice, which experience varying degrees of severity of anaemia, kidney EPO production is appropriate to the severity of anaemia and is regulated by haematocrit level. Neutralisation of endogenous EPO during infection leads to lethal anaemia while timely administration of exogenous EPO rescues mice although reticulocytosis is suppressed in proportion to the parasitemia level. Characterisation of alterations in splenic erythroid compartments in naive and P. chabaudi AS infected A/J mice revealed that infection, with or without EPO treatment, leads to sub-optimal increases in TER119+ erythroblasts compared to EPO-treated naive mice. A lower percentage of TER119+ erythroblasts in infected mice undergo terminal differentiation to become mature haemoglobin-producing cells. Furthermore, there is a shift in transferrin receptor (CD71) expression from TER119+ cells to a non-erythroid population. Deficiencies in the number and maturation of TER119+ erythroblasts during infection coincide with blunted proliferation to EPO stimulation in vitro by splenocytes, although a high frequency express EPO receptor (EPOR). Together, these data suggest that during malaria, EPO-induced proliferation of early EPOR+ erythroid progenitors is suppressed, leading to sub-optimal generation of TER119+ erythroblasts. Moreover, a shift in CD71 expression may result in impaired terminal maturation of erythroblasts. Thus, suppressed proliferation, differentiation, and maturation of erythroid precursors in association with inadequate reticulocytosis may be the basis of insufficient erythropoiesis during malaria.     

MyD88-dependent activation of dendritic cells and CD4(+) T lymphocytes mediates symptoms, but is not required for the immunological control of parasites during rodent malaria

We investigated the role of different TLRs and MyD88 in host resistance to infection and malaria pathogenesis. TLR2(-/-), TLR4(-/-), TLR6(-/-), TLR9(-/-) or CD14(-/-) mice showed no change in phenotypes (parasitemia, body weight and temperature) when infected with Plasmodium chabaudi chabaudi (AS). MyD88(-/-) mice displayed comparable ability to wild type animals in controlling and clearing parasitemia. Importantly, MyD88(-/-) mice exhibited impaired production of TNF-alpha and IFN-gamma as well as attenuated symptoms, as indicated by changes in body weight and temperature during parasitemia. Consistently, CD11b(+) monocytes and CD11c(+) dendritic cells from infected MyD88(-/-) mice were shown impaired for production of pro-inflammatory cytokines, and in initiating CD4(+) T cell responses. Importantly, the inhibition of T cell activation with anti-CD134L, mostly inhibited IFN-gamma, partially inhibited TNF-alpha production, and protected the animals from malaria symptoms. Our findings suggest that MyD88 and possibly its associated TLRs expressed by dendritic cells play an important role in pro-inflammatory responses, T cell activation, and pathogenesis of malaria, but are not critical for the immunological control of the erythrocytic stage of P. chabaudi.     

IL-12 is required for antibody-mediated protective immunity against blood-stage Plasmodium chabaudi AS malaria infection in mice.

In this study, we investigated the role of endogenous IL-12 in protective immunity against blood-stage P. chabaudi AS malaria using IL-12 p40 gene knockout (KO) and wild-type (WT) C57BL/6 mice. Following infection, KO mice developed significantly higher levels of primary parasitemia than WT mice and were unable to rapidly resolve primary infection and control challenge infection. Infected KO mice had severely impaired IFN-gamma production in vivo and in vitro by NK cells and splenocytes compared with WT mice. Production of TNF-alpha and IL-4 was not compromised in infected KO mice. KO mice produced significantly lower levels of Th1-dependent IgG2a and IgG3 but a higher level of Th2-dependent IgG1 than WT mice during primary and challenge infections. Treatment of KO mice with murine rIL-12 during the early stage of primary infection corrected the altered IgG2a, IgG3, and IgG1 responses and restored the ability to rapidly resolve primary and control challenge infections. Transfer of immune serum from WT mice to P. chabaudi AS-infected susceptible A/J mice completely protected the recipients, whereas immune serum from KO mice did not, as evidenced by high levels of parasitemia and 100% mortality in recipient mice. Furthermore, depletion of IgG2a from WT immune serum significantly reduced the protective effect of the serum while IgG1 depletion had no significant effect. Taken together, these results demonstrate the protective role of a Th1-immune response during both acute and chronic phases of blood-stage malaria and extend the immunoregulatory role of IL-12 to Ab-mediated immunity against Plasmodium parasites.     

