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Tag: malaria

Kurup wins prestigious PATH award for groundbreaking malaria research

Donna Huber on June 10, 2025

Assistant Professor Samarchith “Sam” Kurup is the first UGA researcher to receive the Burroughs Wellcome Fund’s Investigators in Pathogenesis of Infectious Disease (PATH) award. Kurup studies the parasites that cause malaria and how they penetrate the body’s defenses, which could lead to more effective therapeutics. (Photo by Lauren Corcino)

Every year, malaria evades the immune defenses of nearly 250 million people. But Samarchith “Sam” Kurup is determined to outsmart the parasite before it strikes. Now, with the Burroughs Wellcome Fund’s prestigious Investigators in Pathogenesis of Infectious Disease (PATH) award in hand, his lab is one step closer.

Burroughs Wellcome recently announced its 2025 cohort of eight innovative scientists. Kurup is the first University of Georgia faculty member to receive this highly competitive award.

Growing up in India, Kurup saw malaria’s toll firsthand. That drove him to study parasites—first as a veterinarian, and then as a Ph.D. student. After completing training in veterinary medicine, he pursued his Ph.D. at UGA, studying another parasite that infects both humans and animals, Trypanosoma cruzi. He also began pairing his parasitology knowledge with immunology.

After graduating, Kurup returned as a postdoc to the study of Plasmodium, the parasite that causes malaria. In 2019, Kurup joined the faculty in the Franklin College of Arts and Sciences and the Center for Tropical and Emerging Global Diseases where he has established a robust research program.

“My lab is trying to understand how we, as hosts, fight malaria parasites in the liver,” said Kurup. “We know the liver cells have their own ‘home defense system’ and don’t have to call in other immune cells to handle the parasites. But somehow a few parasites are able to circumvent this defense system.”

This image shows a Plasmodium parasite (green) being surrounded and attacked by guanylate binding proteins (red), the host’s defense. The host cell nucleus is shown in blue. All of this action happens within the host’s liver cell, and Sam Kurup is trying to determine how the parasite is able to thwart such an attack. (Image courtesy of Kurup Lab)

In 2022, Kurup was awarded a five-year National of Institutes of Health grant to study how our liver cells target Plasmodium. Human malaria infection begins in what is called the liver stage of the parasite’s life cycle. After an infected mosquito bites a person, the parasite then travels to the liver where it replicates. While a person is not symptomatic at this point, the human immune system is already deploying its defenses. Kurup’s lab wants to understand why the human immune system is unable to fully clear the infection at this point.

“About 10% of the parasites are able to evade our immune responses within the hepatocytes,” said Kurup. “If we can figure out the parasite’s strategy, how they get through our defenses, then we have a chance of shutting them down completely.”

The Kurup lab has identified special proteins (which they call “exported effectors”) that the parasite releases. They believe these proteins help the parasite to slip past the human immune system. However, little is known about how they work.

“We want to find out what the parasite is targeting in the host cell,” said Kurup. “This would open up whole new doors in therapeutic research.”

Plasmodium falciparum is often resistant to current drug treatments. As the most widespread and lethal strain of malaria, it is critical to find new ways to treat the infection. Kurup believes that by targeting the malaria parasite in the liver, the disease can be stopped in its tracks.

The PATH award funds early career scientists to pursue cutting-edge research that may be considered too risky for traditional funding opportunities. The award to Kurup also comes with $505,000 in flexible research support over the next five years to identify the “exported effector” proteins, study their behavior, and explore how they interact with the host’s liver cells.

“In addition to being a recognition of the important work that we do as a team, this award is an endorsement to chasing bold ideas and having lofty goals,” Kurup said. “If we crack the parasite’s playbook, we could turn the tide against malaria.”

Regulatory T cell memory: implications for malaria

Donna Huber on April 23, 2025

Figure 1.Hypothetical model of memory Treg development. Activated Tregs, which proliferate in the acute phase of malaria, leave a memory Treg pool in mice and humans.

