Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We analyzed the role of adhesion molecules in the pathogenesis of experimental cerebral malaria (ECM), since tumor necrosis factor (TNF) plays a major role in this condition and has been shown to up-regulate in vitro expression of cell adhesion molecules (CAM), particularly intercellular CAM-1 (ICAM-1). We found increased expression of ICAM-1 on brain endothelial cells from mice with ECM. Treatment with monoclonal antibodies (mAb) directed against leukocyte function-antigen 1 (LFA-1, the ligand of ICAM-1) on days 6, 8 and 10 almost totally prevented ECM, while decreasing blood TNF levels. To exclude the possibility that the effects of anti-LFA-1 mAb resulted from an even partial inhibition of TNF overproduction, mice with signs of imminent death (hypothermia and neurologic defects) were treated with the anti-LFA-1 mAb, with dramatically protective effect. In contrast, injection of anti-ICAM-1 mAb on day 6 caused rapid death, while it was innocuous in normal mice. An mAb directed against complement receptor type 3 (CR3) was ineffective, as were injections of soluble human ICAM-1. These results suggest that adhesion of LFA-1+ cells to endothelial cells, stimulated by TNF to express high levels of ICAM-1, is critical in the pathogenesis of ECM. Emergency therapy at interfering with cytoadherence could be considered in the treatment of cerebral malaria in man, in which high blood TNF levels are also observed.
 ...
PMID:Late administration of monoclonal antibody to leukocyte function-antigen 1 abrogates incipient murine cerebral malaria. 167 17

Increased energy expenditure often occurs during illness or after injection of endotoxin and can contribute to the generation of fever. In laboratory rats and mice the thermogenic response has been attributed to the sympathetic activation of brown adipose tissue (BAT), although mice often fail to show pyrexia. In this study the effects of malaria on O2 consumption and BAT were studied in mice inoculated with Plasmodium berghei. Parasitemia was maximal (greater than 50% of erythrocytes showing positive Leishman staining) 72 h after inoculation. Up to this time body weight and food intake were similar to values for control mice, although colonic temperatures were slightly depressed in infected mice. Thereafter, infected mice showed marked hypophagia, loss of body weight, and severe hypothermia; colonic temperature was less than 31 degrees C at 96 h when the experiment was terminated. Resting O2 consumption (VO2) measured at 24 degrees C was slightly elevated in infected mice 12 h after inoculation and reached a peak value (31% above controls) at 48 h. VO2 returned to the same value as controls at 96 h. In vitro thermogenic activity of BAT (assessed from binding of guanosine diphosphate to isolated mitochondria) was not significantly altered in infected mice. These data demonstrate a marked thermogenic response to malarial infection, but this is not accompanied by fever in mice and is dissociated from stimulation of BAT activity.
 ...
PMID:Effects of malaria on O2 consumption and brown adipose tissue activity in mice. 267 49

Laboratory mice infected with rodent malaria (Plasmodium berghei or P. chabaudi) or St. Louis encephalitis virus (SLE) were not hyperthermic during the infection period. However, all infected animals displayed pathogen-specific periods of hypothermia. Hamsters infected with P. berghei were hyperthermic on day 7 postinfection (PI) but became hypothermic on day 8 PI and remained so until death, approximately 20 days PI. Body temperatures of mice infected with P. yoelii were not significantly different from those of uninfected control mice. Mosquitoes (Aedes aegypti, Anopheles stephensi and Culex quinquefasciatus) successfully engorged on restrained, uninfected mice, but were unable to engorge on unrestrained, uninfected mice due to the natural antimosquito behavior of the healthy rodents. Mosquitoes successfully engorged on unrestrained, malaria or SLE infected mice only during certain pathogen-specific periods of infection, but were able to engorge on all restrained, infected mice throughout the infection period regardless of the animal's body temperature. Daily activity patterns of malaria infected mice followed pathogen-specific profiles which closely conformed to the observed mosquito-engorgement profiles.
 ...
PMID:The importance of disease induced changes in mammalian body temperature to mosquito blood feeding. 614 3

