Generic selectors
Exact matches only
Search in title
Search in content
Post Type Selectors

Tag: Vasant Muralidharan

UGA Researcher Seeks to Unlock Secrets of Malaria Parasite

malaria parasites
Super-resolution microscopy showing malaria parasites infecting human red blood cells. Image credit: Muthugapatti Kandasamy, Biomedical Microscopy Core

Vasant Muralidharan and his research team at the University of Georgia’s Center for Tropical and Emerging Global Diseases are making great strides in understanding how the malaria parasite hijacks red blood cells to cause disease but many of the parasite’s strategies remain elusive.  A new $1.875 million grant from the National Institutes of Health will allow them to continue this research.

Malaria is a parasitic disease that infects nearly 220 million people and kills nearly half a million people every year. Almost all the deaths occur in young children and primarily in sub-Saharan Africa. The parasite Plasmodium falciparum invades human red blood cells which directly leads to malaria symptoms that include headaches, muscle pain, periodic fevers with shivering, severe anemia, trouble breathing, and kidney failure. The parasite can also cause the most severe forms of malaria, such as cerebral malaria which can lead to brain damage, coma and death, and placental malaria, which occurs in pregnancy and can be life-threatening to both the mother and fetus.

Complete control of the infected red blood cell is required for parasites to grow and spread. The malaria parasite remodels the host cell by exporting hundreds of parasite proteins across numerous membranes that transform all aspects of infected red blood cells to suit its needs. The export of these proteins by P. falciparum to the host red blood cells is a unique parasite-driven process that is associated with many of the clinical manifestations of malaria, including death. The mechanisms which these proteins are exported are unknown.

“Exported proteins, many of them absolutely essential for the growth of the parasite, are recognized and sorted throughout the trafficking process by dedicated machinery that we have only now begun to understand,” said Muralidharan, assistant professor in the department of cellular biology.

His lab hopes to reveal unique protein trafficking mechanisms of P. falciparum that may be targets for antimalarial drug development.

 “We expect that this project will significantly advance our understanding of the protein export pathway in P. falciparum and how key decisions are made within the parasite that usher exported proteins to their site of action in the infected red blood cells,” concluded Muralidharan.

National Institutes of Health Award R01 AI130139 “Elucidating the trafficking mechanisms of effector proteins to the Plasmodium infected red blood cell.”

An ancient bacterial protein complex in human malaria parasites is essential for parasite growth

Vasant Muralidharan and Anat Florentin

Several species of Plasmodium parasites cause malaria in humans and results in nearly 450,000 deaths annually. The deadliest of these species is Plasmodium falciparum. Unfortunately, it is also drug resistance to many of the currently available treatments. Vasant Muralidharan, assistant professor in the department of cellular biology, and his research group at The Center for Tropical and Emerging Global Diseases at The University of Georgia reported on an essential protein in hopes of identifying new drug targets.

Plasmodium parasites contain an organelle known as the apicoplast that evolved via the endosymbiosis of a red alga. The apicoplast produces several essential metabolites required for parasite growth and survival. Therefore, drugs that target the apicoplast are clinically effective. However, there is still not a lot known about this organelle. Understanding the function, structure, and biogenesis of the apicoplast provides a gold mine of antimalarial drug targets.

The role of Clp proteins in Plasmodium apicoplast

Clp (Caseinolytic Proteases) are conserved prokaryotic proteins that serve a wide variety of biological functions in bacteria, the evolutionary ancestors of the apicoplast. Several Clp proteins have been reported to localize in the apicoplast of the parasite but their biological functions were unknown.

The research team used different genetic tools to conditionally inhibit the function of various apicoplast-Clp proteins. “It is similar to understanding the role of a single card in holding up a house of cards by removing it from the structure,” said Muralidharan.

Their data show that the Clp chaperone PfClpC is essential for parasite viability and that its inhibition resulted in morphological defects, and loss of the apicoplast. They also revealed that the chaperone activity is required to stabilize a Clp Protease, PfClpP, suggesting that, similar to bacteria and plants chloroplasts, these two proteins form a proteolytic complex. These data may be relevant to the function of bacterial and plant Clp complexes. “Our findings shed light on the biological roles of the apicoplast Clp Proteins and their involvement in apicoplast replication,” said Dr. Anat Florentin, lead author on the study.

Significance of the findings

The role that bacterial Clp proteins play in cell division, stress response and ability to cause disease have placed them at the center of several drug discovery programs. The new understanding of Clp proteins in Plasmodium provides an avenue for drug development in malaria in which highly active antibacterial compounds can be repurposed as effective anti-malarial agents.

 

An online version of this study is available: A. Florentin,  D.W. Cobb, J.D. Fishburn, M. J. Cipriano, P.S. Kim, M.A. Fierro, B. Striepen, V. Muralidharan. 2017. PfClpC is an essential Clp chaperone required for plastid integrity and Clp protease stability in Plasmodium falciparum. Cell Reports 21, 1 – 11. http://dx.doi.org/10.1016/j.celrep.2017.10.081