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

The attachment of erythrocytes infected with P. falciparum to human venular endothelium is the primary step leading to complications from severe and cerebral malaria. Intercellular adhesion molecule-1 (ICAM-1, CD54) has been implicated as a cytoadhesion receptor for P. falciparum-infected erythrocytes. Characterization of domain deletion, human/murine chimeric ICAM-1 molecules, and amino acid substitution mutants localized the primary binding site for parasitized erythrocytes to the first amino-terminal immunoglobulin-like domain of ICAM-1. The ICAM-1 binding site is distinct from those recognized by LFA-1, Mac-1, and the human major-type rhinoviruses. Synthetic peptides encompassing the binding site on ICAM-1 inhibited malaria-infected erythrocyte adhesion to ICAM-1-coated surfaces with a Ki of 0.1-0.3 mM, whereas the Ki for soluble ICAM-1 is 0.15 microM. These findings have implications for the therapeutic reversal of malaria-infected erythrocyte sequestration in the host microvasculature.
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PMID:Plasmodium falciparum-infected erythrocytes bind ICAM-1 at a site distinct from LFA-1, Mac-1, and human rhinovirus. 134 57

Certain stages of the immune response require interaction of leukocytes with each other and with non-hematopoietic cells. One of the systems implicated in these interactions involves an integrin, LFA-1 (Lymphocyte Function Antigen-1), expressed by all leukocytes at their cell surface, and a molecule belonging to the immunoglobulin superfamily, ICAM-1 (Intercellular Adhesion Molecule-1). The avidity of LFA-1 for ICAM-1 is transient. It is modulated both by regulation of ICAM-1 expression and by activation of LFA-1 molecules constitutively expressed on leukocyte membranes. This activation, which induces a conformational change in the molecule, depends on the presence of divalent cations, notably Mg++. This has been demonstrated by using a specific monoclonal antibody, MAb 24. In addition to being a ligand for LFA-1, ICAM-1 is sometimes used as a cell receptor by pathogens such as Plasmodium falciparum, the causative organism of malaria. Very careful study of the binding site of this pathogen using specific antibodies, mutagenesis studies and the construction of a three-dimensional model of the molecule suggests some interesting therapeutic possibilities for the treatment of malaria.
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PMID:Leukocyte integrin activation. 136 59

The intercellular adhesion molecule-1 (ICAM-1, CD54) is one of three putative endothelial receptors that mediate in vitro cytoadherence of P. falciparum-infected erythrocytes. Since cytoadherence to postcapillary venular endothelium is thought to be a major factor in the virulence of P. falciparum malaria, we have examined the interaction between ICAM-1 and the P. falciparum-infected cell, and have compared it with the interaction to the physiological counter receptor, the leukocyte integrin LFA-1. Our results demonstrate that the malaria-binding site resides in the first two domains of the ICAM-1 molecule and overlaps, but is distinct from, the LFA-1 site.
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PMID:The binding site on ICAM-1 for Plasmodium falciparum-infected erythrocytes overlaps, but is distinct from, the LFA-1-binding site. 137 Jun 56

CD8+ T cell clones specific for a defined epitope present in the circumsporozoite protein of Plasmodium yoelii display striking differences in their in vivo antiplasmodial activity. The adoptive transfer of certain clones (YA23 and YA26) into naive mice inhibits by 90% or more the development of liver stages of malaria parasites and protects against malaria infection. The adoptive transfer of two other T cell clones (YB8 and YA15) results, respectively, in partial or no inhibitory activity on parasite development. We found that "protective" and "nonprotective" cytotoxic T lymphocyte (CTL) clones do not differ in their fine epitope specificity and display similar levels of lysis and DNA degradation of target cells in vitro. Their pattern of production of lymphokines and granule-associated proteins also failed to correlate with their in vivo antiplasmodial activity. Histological studies combined with autoradiography showed that, upon adoptive transfer, only T cells from the protective CTL clones are capable of "associating" with a significant percentage of parasitized hepatocytes. Fluorescence-activated cell sorter analysis of surface molecules revealed pronounced differences in the levels of CD44 and VLA-4 expression by the different clones, correlating closely with their in vivo protective activity. The correlation between in vivo antiparasite activity and the expression of CD44 was further corroborated by the results of sorting, from the partially protective YB8 clone, two sub-populations expressing high and low levels of CD44. These were protective and nonprotective, respectively. The clones also differed in their adhesive properties. Cross-linking of CD44, using specific antibodies, induced LFA-1-mediated homotypic aggregation of protective clones, while nonprotective cells failed to aggregate.
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PMID:The in vivo cytotoxic activity of CD8+ T cell clones correlates with their levels of expression of adhesion molecules. 137 47

Acute P. falciparum malaria is associated with loss of in vitro T cell responsiveness to antigenic stimulation, and with high plasma levels of soluble interleukin 2 receptor (IL 2R). In the present study peripheral T cells from acute P. falciparum malaria patients from a malaria-endemic area of Sudan were analyzed for expression of cell surface antigens associated with T lymphocyte adhesion, activation and maturation. The results were compared to results from T cells obtained from the same donors either before the attack, or during convalescence. Most donors showed a remarkable loss of T cells with high expression of the surface marker LFA-1 (CD11a/CD18) during the clinical episode, in addition to the functional changes described above. Two donors that did not show phenotypic changes were furthermore characterized by having an unabated proliferative response and normal plasma IL 2R levels. All peripheral CD3+ T lymphocytes expressed LFA-1, which had a clearly bimodal distribution on these cells. The T cell subpopulation having high LFA-1 expression (LFA-1++) was composed of both memory and unprimed T cells, according to their expression of CD45RA and CD45R0. Analysis of expression of membrane-bound IL 2R (CD25) and ICAM-1 (CD54) did not reveal in vivo activated T cells in the peripheral blood of the patients. Taken together, these data suggest that circulating T cells recognizing parasite antigens are temporarily withdrawn from peripheral circulation during P. falciparum malaria.
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PMID:Transient depletion of T cells with high LFA-1 expression from peripheral circulation during acute Plasmodium falciparum malaria. 167 90