Regulatory T cells (Tregs) can persist as memory cells (mTregs) in both infectious and non-infectious settings. However, their functional behavior, phenotypic stability, and suppressive properties upon antigen re-exposure remain poorly understood. Emerging evidence suggests that mTregs exhibit enhanced proliferation and suppressive capacity upon re-encountering the same antigen, a feature that may be critical in recurrent infections such as malaria. In malaria, Tregs are known to modulate immune responses and influence acute disease outcomes, suggesting that mTreg recall may play a significant role in long-term immunity. This review explores the biology of Treg memory, with a focus on malaria, and examines the immunological implications of maintaining a suppressive mTreg population in malaria immunity.

Nana Appiah Essel Charles-Chess, Samarchith P Kurup. J Immunol. 2025 Apr 23:vkaf067. doi: 10.1093/jimmun/vkaf067

Type I interferons induce guanylate-binding proteins and lysosomal defense in hepatocytes to control malaria

Donna Huber on March 25, 2025

graphical abstractPlasmodium parasites undergo development and replication within hepatocytes before infecting erythrocytes and initiating clinical malaria. Although type I interferons (IFNs) are known to hinder Plasmodium infection within the liver, the underlying mechanisms remain unclear. Here, we describe two IFN-I-driven hepatocyte antimicrobial programs controlling liver-stage malaria. First, oxidative defense by NADPH oxidases 2 and 4 triggers a pathway of lysosomal fusion with the parasitophorous vacuole (PV) to help clear Plasmodium. Second, guanylate-binding protein (GBP) 1-mediated disruption of the PV activates the caspase-1 inflammasome, inducing pyroptosis to remove infected host cells. Remarkably, both human and mouse hepatocytes enlist these cell-autonomous immune programs to eliminate Plasmodium, with their pharmacologic or genetic inhibition leading to profound malarial susceptibility in vivo. In addition to identifying IFN-I-mediated cell-autonomous immune circuits controlling Plasmodium infection in the hepatocytes, our study also extends the understanding of how non-immune cells are integral to protective immunity against malaria.

Camila Marques-da-Silva, Clyde Schmidt-Silva, Carson Bowers, Nana Appiah Essel Charles-Chess, Cristina Samuel, Justine C Shiau, Eui-Soon Park, Zhongyu Yuan, Bae-Hoon Kim, Dennis E Kyle, John T Harty, John D MacMicking, Samarchith P Kurup. Cell Host Microbe. 2025 Mar 25:S1931-3128(25)00091-5. doi: 10.1016/j.chom.2025.03.008.

Stereospecific Resistance to N2-Acyl Tetrahydro-β-carboline Antimalarials Is Mediated by a PfMDR1 Mutation That Confers Collateral Drug Sensitivity

Donna Huber on January 14, 2025

Half the world’s population is at risk of developing a malaria infection, which is caused by parasites of the genus Plasmodium. Currently, resistance has been identified to all clinically available antimalarials, highlighting an urgent need to develop novel compounds and better understand common mechanisms of resistance. We previously identified a novel tetrahydro-β-carboline compound, PRC1590, which potently kills the malaria parasite. To better understand its mechanism of action, we selected for and characterized resistance to PRC1590 in Plasmodium falciparum. Through in vitro selection of resistance to PRC1590, we have identified that a single-nucleotide polymorphism on the parasite’s multidrug resistance protein 1 (PfMDR1 G293V) mediates resistance to PRC1590. This mutation results in stereospecific resistance and sensitizes parasites to other antimalarials, such as mefloquine, quinine, and MMV019017. Intraerythrocytic asexual stage specificity assays have revealed that PRC1590 is most potent during the trophozoite stage when the parasite forms a single digestive vacuole (DV) and actively digests hemoglobin. Moreover, fluorescence microscopy revealed that PRC1590 disrupts the function of the DV, indicating a potential molecular target associated with this organelle. Our findings mark a significant step in understanding the mechanism of resistance and the mode of action of this emerging class of antimalarials. In addition, our results suggest a potential link between resistance mediated by PfMDR1 and PRC1590’s molecular target. This research underscores the pressing need for future research aimed at investigating the intricate relationship between a compound’s chemical scaffold, molecular target, and resistance mutations associated with PfMDR1.

