Inhibition of Platelet Adherence to Brain Microvasculature Protects against Severe<i>Plasmodium berghei</i>Malaria

Sun, Guan; Chang, Wun-Ling; Li, Jie; Berney, S.M.; Kimpel, Donald L.; Heyde, Henri C. van der

doi:10.1128/iai.71.11.6553-6561.2003

Cited by 73 publications

(69 citation statements)

References 39 publications

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“…First, as mentioned above, as increased ICAM-1 expression was prevented by IFN-␣ treatment, this could have limited interactions between intravascular leukocytes and T cells and brain endothelial cells. However, this is unlikely, as it was shown recently that in mice deficient for ICAM-1, leukocyte accumulation in the brain during CM is still observed (28,43). Second, although a single injection of IFN-␣ was shown previously to modify leukocyte circulation leading to leukocyte sequestration in lymphoid organs (31), repeated daily injections for 7 days did not induce leukocyte accumulation in spleen or lymph nodes in infected mice.…”

Section: Discussionmentioning

confidence: 68%

Recombinant Human IFN-α Inhibits Cerebral Malaria and Reduces Parasite Burden in Mice

Vigário

Belnoue

Grüner

et al. 2007

The Journal of Immunology

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Most C57BL/6 mice infected i.p. with Plasmodium berghei ANKA (PbA) die between 7 and 14 days with neurologic signs, and the remainder die later (>15 days) with severe anemia. Daily i.p. injections of a recombinant human IFN-α (active on mouse cells) prevented death by cerebral malaria (87% deaths in the control mice vs 6% in IFN-α-treated mice). The mechanisms of this IFN-α protective effect were multiple. IFN-α-treated, PbA-infected mice showed 1) a marked decrease in the number of PbA parasites in the blood mediated by IFN-γ, 2) less sequestered parasites in cerebral vessels, 3) reduced up-regulation of ICAM-1 expression in brain endothelial cells, 4) milder rise of blood levels of TNF, 5) increased levels of IFN-γ in the blood resulting from an increased production by splenic CD8+ T cells, and 6) fewer leukocytes (especially CD8+ T cells) sequestered in cerebral vessels. On the other hand, IFN-α treatment did not affect the marked anemia observed in PbA-infected mice. Survival time in IFN-α-treated mice was further increased by performing three blood transfusions over consecutive days.

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Section: Discussionmentioning

confidence: 68%

Recombinant Human IFN-α Inhibits Cerebral Malaria and Reduces Parasite Burden in Mice

Vigário

Belnoue

Grüner

et al. 2007

The Journal of Immunology

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“…Platelets play a dual role in the development of CM (30,31). On the one hand, they initiate the repair of the injured endothelial barrier; on the other hand, they trigger multiple pathogenic processes, leading to microvascular alteration (10,32).…”

Section: Discussionmentioning

confidence: 99%

Protection against cerebral malaria by the low-molecular-weight thiol pantethine

Penet

Abou-Hamdan

Coltel

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

102

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We report that administration of the low-molecular-weight thiol pantethine prevented the cerebral syndrome in Plasmodium berghei ANKA-infected mice. The protection was associated with an impairment of the host response to the infection, with in particular a decrease of circulating microparticles and preservation of the blood-brain barrier integrity. Parasite development was unaffected. Pantethine modulated one of the early steps of the inflammation-coagulation cascade, i.e., the transbilayer translocation of phosphatidylserine at the cell surface that we demonstrated on red blood cells and platelets. In this, pantethine mimicked the inactivation of the ATP-binding-cassette transporter A1 (ABCA1), which also prevents the cerebral syndrome in this malaria model. However, pantethine acts through a different pathway, because ABCA1 activity was unaffected by the treatment. The mechanisms of pantethine action were investigated, using the intact molecule and its constituents. The disulfide group (oxidized form) is necessary to lower the platelet response to activation by thrombin and collagen. Thio-sensitive mechanisms are also involved in the impairment of microparticle release by TNF-activated endothelial cells. In isolated cells, the effects were obtained by cystamine that lacks the pantothenic moiety of the molecule; however, the complete molecule is necessary to protect against cerebral malaria. Pantethine is well tolerated, and it has already been administered in other contexts to man with limited side effects. Therefore, trials of pantethine treatment in adjunctive therapy for severe malaria are warranted.blood-brain barrier ͉ phosphatidylserine ͉ Plasmodium ͉ platelet activation L ow-molecular-weight thiols, widely distributed in the living world, show broad physiological activity involving multiple targets. Among them, the dietary provitamin pantethine, a dimer of pantothenic acid linked by disulfide cystamine (1), has been the subject of much research. As a part of CoA, pantethine is a key regulator of lipid metabolism (2-4). Pantethine has been shown also to inhibit in vitro platelet aggregation in a dosedependent manner (5-7), an action that was not clearly understood (5).Because platelets play a central role in the pathological process associated with cerebral malaria (CM), we examined the effects of pantethine administration to mice infected with Plasmodium berghei strain ANKA (PbA). The processes identified by using this model are relevant to the human pathology (8). Susceptible strains of mice infected with PbA develop neurological manifestations rapidly followed by death. The pathology is due not to the direct action of the parasite but to a deleterious immune response of the infected host, involving cerebral vascular inflammation with microcirculatory dysfunction (9-13). The ultimate consequence is disruption of the brain microvasculature, enhancement of blood-brain barrier (BBB) permeability, and edema formation leading to major hemodynamic dysfunction (14-16).One of the earliest steps of the inflamm...

