Delayed Mortality and Attenuated Thrombocytopenia Associated with Severe Malaria in Urokinase- and Urokinase Receptor-Deficient Mice
| Autor: | Giorgio Senaldi, Georges E. Grau, Fabienne Tacchini-Cottier, Chen Da Laperrousaz, Pierre F. Piguet, Christian Vesin |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
Blood Platelets
Cell Survival Plasmodium berghei Immunology Receptors Cell Surface Parasitemia Microbiology Receptors Urokinase Plasminogen Activator Mice chemistry.chemical_compound Aprotinin medicine Animals RNA Messenger skin and connective tissue diseases neoplasms Lung Mice Knockout Urokinase biology Tumor Necrosis Factor-alpha Cell adhesion molecule Fibrinogen Organ Size Thrombocytopenia Urokinase-Type Plasminogen Activator biological factors Malaria Mice Inbred C57BL Urokinase receptor enzymes and coenzymes (carbohydrates) Kinetics Infectious Diseases chemistry Blood-Brain Barrier Cerebral Malaria Tissue Plasminogen Activator Plasminogen activator inhibitor-1 Knockout mouse biology.protein Parasitology Vitronectin Tumor necrosis factor alpha biological phenomena cell phenomena and immunity Fungal and Parasitic Infections Spleen medicine.drug |
| Zdroj: | Infection and Immunity. 68:3822-3829 |
| ISSN: | 1098-5522 0019-9567 |
| DOI: | 10.1128/iai.68.7.3822-3829.2000 |
| Popis: | In mice, infection by Plasmodium bergei ANKA leads, in susceptible mouse strains, to a lethal syndrome, commonly known as cerebral or severe malaria (SM), in which mice die 7 to 9 days after infection in a state of coma associated with neurological manifestations; (51; reviewed in reference 49). Prominent in this syndrome are a breakdown of the blood-brain barrier, microhemorrhages, and sequestration of macrophages in the cortical venules (6, 12, 46). In addition, there is a sequestration of macrophages, polymorphonuclear neutrophils (PMNs), parasitized red blood cells (pRBC), and platelets in other organs, notably the lung (12, 46). Hence, since this syndrome is not limited to the brain, it is also referred to as SM. Various studies using antibodies, recombinant cytokines or knockout mice have shown that the secretion of tumor necrosis factor (TNF) is an important effector of the mortality of SM (15, 20, 43). In humans, acute phase of malaria infection can also result in severe complications, leading eventually to death, with symptoms ranging from respiratory distress up to coma (reviewed in references 49 and 50). Especially in children, Plasmodium falciparum infection can manifest itself as a coma, associated with neurological dysfunctions resembling ANKA infection in susceptible mice. The pathogenesis of coma is poorly understood and might be different in humans and mice since in humans cerebral dysfunction is associated with the sequestration of RBC or pRBC within the brain capillaries, while during ANKA-induced coma in mice, pRBC sequestration is not evident in the brain but is important in the lungs (7, 12, 28). Coma occurring in mice is generally attributed to the sequestration of macrophages within the cortical venules, an alteration also observed during human SM (36). The sequestration of pRBC within the microcirculation might be critical for the severity of the disease in either species since they might release a glycosylphosphatidylinositol toxin (44) or, alternatively, they might obstruct the capillary circulation (28). Breakdown of the blood-brain barrier is evident during SM, but its pathogenesis or role in the coma in either species is not established. Microhemorrhages have also been reported in the brain and elsewhere in both human and mouse SM (46). SM, even with predominant neurological symptoms, is a systemic disease, with associated dysfunctions of the major organs. Involvement of the lung is evident during “cerebral malaria” in humans as in mice and is associated with the sequestration of macrophages, neutrophils, platelets, and pRBC in the alveolar capillaries (5, 7, 10, 12, 28). Thrombocytopenia, due to a reduced platelet life span is common to SM in both mice and humans and is not associated with coagulopathy (21, 45, 49). Finally, the essential role of TNF in the mortality appears to be similar in both species since a strong correlation has been documented between TNF production and the lethality of malaria in humans (22, 31). TNF production is induced by an immune response elicited by the presence of the parasite in the blood (19). Indeed, depletion of CD4 T lymphocytes or administration of cyclosporin prevents the acute mortality of ANKA infection in mice, apparently by decreasing TNF production (17, 19, 49). TNF might be responsible for some of the manifestations of SM such as hypoglycemia and the increase of the expression of adhesion molecules. Indeed, TNF induces an upregulation of adhesion molecules on endothelia, notably of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) (26, 27), which might increase the adhesion of leukocytes and other cells and thereby disturb the microcirculation in the brain and other organs. This pathogenic hypothesis is supported by the delayed mortality seen in mice treated with anti-CD11a monoclonal antibody (MAb; LFA-1, a β2-integrin determinant) or in ICAM-1-deficient mice (11, 12, 18). β2 integrin is expressed on leukocytes and is a ligand for ICAM-1, which is widely distributed. Recent evidence indicates that the function of β2 and other integrins is modulated by the urokinase plasminogen activator receptor (uPAR; CD87) (reviewed in reference 4). The uPAR is a 55-kDa glycosylphosphatidylinositol (GPI)-linked surface receptor known to bind urokinase plasminogen activator (uPA), plasminogen activator inhibitor 1 (PAI-1), and vitronectin. Binding of uPA or PAI-1 to uPAR is believed to influence the conformation of the uPAR and its interaction with the integrin. Thus, the binding of uPA to the uPAR might, on one hand, increase the generation of plasmin on the cell surface and, on the other hand, increase the affinity or function of the β2 integrin. In vivo, the traffic of PMNs in the mouse peritoneum has been shown to be delayed in uPAR−/− mice (32). In the present report, we took advantage of mice genetically deficient in the uPA or uPAR genes to explore the contribution of this system to the mortality and sequestration of various cell types induced by ANKA infection. The results indicate that the severity of malaria is attenuated in uPA- and uPAR-deficient mice. |
| Databáze: | OpenAIRE |
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