Susceptibility/resistance to mouse hepatitis virus strain 3 and macrophage procoagulant activity are genetically linked and controlled by two non-H-2-linked genes

The mode of inheritance of susceptibility/resistance to mouse hepatitis strain 3 (MHV-3) was determined by typing the set of AXB/BXA recombinant inbred (RI) strains derived from resistant A/J (A) and susceptible C57BL/6J (B) progenitors for susceptibility to infection as determined by the severity of liver pathology. The strain distribution pattern for susceptibility showed a discontinuous variation: one strain was fully resistant (A-like), four strains were fully susceptible (B-like), and 16 strains showed an intermediate degree of susceptibility. The fully susceptible strains developed fulminant hepatitis and died; the fully resistant strain developed no liver disease, whereas a range of disease ranging from mild focal hepatitis to widespread hepatocellular necrosis was seen in the semisusceptible strains. This SDP best fits the two-recessive-gene model of inheritance, and neither of these two loci is linked to the H-2 complex. Macrophage procoagulant activity (PCA) segregated among the RI strains in a strain distribution pattern identical to that of susceptibility/resistance. PCA levels were greater than sevenfold elevated in fully susceptible RI mice and fourfold elevated in semisusceptible mice with no increase in resistant mice. These observations suggest genetic linkage of susceptibility/resistance to MHV-3 infection and macrophage PCA.     

Genetics of resistance to the African trypanosomes. V. Qualitative and quantitative differences in interferon production among susceptible and resistant mouse strains

The induction of interferon (IFN) was examined in different inbred mouse strains infected with Trypanosoma brucei rhodesiense. Relatively susceptible C3HeB/FeJ mice that do not exhibit variant-specific immunity or control parasitemia did not exhibit detectable IFN throughout the infection. Relatively resistant B10.BR mice that exhibit variant-specific immunity and control the first peak of parasitemia exhibited detectable IFN at two intervals. The appearance of IFN in B10.BR serum first coincided with the onset of the parasitemia 4 days after infection and then disappeared; this IFN peak was predominantly IFN-alpha/beta. The second time of appearance coincided with high titers of antibody and remission of the parasitemia. This IFN was predominantly IFN-gamma. Intermediately susceptible CBA/J mice also exhibited two detectable peaks of IFN; the first IFN-alpha/beta peak coincided with the onset of the parasitemia as in B10.BR mice. The second peak of IFN in the serum of CBA mice, however, was delayed in appearance and lower in concentration compared with B10.BR mice. This peak was characterized as being predominantly IFN alpha/beta. BALB/c mice (also intermediately susceptible) did not exhibit a first peak of IFN-alpha/beta production, but the second peak of IFN-alpha/beta production was similar to that seen in CBA mice. In contrast to infected mice, IFN was induced in both susceptible (C3H) and resistant (B10.BR) mice after immunization with glutaraldehyde-fixed trypanosomes or after chemotherapy of infection. We conclude that both the levels of IFN as well as the type of IFN induced during infection with T. b. rhodesiense depend upon the genetic background of the mouse strain infected. The induction of IFN-gamma in mice of the C57BL background may be linked functionally to more effective parasite control and to the presence of an effective immune response to T. b. rhodesiense.     

A novel ENU-mutation in ankyrin-1 disrupts malaria parasite maturation in red blood cells of mice

The blood stage of the plasmodium parasite life cycle is responsible for the clinical symptoms of malaria. Epidemiological studies have identified coincidental malarial endemicity and multiple red blood cell (RBC) disorders. Many RBC disorders result from mutations in genes encoding cytoskeletal proteins and these are associated with increased protection against malarial infections. However the mechanisms underpinning these genetic, host responses remain obscure. We have performed an N-ethyl-N-nitrosourea (ENU) mutagenesis screen and have identified a novel dominant (haploinsufficient) mutation in the Ank-1 gene (Ank1(MRI23420)) of mice displaying hereditary spherocytosis (HS). Female mice, heterozygous for the Ank-1 mutation showed increased survival to infection by Plasmodium chabaudi adami DS with a concomitant 30% decrease in parasitemia compared to wild-type, isogenic mice (wt). A comparative in vivo red cell invasion and parasite growth assay showed a RBC-autonomous effect characterised by decreased proportion of infected heterozygous RBCs. Within approximately 6-8 hours post-invasion, TUNEL staining of intraerythrocytic parasites, showed a significant increase in dead parasites in heterozygotes. This was especially notable at the ring and trophozoite stages in the blood of infected heterozygous mutant mice compared to wt (p<0.05). We conclude that increased malaria resistance due to ankyrin-1 deficiency is caused by the intraerythrocytic death of P. chabaudi parasites.     

