One human protein helps malaria and kala-azar thrive. JNU scientists took it out

What did JNU scientists do to the human protein p38-MAPK, and how did malaria and kala-azar parasites respond?

JNU scientists removed the human protein p38-MAPK from lab-grown human cells and watched what happened to two parasites. Both malaria parasites and kala-azar parasites struggled when this host protein was destroyed. This matters because most existing medicines attack parasites directly, giving them repeated opportunities to evolve resistance.

The team used NR-7h, a PROTAC molecule, to remove p38-MAPK from human macrophages and red blood cells. The protein was reduced by about half, while its close cousin ERK1/2 was left untouched. In infected macrophages, parasite levels fell by up to about 16-fold. Parasites growing alone were unaffected, showing that NR-7h did not simply poison them directly.

The findings are still limited to laboratory cells. No animal or patient has been treated, so the approach is not yet a therapy. Still, it suggests that changing the parasite’s human host environment could offer a different route against drug-resistant malaria and kala-azar.

What is p38-MAPK, and why is it important inside human cells?

p38-MAPK is short for p38 mitogen-activated protein kinase. It acts like an internal messenger in human cells. When cells detect stress, injury or infection, p38-MAPK helps carry instructions from the cell surface inward. That makes it part of the cell’s response system rather than a parasite protein.

The protein also helps control cytokines. These are chemical alarm signals that immune cells use to communicate. The parasites appear to exploit this cellular signalling. Kala-azar parasites live inside macrophages, while malaria parasites shelter in red blood cells. In both settings, the parasites seem to depend on p38-MAPK.

That dependence makes the protein a possible host-directed treatment target. In the JNU experiments, removing it weakened parasites in infected human cells. However, p38-MAPK also has normal roles in human biology, so the article’s findings do not yet establish whether safely targeting it would work in animals or patients.

How strongly did removing p38-MAPK affect kala-azar parasites in infected human cells?

In infected human macrophages, the JNU team’s PROTAC NR-7h reduced kala-azar parasite levels by up to about 16-fold. That means the infected cells contained roughly 16 times fewer parasites after p38-MAPK was removed. The result shows a strong laboratory effect, although it does not yet show that the treatment would work in a living body.

The key mechanism was host protein removal. NR-7h lowered p38-MAPK in human macrophages by about half and left the related protein ERK1/2 untouched. Parasites growing alone were unaffected by NR-7h. This suggests the molecule did not kill the parasite through direct toxicity; instead, it disrupted something the parasite borrowed from its host cell.

The evidence remains early. The experiments used infected cells in a laboratory dish, and no animal or patient has received the treatment. Further work would be needed before judging its safety, effectiveness or usefulness against visceral leishmaniasis.

Why are malaria and kala-azar difficult to treat with the medicines currently available?

Malaria and kala-azar are difficult to treat because most medicines attack the parasite itself. Parasites can change their own proteins and gradually become less sensitive to drugs. Once resistance spreads, a medicine that previously worked may no longer clear the infection. This problem is especially serious for malaria, which caused an estimated 610,000 deaths and 282 million cases worldwide in 2024.

Chloroquine, once the main malaria treatment, is now largely ineffective against the deadliest Anopheles species in many parts of the world. The medicines introduced after it are also beginning to wobble. Kala-azar, or visceral leishmaniasis, causes fever, weight loss, anaemia and enlarged organs, and is fatal in over 95 percent of untreated cases.

These pressures encourage a different strategy: host-directed therapy. Instead of repeatedly targeting changing parasite proteins, it targets a human protein the parasite needs. The JNU work is an early laboratory example, not an available treatment.

How does a PROTAC such as NR-7h destroy a protein, and how is that different from merely switching the protein off?

A PROTAC is a molecule designed to destroy a chosen protein. Its name means proteolysis-targeting chimaera. The molecule has two functional parts. One part grabs the target protein, such as p38-MAPK. The other grabs an enzyme that tags unwanted proteins for disposal. The cell’s proteasome, a barrel-shaped protein shredder, then breaks down the tagged target.

NR-7h used this two-handed design to remove about half of the p38-MAPK in human macrophages and red blood cells. It left the close relative ERK1/2 untouched, showing selectivity. That matters because damaging nearby proteins could create unwanted effects. Removing a protein is more drastic than simply blocking its activity.

The article reports that switching p38-MAPK off did nothing, whereas destroying it weakened the parasites. This suggests the protein’s physical presence may matter, not only its active signalling. NR-7h remains a laboratory tool in this study, with no animal or patient treatment reported.

What is host-directed therapy, and why might targeting a human protein make it harder for a parasite to evolve drug resistance?

Host-directed therapy turns the usual treatment strategy around. Rather than attacking the invading parasite, it changes the human cell that provides the parasite with support. In this study, the target was p38-MAPK, a human signalling protein that malaria and kala-azar parasites appear to use while living inside human cells.

The approach matters because parasites can alter their own proteins to escape medicines aimed at them. They cannot easily change an essential human protein in the same way. JNU scientists used NR-7h to remove p38-MAPK from human macrophages and red blood cells. Kala-azar parasite levels in infected macrophages fell by up to about 16-fold, while the parasite was unaffected when grown alone.

This does not prove that resistance becomes impossible. It shows why host targeting could provide a different pressure on parasites. The work is still early, and no animal or patient has yet received the approach.

How do malaria and visceral leishmaniasis spread, and where do their parasites live inside the human body?

Malaria is transmitted by the bite of an infected female Anopheles mosquito. Its parasite, Plasmodium, is a single-celled organism. In the human body, malaria parasites take shelter in red blood cells. The article connects this location to the study’s testing of p38-MAPK in human red blood cells.

Visceral leishmaniasis, also called kala-azar, is spread by sandflies, which are tiny blood-feeding insects. Its parasites hide inside macrophages. These immune cells are named for their job of swallowing invaders. That hiding place may help the parasite survive while interacting with the host cell’s internal machinery.

The two parasites use different insects and occupy different human cells. Yet the JNU study found that both appeared to lean on p38-MAPK. Removing the protein weakened them in laboratory experiments. No animal or patient treatment has been reported, so the finding remains an early research result.

Key Facts:

📌 JNU scientists removed p38-MAPK from human cells using a PROTAC.

📌 Both malaria and kala-azar parasites struggled after protein removal.

📌 Simply switching p38-MAPK off did nothing.

📌 p38-MAPK is a stress sensor inside human cells.

📌 It carries instructions about injury and infection.

📌 It helps control cytokines used by immune cells.

📌 NR-7h reduced kala-azar parasite levels by up to about 16-fold.