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.
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PMID:Late administration of monoclonal antibody to leukocyte function-antigen 1 abrogates incipient murine cerebral malaria. 167 17

To explain the observation that acute Plasmodium falciparum malaria is associated with a transient inability of peripheral blood cells to respond to antigenic stimulation in vitro, we have postulated the disease-induced reallocation of peripheral lymphocytes, possibly by adhesion to inflamed endothelium. We measured plasma levels of soluble markers of endothelial inflammation and T cell activation in 32 patients suffering from acute, uncomplication P. falciparum malaria, as well as in 10 healthy, aparasitemic control donors. All donors were residents of a malaria-endemic area of Eastern State Sudan. In addition, we measured the T cell surface expression of the interleukin-2 receptor (CD25) and the lymphocyte function-associated antigen (LFA-1; CD11a/CD18). We found that the plasma levels of all inflammation and activation markers were significantly increased in the malaria patients compared with the control donors. In addition, we found a disease-induced depletion of T cells with high expression of the LFA-1 antigen, particularly in the CD4+ subset. The results obtained provide further support for the hypothesis of T cell reallocation to inflamed endothelium in acute P. falciparum malaria.
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PMID:Evidence of endothelial inflammation, T cell activation, and T cell reallocation in uncomplicated Plasmodium falciparum malaria. 752 74

The adhesion of erythrocytes infected with Plasmodium falciparum (P. falciparum) is one of the major pathological features of severe malaria. Several potential receptors to endothelium for falciparum-infected erythrocyte on endothelium have been described. Recently, the malaria binding site on ICAM-1(CD54) has been mapped to a site distinct but overlapping with the LFA-1 (CD11a/CD18) site. We detected by flow cytometry, confocal laser microscopy and immunoprecipitation, a molecule expressed at the surface of erythrocytes infected with mature stages of the M96 strain of P. falciparum that was recognized by a monoclonal antibody (mAb) (TS1/22) directed against an LFA-1 epitope. However, this molecule was not recognized by mAbs directed against other epitopes of LFA-1 or against other integrins. Furthermore, the mAb TS1/22 partially inhibited cytoadherence of parasitized red blood cells to human-brain microvascular endothelial cells. The expression of a molecule sharing an epitope with human LFA-1 integrin on the parasitized erythrocyte surface could be involved in the sequestration of these cells and thus in the pathogenesis of severe disease.
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PMID:Detection of a LFA-1-like epitope on the surface of erythrocytes infected with a strain of Plasmodium falciparum. 754 75

Acute P. falciparum malaria is associated with a loss of antigen-responsiveness of peripheral T cells, depletion of T cells characterized by high surface expression of the adhesion molecule LFA-1, and increased plasma levels of the T-cell activation marker soluble IL-2 receptor (sIL-2R). In the present study we show that clinical episodes of P. falciparum malaria produced an increase in plasma levels of soluble ICAM-1 (sICAM-1) and ELAM-1 (sELAM-1). The increase was transient and subsided slowly (sICAM-1) or rapidly (sELAM-1) following drug cure. The increases in plasma sICAM-1 and sELAM-1 were significantly correlated, and were furthermore associated with a concomitant increase in plasma levels of sIL-2R. Finally, plasma levels of sICAM-1, but not sELAM-1, were inversely correlated to the fraction of peripheral T cells having high surface expression of LFA-1, the receptor for T-cell adhesion to ICAM-1. Taken together, these observations suggest that acute P. falciparum malaria is characterized by a state of endothelial inflammation associated with the adherence of activated T cells.
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PMID:Increased plasma levels of soluble ICAM-1 and ELAM-1 (E-selectin) during acute Plasmodium falciparum malaria. 768 46

Pathogenic mechanisms of brain microvascular injury were studied in an experimental model of cerebral malaria (CM). The lesion, leading to perivascular microhemorrhages, is due to cytokine overproduction, and is associated with the sequestration of macrophages and parasitized erythrocytes in cerebral venules. In this in vivo model, we demonstrate that platelets are critical effectors of the neurovascular injury. First, electron microscopy indicated that during CM platelets adhere to and probably damage brain endothelial cells. Second, radiolabelled platelet distribution studies indicated that platelets sequestered in the brain and lung vasculature during CM. Non-cerebral malaria was not associated with cerebral sequestration of platelets. Third, in vivo treatment with a mAb to LFA-1 (which is expressed on platelets) selectively abrogated the cerebral sequestration of platelets, and this correlated with prevention of CM. Fourth, malaria-infected animals rendered thrombocytopenic were significantly protected against CM, further indicating that platelets are central to the pathogenesis of CM. Thus, a CD11a-dependent interaction between platelets and endothelial cells appears pivotal to microvascular damage. These data suggest a novel mechanism of action for anti-LFA-1 mAb in vivo and illustrate an unexpected role of platelets, in addition to monocytes, in vascular pathology.
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PMID:TNF-induced microvascular pathology: active role for platelets and importance of the LFA-1/ICAM-1 interaction. 791 Apr 90


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