Mice infected with Plasmodium berghei K173-parasitized erythrocytes develop severe hypothermia followed by death as a consequence of murine cerebral malaria early in the second week after infection. A single intraperitoneal injection of 10(5) Units of IFN-gamma given between Day 4 and Day 6 postinfection results in a transient decrease of body temperature. No effect on parasitemia and cerebral malaria is obtained by this treatment. Daily injections of relatively low doses of IFN-gamma delays the patency of the infection for 2 days. Furthermore the proliferation rate of the parasites is reduced and the development of cerebral malaria is also delayed for 2 days. The reduction of body temperature, as found in untreated infected mice, is absent. Administration of IFN-gamma by means of a continuous delivery from intraperitoneally inserted osmotic pumps (1.2 x 10(4) Units of IFN-gamma/24 hr) also delays patency and inhibits parasitemia. Body temperature decreases during infection but mice are protected against the development of cerebral malaria. In nude mice, this treatment inhibits parasitemia to the same extent. However, reduction of body temperature was also prevented. High doses of IFN-gamma delivered by osmotic pumps (2.5 x 10(4) or 10(5) Units of IFN-gamma/24 hr) appear to be lethally toxic in conventional as well as in nude mice, independently of infection. Cerebral malaria-like symptoms are found in these mice. Treatment of infected C57BL/6J mice with antibody to IFN-gamma 4 days before and after infection as well as on the day of infection enhances parasitemia but does not affect the development of murine cerebral malaria. Single injections of anti-IFN-gamma-antibody 6 hr prior to infection or 7 days after infection have no effect. In CBA/Ca mice, treatment with anti-IFN-gamma-antibody enhances parasitemia; furthermore protection against cerebral malaria was obtained in part of the mice.
 ...
PMID:Plasmodium berghei: recombinant interferon-gamma and the development of parasitemia and cerebral lesions in malaria-infected mice. 837 90

Infection with Plasmodium berghei ANKA is usually lethal. The parasite causes in some mouse strains a neurovascular syndrome, experimental cerebral malaria (ECM), involving immunopathological reactions. The effects on the development of ECM of the mouse genetic background have been clearly demonstrated, but nothing is known about the effects of the clonal diversity of the parasite. We showed that various cloned lines derived from a polyclonal line of P. berghei ANKA caused ECM but that the extent of ECM induction was dependent on the amount of inoculum. Subtle differences in ECM characteristics (survival time and hypothermia) were also observed. We also confirmed, using the 1.49L cloned line, that the mouse genetic background strongly affects ECM.
 ...
PMID:Cloned lines of Plasmodium berghei ANKA differ in their abilities to induce experimental cerebral malaria. 971 53

We have sought to characterize Plasmodium chabaudi chabaudi infection 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-gamma in vivo led 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-gamma, presumably because of larger numbers of circulating parasites. These data suggest that IFN-gamma does not directly contribute to the lethal outcome of infection in susceptible strains of mice.
 ...
PMID:Plasmodium chabaudi chabaudi (AS): inflammatory cytokines and pathology in an erythrocytic-stage infection in mice. 980 66

Infection of interleukin-10 (IL-10)-nonexpressing (IL-10(-/-)) mice with Plasmodium chabaudi chabaudi (AS) leads to exacerbated pathology in female mice and death in a proportion of them. Hypoglycemia, hypothermia, and loss in body weight were significantly greater in female IL-10(-/-) mice than in male knockout mice and all wild-type (WT) mice during the acute phase of infection. At this time, both female and male IL-10(-/-) mice produced more gamma interferon (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), and IL-12p40 mRNA than their respective WT counterparts. Inactivation of IFN-gamma in IL-10(-/-) mice by the injection of anti-IFN-gamma antibodies or by the generation of IL-10(-/-) IFN-gamma receptor(-/-) double-knockout mice resulted in reduced mortality but did not affect body weight, temperature, or blood glucose levels. The data suggest that IFN-gamma-independent pathways may be responsible for these pathological features of P. chabaudi malaria and may be due to direct stimulation of TNF-alpha by the parasite. Since male and female knockout mice both produce more inflammatory cytokines than their WT counterparts, it is likely that the mortality seen in females is due to the nature or magnitude of the response to these cytokines rather than the amount of IFN-gamma or TNF-alpha produced.
 ...
PMID:A defect in interleukin-10 leads to enhanced malarial disease in Plasmodium chabaudi chabaudi infection in mice. 1045 84

Tumor necrosis factor alpha (TNF-alpha) is associated with malarial pathology in both humans and mice. In Plasmodium chabaudi chabaudi (AS) infections, the production of TNF-alpha and reactive metabolites from macrophages are also thought to play a role in controlling acute parasitemia. Since many of the biological functions of TNF-alpha are effected through the p55 receptor (p55R), mice made defective in this receptor via a targeted gene disruption (p55R(-/-)) have been used to study its involvement in the immune response against P. chabaudi chabaudi and in the pathology associated with this infection. In the absence of the p55R, mice could overcome their primary infection, although higher acute-blood-stage parasitemias and more significant recrudescences were observed. Hypoglycemia, hypothermia, loss of erythrocytes, and loss of body weight, which occur transiently in this infection, were exacerbated by the lack of the p55R, but the differences were small, suggesting that other factors affect these symptoms. In contrast to wild-type (WT) mice, a second challenge infection in p55R(-/-) mice resulted in a course of infection similar to a primary infection. The malaria-specific immunoglobulin G antibody response of p55R(-/-) mice was lower than that of WT mice and was not increased by the second challenge infection. These data suggest that p55R(-/-) mice do not develop an efficient memory B-cell response against malarial infection and that this antibody response is important in immunity to reinfection.
 ...
PMID:Tumor necrosis factor alpha p55 receptor is important for development of memory responses to blood-stage malaria infection. 1099 77

