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Chorismate synthase mediates cerebral malaria pathogenesis by eliciting salicylic acid-dependent autophagy response in parasite.

ABSTRACT: Cerebral malaria caused by Plasmodium falciparum is the severest form of the disease resulting in the morbidity of a huge number of people worldwide. Development of effective curatives is essential in order to overcome the fatality of cerebral malaria. Earlier studies have shown the presence of salicylic acid (SA) in malaria parasite P. falciparum, which plays a critical role in the manifestation of cerebral malaria. Further, the application of SA for the treatment of acute symptoms in cerebral malaria increases the activity of iNOS leading to severe inflammation-mediated death, also called as Reye's syndrome. Therefore, modulation of the level of SA might be a novel approach to neutralize the symptoms of cerebral malaria. The probable source of parasite SA is the shikimate pathway, which produces chorismate, a precursor to aromatic amino acids and other secondary metabolites like SA in the parasite. In this work, we performed the immunological, pathological and biochemical studies in mice infected with chorismate synthase knocked-out Plasmodium berghei ANKA, which does not produce SA. Fewer cerebral outcomes were observed as compared to the mice infected with wild-type parasite. The possible mechanism behind this protective effect might be the hindrance of SA-mediated induction of autophagy in the parasite, which helps in its survival in the stressed condition of brain microvasculature during cerebral malaria. The absence of SA leading to reduced parasite load along with the reduced pathological symptoms contributes to less fatality outcome by cerebral malaria.

SUBMITTER: Chakrabarti M

PROVIDER: S-EPMC7774894 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Chorismate synthase mediates cerebral malaria pathogenesis by eliciting salicylic acid-dependent autophagy response in parasite.

Chakrabarti Malabika M Kannan Deepika D Munjal Akshay A Choudhary Hadi Hasan HH Mishra Satish S Singh Shailja S

Biology open 20201221 12

Cerebral malaria caused by <i>Plasmodium falciparum</i> is the severest form of the disease resulting in the morbidity of a huge number of people worldwide. Development of effective curatives is essential in order to overcome the fatality of cerebral malaria. Earlier studies have shown the presence of salicylic acid (SA) in malaria parasite <i>P. falciparum</i>, which plays a critical role in the manifestation of cerebral malaria. Further, the application of SA for the treatment of acute symptom ...[more]

PMID: 33268332

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Project description:Cerebral malaria claims the lives of over 600,000 African children every year. To better understand the pathogenesis of this devastating disease, we compared the cellular dynamics in the cortical microvasculature between two infection models, Plasmodium berghei ANKA (PbA) infected CBA/CaJ mice, which develop experimental cerebral malaria (ECM), and P. yoelii 17XL (PyXL) infected mice, which succumb to malarial hyperparasitemia without neurological impairment. Using a combination of intravital imaging and flow cytometry, we show that significantly more CD8(+) T cells, neutrophils, and macrophages are recruited to postcapillary venules during ECM compared to hyperparasitemia. ECM correlated with ICAM-1 upregulation on macrophages, while vascular endothelia upregulated ICAM-1 during ECM and hyperparasitemia. The arrest of large numbers of leukocytes in postcapillary and larger venules caused microrheological alterations that significantly restricted the venous blood flow. Treatment with FTY720, which inhibits vascular leakage, neurological signs, and death from ECM, prevented the recruitment of a subpopulation of CD45(hi) CD8(+) T cells, ICAM-1(+) macrophages, and neutrophils to postcapillary venules. FTY720 had no effect on the ECM-associated expression of the pattern recognition receptor CD14 in postcapillary venules suggesting that endothelial activation is insufficient to cause vascular pathology. Expression of the endothelial tight junction proteins claudin-5, occludin, and ZO-1 in the cerebral cortex and cerebellum of PbA-infected mice with ECM was unaltered compared to FTY720-treated PbA-infected mice or PyXL-infected mice with hyperparasitemia. Thus, blood brain barrier opening does not involve endothelial injury and is likely reversible, consistent with the rapid recovery of many patients with CM. We conclude that the ECM-associated recruitment of large numbers of activated leukocytes, in particular CD8(+) T cells and ICAM(+) macrophages, causes a severe restriction in the venous blood efflux from the brain, which exacerbates the vasogenic edema and increases the intracranial pressure. Thus, death from ECM could potentially occur as a consequence of intracranial hypertension.

Dataset Information

Chorismate synthase mediates cerebral malaria pathogenesis by eliciting salicylic acid-dependent autophagy response in parasite.

Publications

Chorismate synthase mediates cerebral malaria pathogenesis by eliciting salicylic acid-dependent autophagy response in parasite.

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