An equivalence of prokaryotic pore forming proteins of Plasmodium triggers cellular dysfunction responsible for malaria pathogenesis

Autor: Akriti Srivastava, Shailja Singh, Lalit C. Garg, Rahul S. Hada, Abhishek Shivappagowdar, Swati Garg, Soumya Pati
Rok vydání: 2020
Předmět:
DOI: 10.1101/2020.08.01.230623
Popis: Severe malaria caused by Plasmodium falciparum poses a major global health problem with high morbidity and mortality. The P. falciparum harbours a family of pore forming proteins (PFPs), known as perforin like proteins (PLPs), which are structurally equivalent to prokaryotic PFPs. These PLPs are secreted from the parasites and by interacting to host cells they contribute to disease pathogenesis. The severe malaria pathogenesis is associated with dysfunction of various barrier cells including endothelial cells. A number of factors, including PLPs, secreted by parasite contribute to the host cell dysfunction. Here in, we tested the hypothesis that the PLPs mediate dysfunction of barrier cells and might have a role in disease pathogenesis. We analysed various dysfunction in barrier cells following rPLP2 exposure and demonstrate that it causes an increase in intracellular Ca2+ levels. Additionally, rPLP2 exposed barrier cells displayed features of cell death including Annexin/PI positivity, depolarized mitochondrial membrane potential and ROS generation. We further performed the time lapse video microscopy of barrier cells and found the treatment of rPLP2 triggers their membrane blebbing. The cytoplasmic localization of HMGB1, a marker of necrosis, further confirmed the necrotic type of cell death. This study highlights the role of parasite factor PLP in endothelial dysfunction and provides a rational for the design of adjunct therapies against severe malaria.
Databáze: OpenAIRE