Infection of susceptible mice with Plasmodium berghei Anka leads to a syndrome of severe or cerebral malaria. Tumor necrosis factor (TNF) contributes to this syndrome, apparently by acting on its receptor 2 (TNFR2) because TNFR1-/- are susceptible, whereas TNFR2-/- mice are resistant. In this work, we confirmed the essential role of the TNFR2 in cerebral malaria because 6 to 8 days after Plasmodium berghei Anka infection, hypothermia, coma, and death were observed in +/+ or TNFR1-/-, but never in TNFR2-/-, mice. TNF production, evaluated by the serum levels or the mRNA levels in the brain, spleen or lung, was similar in +/+, TNFR1-/-, or TNFR2-/- mice. Macrophage or parasitized red blood cell sequestration in brain or lung was similar in TNFR1-/- and TNFR2-/- mice. Accordingly, up-regulation of CD54 or CD40 in brain or lung was also similar in TNFR1-/- or TNFR2-/- mice. Platelet loss, manifested by thrombocytopenia and the presence of microparticles in plasma, was similar in TNFR1-/- or TNFR2-/- mice. Breakdown of the blood-brain barrier, detected by the diffusion of tracers, was attenuated in both TNFR1-/- and TNFR2-/-, compared with +/+, mice. Endothelial cells from brain capillaries, examined by transmission electron microscopy, were similar in infected TNFR1-/- or TNFR2-/- mice, whereas the basement membrane was enlarged in TNFR1-/- mice. Hypothermic mice were also hyperglycemic, and this was evident in +/+ and TNFR1-/-, but not in TNFR2-/-, mice. In addition, infected +/+ and TNFR1-/- mice became insulin resistant, while in contrast TNFR2-/- became extremely insulin sensitive. This study supports the possibility that coma and death are mediated not by cell sequestration or breakdown of vascular permeability, similar in TNFR1-/- or TNFR2-/- mice, but by metabolic disturbances selectively mediated by the TNFR2.
 ...
PMID:Role of the tumor necrosis factor receptor 2 (TNFR2) in cerebral malaria in mice. 1221 76

Interleukin-10 (IL-10)-deficient (IL-10(-/-)) mice infected with Plasmodium chabaudi (AS) suffer a more severe disease and exhibit a higher rate of mortality than control C57BL/6 mice. Here, we show that a drop in body temperature to below 28 degrees C and pronounced hypoglycemia of below 3 mM are reliable indicators of a lethal infection. Elevated inflammatory responses have been shown to accompany pathology in infected IL-10(-/-) mice. We show that neutralization of tumor necrosis factor alpha (TNF-alpha) in IL-10(-/-) mice abolishes mortality and ameliorates the hypothermia, weight loss, and anemia but does not affect the degree of hypoglycemia. These data suggest that TNF-alpha is involved in some of the pathology associated with a P. chabaudi infection in IL-10(-/-) mice but other factors play a role. IL-10(-/-) mice that survive a primary infection have been shown to control gamma interferon (IFN-gamma) and TNF-alpha production, indicating that other cytokines or mechanisms may be involved in their down-regulation. Significantly higher levels of transforming growth factor beta (TGF-beta), a cytokine with such properties, are present in the plasma of infected IL-10(-/-) mice at a time that coincides with the disappearance of IFN-gamma and TNF-alpha from the blood. Neutralization of TGF-beta in IL-10(-/-) mice resulted in higher circulating amounts of TNF-alpha and IFN-gamma, and all treated IL-10(-/-) mice died within 12 days with increased pathology but with no obvious increase in parasitemia. Our data suggest that a tight regulation of the balance between regulatory cytokines such as IL-10 and TGF-beta and inflammatory cytokines such as IFN-gamma and TNF-alpha is critical for survival in a mouse malaria infection.
 ...
PMID:Pathology of Plasmodium chabaudi chabaudi infection and mortality in interleukin-10-deficient mice are ameliorated by anti-tumor necrosis factor alpha and exacerbated by anti-transforming growth factor beta antibodies. 1293 25


1 2 3 Next >>