Manifestation of cerebral malaria-like symptoms in the WM/Ms rat infected with Plasmodium berghei strain NK65

Conditions required for the induction of cerebral malaria (CM)-like symptoms were investigated using 12 strains of rats and 5 murine malaria strains. Among various combinations, only inbred WM/Ms rats infected with P. berghei (NK65) developed neuropathological complications that closely resembled human CM cases. When young WM/Ms rats were infected with the parasites, neurologic signs were induced followed by death in 5-10 days with almost 100% incidence, whereas aged hosts revealed strong resistance. Histologically, edematous changes, occlusion of vessels, and petechial hemorrhages were found in the brain. There was an optimum dose of parasites to induce the manifestations, and a low incidence was obtained by increased or decreased inoculum size. No correlation was found between the level of parasitemia and incidence of the disease. The other 11 rat strains inoculated with this parasite showed high levels of parasitemia, but most of their infections were self-limiting or malarial death occurred without CM-like signs. Inoculation into WM/Ms rats with other murine malaria parasites, including P. chabaudi, P. vinckei, P. yoelii (17X), and P. yoelii (nigeriensis) failed to induce CM-like manifestations irrespective of the inoculation size and the degree of parasitemia. These results indicated that P. berghei (NK65)-infected WM/Ms rats represent an experimental model for CM and certain appropriate conditions are needed for its development in both parasite and host sides.     

Immunoregulation in murine malaria. Susceptibility of inbred mice to infection with Plasmodium yoelii depends on the dynamic interplay of host and parasite genes

Inbred and H-2 congenic mouse strains were tested for their ability to resist infections with the non-lethal 17X or with the lethal YM isolates of Plasmodium yoelii. DBA/2 and B10.D2 mice, which best resisted infections with non-lethal P. yoelii, were exquisitely susceptible to infection with lethal isolates of this malaria species. In contrast, B6 and B10 mice, which were susceptible to infection with non-lethal P. yoelii, were resistant to infection with the lethal isolates. This reversal of host response phenotype was influenced by H-2 genes, as evidenced by the divergent responses of the H-2 congenic strains B10 and B10.D2. However, a survey of mouse strains sharing common H-2 genes, but expressing different genetic backgrounds, demonstrated that genes outside the H-2 complex also influence the outcome of P. yoelii infections. By enumerating the numbers of P. yoelii-specific antibody-secreting cells in the spleens of infected mice, it was demonstrated that B6 mice, although susceptible to infection with non-lethal P. yoelii, nonetheless made a far stronger anti-parasite response after infection than did resistant DBA/2 mice. Using FACS analysis it was shown that infected B6 mice also produced large amounts of antibodies which bound to the surface of uninfected RBC. Thus, in B6 mice infected with non-lethal P. yoelii, a strong parasite-induced immune response was associated with susceptibility rather than resistance to infection. When T cell-deficient nude mice and their normal littermates were infected with the different isolates of P. yoelii, the nude mice had lower levels of parasitemia and higher RBC counts during the early stages of these infections, and lived longer than did normal littermates after infection with the lethal isolate. These data and the data from studies of B6 and DBA/2 mice support the idea that a strong immune response may be associated with susceptibility rather than resistance to P. yoelii, at least during the early stages of the infection. The finding that a single strain of mouse may present as resistant to infection with one P. yoelii isolate yet be exquisitely susceptible to infection with another suggests that the outcome of these murine malaria infections is dependent on a dynamic interplay between host and parasite genes. Thus, when genetic variability exists in both the host and the parasite populations, as would occur in nature, there may be little directed evolutionary change toward one phenotype or another.(ABSTRACT TRUNCATED AT 400 WORDS)     

An ultrastructural investigation of Leishmania donovani infection in genetically resistant and susceptible mouse strains

Natural resistance to the growth of Leishmania donovani in mice is controlled by a gene (Lsh) which is expressed, in an unknown fashion, in macrophages. Early net growth rate of the parasite is much higher in mice strains bearing the susceptible allele (Lshs) than in resistant (Lshr) mice. Intracellular events occurring in the Kupffer cells during this period have been studied at the ultrastructural level. It was found that the number of dividing amastigotes per thin section of infected cell was approximately 10-fold greater in susceptible (B10.A SgSn) than in resistant (A/J) strains of mice, both 7 and 14 days following infection. These findings support the hypothesis that high natural resistance to leishmaniasis (Lshr) is expressed as a microbistatic effect, exerted within the parasitized macrophage of the host.     

Trypanosoma cruzi: role of the immune response in the natural resistance of inbred strains of mice.

Nine inbred strains of mice were challenged with 10⁴ or 10⁵ trypomastigotes of the Brazil strain of Trypanosoma cruzi. A spectrum of resistance was evident ranging from highly susceptible strains, e.g., C3H, which developed high parasitemias and died within 3 to 4 weeks, to resistant strains, e.g., C57BL/10, which developed low parasitemias and survived. Impairment of the immune system in resistant C57BL/10 mice by X-irradiation, splenectomy, or treatment with silica led to high, often fatal parasitemias. Athymic nude mice, in particular, attained exceptionally high parasitemias before dying. The immune response appears to be necessary for survival and to play a role in the natural resistance of some mouse strains by effectively eliminating parasites and minimizing parasitemia. Using congenic strains of mice, it was shown that the principal genetic determinant of resistance is not associated with their H-2 haplotype.