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“…In mice infected with P. berghei ANKA, mice deficient of tissue and uroquinase plasminogen activators demonstrated less capillary sequestration of platelets and less severe malaria (Piguet et al 2000). Blocking GPIIb with anti-CD41 monoclonal antibodies in the first day of murine infection with P. berghei also led to higher production of interleukin (IL)-10, IL-1α, IL-6, interferon-α and TNF and less mortality among mice, suggesting that platelets may act as cofactors of severe malaria (Sun et al 2003, van der Heyde et al 2005. There was also an inverse correlation between platelet count and TNF in patients with vivax infection and no association between specific mutation G→A in the position 308 in the TNF gene (a polymorphism whose functional effect upon severe disease is hypothesised) and platelet count was observed.…”

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confidence: 99%

Thrombocytopenia in malaria: who cares?

Lacerda

Mourão

Coelho

et al. 2011

Mem. Inst. Oswaldo Cruz

183

173

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Key words: Plasmodium falciparum -Plasmodium vivax -malaria -thrombocytopenia -plateletsMalaria and thrombocytopenia • Marcus Vinícius Guimarães Lacerda et al. 53Data on the real burden of thrombocytopenia associated with malaria is contradictory in the literature and it is not usually considered when conducting patient selection. Table I shows the major publications estimating the frequency of thrombocytopenia. Most of these data were published in the late 1990s, probably in time with the surge in the availability of affordable automated machines capable of performing full blood counts (FBC). Manual platelet counting is time-consuming and usually needs to be requested by the physician with the routine blood count in most of the endemic areas for malaria. In only three publications is there an adequate randomised enrollment of patients with appropriate sample size calculation to estimate the frequency of bleeding and its association with the respective platelet count (Lacerda 2007, Silva 2009, Kochar et al. 2010. Only one study has ruled out other common causes of thrombocytopenia that are also endemic in the studied area (Lacerda 2007). There is a wide range of thrombocytopenia occurrence in these reports, which may be explained by distinct selection criteria of the enrolled patients. There are also differences in the selection of outpatients or inpatients from tertiary care centres that tend to present with severe thrombocytopenia. Furthermore, clinical manifestations of thrombocytopenia are usually described as case reports and most of these are due to P. vivax (Table II).In 2005, 138 of 684 (20.1%) malarial cases hospitalised in a tertiary care centre in Manaus had thrombocytopenia as the cause of admission, which corresponded to 6.8% of hospitalisations due to all causes in this reference institution (unpublished observations). Hospitalisation, however, does not add any benefit to the patient and because there is no evidence for any intervention, this simply increases public health costs in underdeveloped and under-resourced areas.Pathogenesis of malarial thrombocytopenia -Coagulation disturbances -A study based on 31 American soldiers in Vietnam with chloroquine-resistant falciparum malaria noted the following changes in the acute phase of the disease using the same patients as their own controls during convalescence: decrease in the platelet count and prothrombim activation time, increase in the activated thromboplastin time, and reduction in factors V, VII and VIII with normal fibrinogen (Dennis et al. 1967). This report suggested that thrombocytopenia was simply a consequence of the coagulation disorders presented by these patients, an idea that persisted for many decades in the literature. In another series of 21 patients with falciparum malaria, six had developed disseminated intravascular coagulation (DIC). The authors noted that the patients with more severe thrombocytopenia also had DIC and that there was correlation between platelet count and C3 protein levels. However, the reduction in C3 was pr...

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Inhibition of Platelet Adherence to Brain Microvasculature Protects against SeverePlasmodium bergheiMalaria

Cited by 73 publications

References 39 publications

Recombinant Human IFN-α Inhibits Cerebral Malaria and Reduces Parasite Burden in Mice

Recombinant Human IFN-α Inhibits Cerebral Malaria and Reduces Parasite Burden in Mice

Protection against cerebral malaria by the low-molecular-weight thiol pantethine

Thrombocytopenia in malaria: who cares?

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