Emily K Bremers, Joshua H Butler, Leticia S Do Amaral, Emilio F Merino, Hanan Almolhim, Bo Zhou, Rodrigo P Baptista, Maxim Totrov, Paul R Carlier, Maria Belen Cassera. ACS Infect Dis. 2025 Jan 14. doi: 10.1021/acsinfecdis.4c01001.

 

ANTI-MALARIAL ACTIVITY OF AMENTOFLAVONE ISOLATED FROM LEAF OF CALOPHYLLUM TOMENTOSUM WEIGHT

Donna Huber on October 14, 2024

Calophyllum tomentosum belonging to Clusiaceae family is an Indian medicinal plant used as folklore medicine to cure various kinds of diseases reported in Ayurveda, and the leaves of the plant are also used as an active ingredient for the preparation of a botanical medicine known as ‘Punnaga’, ‘Surapunnaga’ and ‘Tamoil’ among other common names. Chemical profiling of the methanol extract of the defatted leaf revealed the presence of amentoflavone as one of the constituents along with coumarins, terpenoids, steroids, and apetalic acids. Structural determination of these amentoflavone has been conducted by chemical, spectral, and spectrometric methods in comparison with spectral values available in the literature and confirmed by a single crystal X-ray diffraction study. Amentoflavone (1) and its derivative (2-5) tested to check the efficacy of anti-malarial activity against Plasmodium falciparum. Amongst them, only tetra methoxy amentoflavone, (2) exhibited moderate anti-malarial activity with IC50 value 1.99 ± 0.42 µM against Plasmodium falciparum in comparison with artemisinin as control, whereas the other products possessed almost negligible activity although their structural skeletons are identical with little variation of number and nature of substituents. The structure activity relationship (SAR) of the active constituent and its derivatives is reported herein.

Ajoy Kumar Bauri, Joshua H Butler, Maria B Cassera, Sabine Foro. Chem Biodivers. 2024 Oct 14:e202401576. doi: 10.1002/cbdv.202401576.

Researchers discover malaria gene needed to make pair of invasion organelles

Donna Huber on October 2, 2024

by Donna Huber

Vasant Muralidharan and his research group at the University of Georgia’s Center for Tropical and Emerging Global Diseases have uncovered the role of an essential protein in Plasmodium falciparum, the parasite that causes the deadliest form of malaria. The discovery offers new insights for vaccine and drug development.

The parasite that causes malaria was discovered more than 125 years ago, but much is still unknown about this complex, single-celled organism. Researchers in the University of Georgia’s Center for Tropical and Emerging Global Diseases, however, have uncovered the role of one of the parasite’s essential proteins, offering new insights for vaccine and drug development.

Plasmodium falciparum causes the deadliest form of malaria, a disease the World Health Organization estimates killed more than 600,000 people worldwide died in 2022. A large majority of those deaths were children under the age of 5.

Historically, the parasite has been difficult to study due to its complex lifecycle, which includes three stages. One occurs in the mosquito, while the liver and blood stages take place in humans. The blood stage is when the infected person exhibits symptoms of malaria.

In the blood stage, the parasite invades red blood cells (RBCs) where they replicate and can be transmitted to the mosquito. The receptor-ligand complexes that enable RBC invasion have been well-studied and it is one of the targets of anti-malarial vaccines currently in clinical trials. But questions still remain.

“How does the parasite know it has encountered a red blood cell?” asked Vasant Muralidharan, associate professor in Franklin College’s Department of Cellular Biology and leader of the Muralidharan Research Group, where the study took place.

Interested, the team took a closer look at a protein called RON11, which is sent to a pair of unique club-shaped secretory organelles known as the rhoptry (Greek for club) that houses proteins needed to invade the RBC.

Click play to listen to an excerpt of Vasant Muralidharan discussing the cellular mechanics of malaria infection.

