Pathogenic Pore Forming Proteins of Plasmodium Triggers the Necrosis of Endothelial Cells Attributed to Malaria Severity

Abstract

Severe malaria caused by Plasmodium falciparum poses a major global health problem with high morbidity and mortality. P. falciparum harbors 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, they contribute to disease pathogenesis by interacting with host cells. The severe malaria pathogenesis is associated with the dysfunction of various barrier cells, including endothelial cells (EC). Several factors, including PLPs secreted by parasites, contribute to the host cell dysfunction. Herein, we have tested the hypothesis that PLPs mediate dysfunction of barrier cells and might have a role in disease pathogenesis. We analyzed various dysfunctions 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 the mitochondrial membrane potential, and ROS generation. We have further performed the time-lapse video microscopy of barrier cells and found that 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 rationale for the design of adjunct therapies against severe malaria.

Mitochondria as a Cellular Hub in Infection and Inflammation

“…Decreased OXPHOS activity [144,145] Reduced activity of GPx, GSH and MnSOD [146,147] Increased ROS [148][149][150] Increased oxidative stress [151,152] Increased basal respiration, proton leak and ATP production [153] Plasmodium spp. Impaired ∆ψm, increased ROS [154] Fission and apoptosis [155][156][157] Toxoplasma gondii…”

“…Shivappagowdar and co-workers provided new insights on malaria pathogenesis. They identified that the P. falciparum pore-forming proteins (PFPs) have damaging effects to primary vascular endothelial cells, where exposed cells had impaired Δψm, increased ROS and apoptosis [ 154 ]. In a similar approach, it was shown that infection by Plasmodium yoelii makes host hepatocytes susceptible to mitochondria-initiated apoptosis, through a mechanism that involve increased expression of the proapoptotic Bcl-2, leading to mitochondrial fission and apoptosis [ 155 , 156 , 157 ].…”

Metalloprotease Gp63-Targeting Novel Glycoside Exhibits Potential Antileishmanial Activity

“…MDCK cells were derived from the kidney tissue of an adult female Cocker Spaniel. These were grown in Dulbecco’s modified Eagle’s minimal essential medium (DMEM) in the presence of 10% (v/v) FBS and 100 U/ml penicillin−100 µg/ml streptomycin (Gibco, Invitrogen, Thermo Fisher Scientific, NY, USA) at 37°C (humidified) and 5% CO 2 ( Ayana et al., 2018 ; Shivappagowdar et al., 2021 ).…”