Identification and characterization of a novel Bax inhibitor-1 gene in Leishmania donovani
Kikku Sharma
Ahmedabad University, India
Leishmaniasis, triggered by various species of the Leishmania genus, poses a significant public health challenge with its outbreak potential. Understanding the mechanisms and pathways of cell death in these parasites is complicated due to the absence of several key apoptosis regulator genes in the Leishmania genome, despite reports of apoptosis-like cell death behaviors. Our research has centered on Bax inhibitor-1 (BI-1), a protein known for its evolutionary conservation across plants, animals, and yeast, and its role in inhibiting the Bax protein, which is involved in apoptosis. In examining the Leishmania genome, we discovered a sequence similar to Bax inhibitor-1, which we have named LdBI-1. This sequence shares limited similarity with its human analogue but retains critical transmembrane domains. Utilizing the CRISPR/Cas9 technique, we created a cell line with a disrupted LdBI-1 gene. Its absence leads to increased sensitivity to cell death stimuli. We also developed a cell line overexpressing LdBI-1 to further investigate its role, particularly in relation to autophagy and overall cellular biology, including subcellular localization. Our ongoing study seeks to understand LdBI-1's evolutionary conservation and functional role in Leishmania, potentially paving the way for new antileishmanial treatments by targeting this novel gene.
Using the Cross-Species Transmission of Plasmodium coatneyi, a Newly Identified Zoonotic Agent, to Unravel the Pathogenesis of Fatal Cerebral Malaria
Jing Wen Hang1, Yew Wai Leong1,2, Vipin Narang3, Piyanate Sunyakumthorn4, Josephine Lum3, Shanshan Wu Howland3, Bernett Lee3, Laurent Rénia2,5, Samuel C. Wassmer6, Eric D. Lombardini4, Rossarin Suwanarusk7, Bruce Russell7,8, Benoît Malleret1,3
1Department of Microbiology and Immunology, Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.; 2A*STAR Infectious Diseases Labs, Agency for Science, Technology and Research (A*STAR), Singapore.; 3Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.; 4Department of Veterinary Medicine, Armed Forces Research Institute of Medical Sciences (AFRIMS); Bangkok, Thailand.; 5Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.; 6Department of Infection Biology, London School of Hygiene & Tropical Medicine, United Kingdom.; 7Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand.; 8Department of Protozoology, Institute of Tropical Medicine (NEKKEN), Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
Cerebral malaria (CM) is an often-fatal neurological complication of Plasmodium falciparum infection, with survivors frequently experiencing enduring neurologic sequelae. The disruption of the blood-brain barrier (BBB) has been identified in several studies as a key factor leading to CM progression. We utilized Plasmodium coatneyi-infected rhesus macaques as a non-human primate (NHP) model to unravel the pathogenesis of falciparum malaria, given their similar pathophysiological features with P. falciparum infection in humans. Through differential gene expression analysis, we demonstrated the effectiveness of methylene blue treatment in reversing the effects of infection on the brainstem. Comparing our brainstem dataset from P. coatneyi-infected Macaca mulatta with two other transcriptomic datasets (P. coatneyi-infected M. mulatta blood and P. falciparum-infected human blood), we identified nine genes associated with CM severity. Many of these genes are expressed by neutrophils and could serve as blood biomarkers for the diagnosis of lethal falciparum CM. The potential role of P. coatneyi as a zoonotic parasite poses significant implications for public health, suggesting the need for further investigation into its capability to infect humans and contribute to malaria transmission dynamics. This study highlights the importance of considering zoonotic malaria species in the broader context of malaria research and control strategies.
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