“When we knocked out this protein, we found that the parasite could do everything it usually does – create a putative pore in the membrane of the RBC, send proteins needed for parasite invasion through this putative opening into the RBC – but the parasite itself cannot enter the red blood cell,” Muralidharan explained. “If a parasite cannot enter the red blood cell, the life cycle is interrupted and the parasite dies.”

And then things got really interesting.

“We found that the parasites lacking RON11 were only producing half the rhoptry proteins, which are used in invasion,” Muralidharan said.

While it is known that Plasmodium parasites have two rhoptry organelles, they are so teeny-tiny they have been relatively understudied due to a lack of proper tools. However, new tools and techniques are emerging. David Anaguano, a cellular biology graduate student who led the study, traveled on a Daniel G. Colley Training in Parasitology fellowship to the Absalon Laboratory at Indiana University School of Medicine to learn a new tool known as Ultrastructure Expansion Microscopy.

Vasant Muralidharan is an associate professor in Franklin College’s Department of Cellular Biology. (Photo by Lauren Corcino)

“Electron microscopy is labor intensive, and since it uses thin slices of the parasite you are never sure if what you’re looking for really isn’t there or just not in the slice of the sample you have,” Muralidharan said. “Expansion microscopy is like using light microscopy but with a special gel to expand the cell proportionately in all directions. Thus, you don’t get the distortion you would with just an enlarged cell and you can image the entire infected cell in all dimensions. It has been a real game changer.”

As reported in the PLoS Biology paper, the Muralidharan group generated for the first time a Plasmodium cell with only one rhoptry organelle when they removed RON11 from malaria parasites.

“It’s not unusual for an organism to have a backup copy, but we can see that the parasite can create the first rhoptry just fine – without defect – but the second one that should form during the end of the replication cycle never forms,” Muralidharan said. “Why is that?”

As it appears that this second rhoptry is needed for RBC invasion, understanding the mechanisms that control its development could open up new targets for vaccine and drug treatment discovery as well as answering crucial questions like whether the two rhoptries are identical.

“This has been a long unanswered question,” Muralidharan said. “Now with this RON11 knockout parasite that doesn’t form a second rhoptry, we have the tools to answer it.”

Optimization of diastereomeric dihydropyridines as antimalarials

Donna Huber on June 18, 2024

graphical abstract

The increase in research funding for the development of antimalarials since 2000 has led to a surge of new chemotypes with potent antimalarial activity. High-throughput screens have delivered several thousand new active compounds in several hundred series, including the 4,7-diphenyl-1,4,5,6,7,8-hexahydroquinolines, hereafter termed dihydropyridines (DHPs). We optimized the DHPs for antimalarial activity. Structure-activity relationship studies focusing on the 2-, 3-, 4-, 6-, and 7-positions of the DHP core led to the identification of compounds potent (EC50 < 10 nM) against all strains of P. falciparum tested, including the drug-resistant parasite strains K1, W2, and TM90-C2B. Evaluation of efficacy of several compounds in vivo identified two compounds that reduced parasitemia by >75 % in mice 6 days post-exposure following a single 50 mg/kg oral dose. Resistance acquisition experiments with a selected dihydropyridine led to the identification of a single mutation conveying resistance in the gene encoding for Plasmodium falciparum multi-drug resistance protein 1 (PfMDR1). The same dihydropyridine possessed transmission blocking activity. The DHPs have the potential for the development of novel antimalarial drug candidates.

Kurt S Van Horn, Yingzhao Zhao, Prakash T Parvatkar, Julie Maier, Tina Mutka, Alexis Lacrue, Fabian Brockmeier, Daniel Ebert, Wesley Wu, Debora R Casandra, Niranjan Namelikonda, Jeanine Yacoub, Martina Sigal, Spencer Knapp, David Floyd, David Waterson, Jeremy N Burrows, James Duffy, Joseph L DeRisi, Dennis E Kyle, R Kiplin Guy, Roman Manetsch. Eur J Med Chem. 2024 Jun 18:275:116599. doi: 10.1016/j.ejmech.2024.116599.