Induction of pro-inflammatory mediators in Plasmodium berghei infected BALB/c mice breaks blood-brain-barrier and leads to cerebral malaria in an IL-12 dependent manner

Schmidt, Kim E.; Schumak, Beatrix; Specht, Sabine; Dubben, Bettina; Limmer, Andreas; Hoerauf, Achim

doi:10.1016/j.micinf.2011.04.006

Cited by 24 publications

(24 citation statements)

References 37 publications

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“…Altered respiratory patterns are associated with lung injury and have been observed in a number of respiratory models, including Penh data that have been used in different murine models [35–37]. The high parasitemia that is associated with adverse outcomes has been shown in a number of murine malaria models [38, 39], further supporting our choice to use these parameters to distinguish mice suffering from ALI/ARDS. Despite some controversy regarding the use of Penh [20], our results clearly show that this parameter varies between mice that will or will not die of ALI/ARDS.…”

Section: Discussionmentioning

confidence: 96%

Predictive Criteria to Study the Pathogenesis of Malaria-Associated ALI/ARDS in Mice

Ortolan

Sercundes

Barboza

et al. 2014

Mediators of Inflammation

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Malaria-associated acute lung injury/acute respiratory distress syndrome (ALI/ARDS) often results in morbidity and mortality. Murine models to study malaria-associated ALI/ARDS have been described; we still lack a method of distinguishing which mice will develop ALI/ARDS before death. This work aimed to characterize malaria-associated ALI/ARDS in a murine model and to demonstrate the first method to predict whether mice are suffering from ALI/ARDS before death. DBA/2 mice infected with Plasmodium berghei ANKA developing ALI/ARDS or hyperparasitemia (HP) were compared using histopathology, PaO2 measurement, pulmonary X-ray, breathing capacity, lung permeability, and serum vascular endothelial growth factor (VEGF) levels according to either the day of death or the suggested predictive criteria. We proposed a model to predict malaria-associated ALI/ARDS using breathing patterns (enhanced pause and frequency respiration) and parasitemia as predictive criteria from mice whose cause of death was known to retrospectively diagnose the sacrificed mice as likely to die of ALI/ARDS as early as 7 days after infection. Using this method, we showed increased VEGF levels and increased lung permeability in mice predicted to die of ALI/ARDS. This proposed method for accurately identifying mice suffering from ALI/ARDS before death will enable the use of this model to study the pathogenesis of this disease.

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Section: Discussionmentioning

confidence: 96%

Predictive Criteria to Study the Pathogenesis of Malaria-Associated ALI/ARDS in Mice

Ortolan

Sercundes

Barboza

et al. 2014

Mediators of Inflammation

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“…3D non-enhanced T1w images were subtracted from enhanced T1w images; pathological enhancement of difference images was graded into mild (=1), moderate (=2) and severe (=3). Cerebral vascular leakage was investigated using Evans Blue72. Histological examinations of mouse brain sections was performed as described73.…”

Section: Methodsmentioning

confidence: 99%

Oxidative insult can induce malaria-protective trait of sickle and fetal erythrocytes

et al. 2016

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Plasmodium falciparum infections can cause severe malaria, but not every infected person develops life-threatening complications. In particular, carriers of the structural haemoglobinopathies S and C and infants are protected from severe disease. Protection is associated with impaired parasite-induced host actin reorganization, required for vesicular trafficking of parasite-encoded adhesins, and reduced cytoadherence of parasitized erythrocytes in the microvasculature. Here we show that aberrant host actin remodelling and the ensuing reduced cytoadherence result from a redox imbalance inherent to haemoglobinopathic and fetal erythrocytes. We further show that a transient oxidative insult to wild-type erythrocytes before infection with P. falciparum induces the phenotypic features associated with the protective trait of haemoglobinopathic and fetal erythrocytes. Moreover, pretreatment of mice with the pro-oxidative nutritional supplement menadione mitigate the development of experimental cerebral malaria. Our results identify redox imbalance as a causative principle of protection from severe malaria, which might inspire host-directed intervention strategies.

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“…Major pathological consequences of malaria arise from inappropriate or excessive immune response mounted by the host in an attempt to eliminate the parasite. In P. berghei ANKA-infected mice, inflammation of the cerebral microvasculature and leukocyte recruitment were clearly evident and found to be driven by production of pro-inflammatory cytokines (IL-12, IFN-γ) and CM development [121]. On the other hand, P. berghei NK65-infected mice showed enhanced production of LT-α and several chemokines (CXCL-9/MIG, CCL-2/MCP-1, CCL-3/MIP-1α and CCL-5/RANTES), but no neurological symptoms [47,122].…”

Section: Introductionmentioning

confidence: 99%

Host matrix metalloproteinases in cerebral malaria: new kids on the block against blood–brain barrier integrity?

Polimeni

Prato

2014

Fluids Barriers CNS

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Cerebral malaria (CM) is a life-threatening complication of falciparum malaria, associated with high mortality rates, as well as neurological impairment in surviving patients. Despite disease severity, the etiology of CM remains elusive. Interestingly, although the Plasmodium parasite is sequestered in cerebral microvessels, it does not enter the brain parenchyma: so how does Plasmodium induce neuronal dysfunction? Several independent research groups have suggested a mechanism in which increased blood–brain barrier (BBB) permeability might allow toxic molecules from the parasite or the host to enter the brain. However, the reported severity of BBB damage in CM is variable depending on the model system, ranging from mild impairment to full BBB breakdown. Moreover, the factors responsible for increased BBB permeability are still unknown. Here we review the prevailing theories on CM pathophysiology and discuss new evidence from animal and human CM models implicating BBB damage. Finally, we will review the newly-described role of matrix metalloproteinases (MMPs) and BBB integrity. MMPs comprise a family of proteolytic enzymes involved in modulating inflammatory response, disrupting tight junctions, and degrading sub-endothelial basal lamina. As such, MMPs represent potential innovative drug targets for CM.

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Induction of pro-inflammatory mediators in Plasmodium berghei infected BALB/c mice breaks blood-brain-barrier and leads to cerebral malaria in an IL-12 dependent manner

Cited by 24 publications

References 37 publications

Predictive Criteria to Study the Pathogenesis of Malaria-Associated ALI/ARDS in Mice

Predictive Criteria to Study the Pathogenesis of Malaria-Associated ALI/ARDS in Mice

Oxidative insult can induce malaria-protective trait of sickle and fetal erythrocytes

Host matrix metalloproteinases in cerebral malaria: new kids on the block against blood–brain barrier integrity?

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