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

Abstract

Cerebral malaria caused by P. falciparum is the severest form of the disease resulting into 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 in malaria parasite P.falciparum which plays a critical role in the manifestation of cerebral malaria. Further, the application of salicylic acid 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 salicylic acid might be a novel approach to neutralize the symptoms of cerebral malaria. The probable source of parasite salicylic acid is the shikimate pathway which produces chorismate, a precursor to aromatic amino acids and other secondary metabolites like salicylic acid in parasite. In this work, we performed the immunological, pathological and biochemical studies in mice infected with chorismate synthase knocked out P. berghei ANKA which does not produce salicylic acid. Less 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 salicylic acid mediated induction of autophagy in 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.