Role of Lipid Signaling in Microneme Secretion Facilitating Plasmodium Invasion into Host Erythrocytes | Shiv Nadar University
Enquire Now
Apply Now
Undergraduate AdmissionsPhD Admissions Spring 2023MBA Admissions 2023MBA Information Session

Role of Lipid Signaling in Microneme Secretion Facilitating Plasmodium Invasion into Host Erythrocytes

Malaria continues to be a major threat to human health killing thousands of people every year. It is caused by an intracellular obligate protozoan parasite, Plasmodium falciparum. All the clinical symptoms of this disease are attributed to the blood stage of P.falciparum life cycle. During this stage, P. falciparum infects and multiplies within host erythrocytes. The process of invasion is mediated by specific interactions between parasite proteins harbored in apical organelles of invasive merozoites called micronemes and the receptors present on host erythrocytes. The timely, regulated discharge of such parasite proteins from micronemes to the merozoite surface enables receptor engagement and is the key to successful invasion. Microneme discharge is triggered by a rise in cytosolic calcium(Ca2+) following the activation of phospholipase C (PLC) leading to the production of two-second messengers, Diacylglycerol (DAG) and Inositol triphosphate (IP3). DAG is converted by DAG kinase (DGK) to Phosphatidic acid (PA), which has been linked to regulating exocytosis, in a wide variety of cell types. PA is rapidly converted to DAG by a phosphatase, type-2 Phosphatidic Acid Phosphatase, PAP2. Together, DGK and PAP2 regulate PA dynamics. In this thesis work, we describe the role of phosphatidic acid (PA) mediated signaling in microneme exocytosis facilitating Plasmodium invasion into host erythrocytes. In this study, we confirm the presence and expression of homolog of two key enzymes of PA mediated signaling in blood stage ofP.falciparum, Diacylglycerol Kinase, PfDGK1 that converts DAG into PA and type-2 phosphatidic acid phosphatase, PfPAP2 that converts PA back to its substrate, DAG. Both PfDGK1 and PfPAP2 harbor the canonical characteristic domains of DGK and PAP2 superfamily respectively. Using immunofluorescence assay, we demonstrate that both these proteins are associated with some vesicular structures in the parasite cytosol. By heterologous expression of PfDGK1 and PfPAP2 in a bacterial and mammalian expression system, we show that PfDGK1 and PfPAP2 possess the characteristic kinase and PAP activity respectively. Using inhibitors of DGK and PAP2, we explored the roles of PfDGK1 and PfPAP2 in maintaining PA homeostasis and regulation of microneme secretion mediated invasion of the parasite into host erythrocytes. Using mass spectrometry, we have identified one of the downstream effector molecules of PA signaling in Plasmodium, PfCDPK1, which has been previously reported as a key player in the regulation of microneme secretion and ultimately invasion. This study explores a novel lipid-mediated signaling pathway in the malaria parasite, which could be used as a potential platform for a new effective drug designing strategy against the deadly malaria parasite.

Department: 
Life Sciences
Year: 
2018
Student Name: 
Poonam Dangi

Directions