Researchers use new finding to clear bloodstream malaria infection in mice

December 12, 2011, University of Iowa Health Care

University of Iowa researchers and colleagues have discovered how malaria manipulates the immune system to allow the parasite to persist in the bloodstream. By rescuing this immune system pathway, the research team was able to cure mice of bloodstream malaria infections.

The findings, which were published Dec. 11 in the Advance Online Publication of the journal , could point the way to a new approach for treating malaria that does not rely on vaccination and is not susceptible to the parasite's notorious ability to develop .

"Malaria is chronic, prolonged infection and the host has a tough time clearing it and sometimes it never clears it," says Noah Butler, Ph.D., UI postdoctoral research scholar and lead study author. "We've determined that this prolonged infection actually drives dysfunction of the that are supposed to be fighting the infection, which in essence allows further persistence of the ."

More specifically, the study showed that the stimulate these key immune cells (known as CD4+ T cells) so that they continuously express molecules called inhibitory receptors. Under normal circumstances, these molecules help to "apply the brakes" to the and prevent over-activation that can be harmful. However, by keeping the mechanism turned on, the malaria parasite damps down the immune response significantly, reducing the T cells' ability to fight the parasite and allowing it to persist.

Importantly, the team also showed that blocking the action of the inhibitory resulted in immediate and complete clearance of the malaria parasite.

"When we blocked the function of these molecules, we took the brakes off the host's immune response and everything got better -- the overall immune response was dramatically improved and there was immediate control and accelerated clearance of the parasite," says John Harty, Ph.D., professor of microbiology and pathology at the UI Carver College of Medicine and senior study author. "These findings suggest an alternative approach for the treatment of existing malaria infection."

200 million malaria cases

More than half the world's population is at risk of malaria, a mosquito-borne parasite that causes anemia and high fever and which can persist for weeks or months. There are more than 200 million cases of malaria each year and an estimated 800,000 children die from malaria annually.

Harty notes that the current study was done in mice and it is not yet know if the same approach will work in humans. However, two factors suggest the strategy may have potential. First, drugs that block inhibitory receptor molecules are available and currently being tested as cancer therapies. And second, the UI team found that malaria infection in humans does lead to increased expression of inhibitory on CD4+ T cells suggesting that these molecules could represent a viable target for human therapies.

The human findings were the product of an important collaboration between the UI team and malaria researchers working in the sub-Saharan country of Mali. The Mali team based at the University of Bamako works in a sophisticated lab set up by the National Institutes of Health. In Mali's dry season there are no mosquitoes, so there's no malaria; in the wet season, the mosquitoes come out and malaria appears.

"Workers in the NIH lab obtained blood samples from malaria-free children at the end of the dry season, and then when some of the children returned to the clinic with malaria at the beginning of the next wet season they were treated immediately and the workers also took a second blood sample," Harty explains. "This allowed us to analyze the blood for expression of this inhibitory molecule before and after infection and we found that the molecule went up after infection."

Malaria further compromises immune system

A second collaboration, born closer to home, allowed Harty's team to prove that it is the CD4+ T cells that are disrupted by the malaria infection.

Using a new technique that was developed in the lab of UI microbiologist Steve Varga, Ph.D., the researchers were able to track the behavior of the responding T cells during malaria infection. They found that chronic led to sustained expression of the inhibitory receptor molecules on the surfaces of this type of T cell and also showed that the T cells' ability to fight the parasite was significantly reduced.

The study also found that as the parasite persists the inhibitory receptor molecules remain upregulated and the became more and more compromised.

"The T-cells are so over-stimulated that they eventually lose their function or even die -- this is known as T-cell exhaustion," Butler explains.

The concept that prolonged persistence of an "insult" to the immune system, such as cancer or chronic viral infections like HIV, disrupts and exhausts the immune response is well established. However, this study is the first time it has been shown for malaria. The study finding suggests that rescuing CD4+ T cells from exhaustion could be an effective strategy to control and clear infections.

Explore further: Novel treatment protects mice against malaria; approach may work in humans as well

Related Stories

Novel treatment protects mice against malaria; approach may work in humans as well

October 26, 2011
Malaria is a major global health concern, and researchers are in need of new therapeutic approaches. To address this concern, a study published Oct. 26 in the online journal PLoS ONE reveals new information about the host ...

Wolbachia bacteria reduce parasite levels and kill the mosquito that spreads malaria

May 19, 2011
Wolbachia are bacteria that infect many insects, including mosquitoes. However, Wolbachia do not naturally infect Anopheles mosquitoes, which are the type that spreads malaria to humans. Researchers at the Johns Hopkins Bloomberg ...

Breakthrough in malaria research looks to body's immune cells

November 25, 2011
Groundbreaking research from the Queensland Institute of Medical Research is set to pave the way for the development of new malaria drugs and vaccines.

Malaria vaccination strategy provides model for superior protection

June 15, 2011
Malaria is a devastating disease caused by the Plasmodium parasite which is transmitted to humans by infected mosquitoes. Hundreds of millions of new cases of malaria are reported each year, and there are more than 750,000 ...

Recommended for you

Functional engineered oesophagus could pave way for clinical trials 

October 18, 2018
The world's first functional oesophagus engineered from stem cells has been grown and successfully transplanted into mice, as part of a pioneering new study led by UCL.

New findings cast light on lymphatic system, key player in human health

October 16, 2018
Scientists at the Oklahoma Medical Research Foundation have broken new ground in understanding how the lymphatic system works, potentially opening the door for future therapies.

New model suggests cuffless, non-invasive blood pressure monitoring possible using pulse waves

October 16, 2018
A large team of researchers from several institutions in China and the U.S. has developed a model that suggests it should be possible to create a cuffless, non-invasive blood pressure monitor based on measuring pulse waves. ...

Age-related increase in estrogen may cause common men's hernia

October 16, 2018
An age-related increase in estrogen may be the culprit behind inguinal hernias, a condition common among elderly men that often requires corrective surgery, according to a Northwestern Medicine study was published Oct. 15 ...

Income and wealth affect the mental health of Australians, study shows

October 16, 2018
Australians who have higher incomes and greater wealth are more likely to experience better mental health throughout their lives, new research led by the Bankwest Curtin Economics Centre has found.

Discovery of inner ear function may improve diagnosis of hearing impairment

October 15, 2018
Results from a research study published in Nature Communications show how the inner ear processes speech, something that has until now been unknown. The authors of the report include researchers from Linköping University, ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.