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Updated: Nov 27, 2025
Author Spotlight: Identifying Compensatory Pathways in Malaria Parasites Containing Hypomorphic Allele of Essential Protein Kinases
Published on: November 22, 2024
Chorismate synthase mediates cerebral malaria pathogenesis by eliciting salicylic acid-dependent autophagy response
Malabika Chakrabarti1, Deepika Kannan2, Akshay Munjal1
1Host-Parasite Interaction & Disease Modelling Laboratory, Special Center for Molecular Medicine, Jawaharlal Nehru University, New Delhi-110067, India.
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.
Insights
Reducing salicylic acid (SA) in malaria parasites prevents severe cerebral malaria. Knocking out SA production in Plasmodium parasites decreased parasite load and reduced fatal outcomes in infected mice.
Area of Science:
- Malariology
- Parasitology
- Biochemistry
Background:
- Cerebral malaria, a severe Plasmodium falciparum complication, causes significant global morbidity.
- Salicylic acid (SA) in malaria parasites is linked to cerebral malaria pathogenesis and Reye's syndrome via iNOS induction.
- Modulating parasite SA levels presents a potential therapeutic strategy for cerebral malaria.
Purpose of the Study:
- To investigate the role of parasite-derived salicylic acid (SA) in cerebral malaria pathogenesis.
- To evaluate the therapeutic potential of inhibiting SA production in malaria parasites.
- To elucidate the protective mechanisms against cerebral malaria in the absence of parasite SA.
Main Methods:
- Immunological, pathological, and biochemical analyses were conducted in mice infected with Plasmodium berghei ANKA.
- A chorismate synthase knockout (CS-KO) P. berghei ANKA strain, incapable of producing SA, was used.
- Comparison of cerebral outcomes between mice infected with CS-KO and wild-type parasites.
Main Results:
- Mice infected with the SA-deficient P. berghei ANKA exhibited fewer cerebral malaria outcomes compared to wild-type infections.
- Reduced parasite load and attenuated pathological symptoms were observed in the absence of parasite SA.
- The protective effect may involve the inhibition of SA-induced autophagy, crucial for parasite survival.
Conclusions:
- Inhibiting salicylic acid production in malaria parasites offers a protective effect against cerebral malaria.
- Targeting the parasite's SA biosynthesis pathway is a promising strategy for cerebral malaria treatment.
- Reduced parasite SA levels mitigate disease severity and fatality by decreasing parasite load and associated pathology.
