Immune cell variations contribute to malaria severity

October 4, 2018, Massachusetts Institute of Technology
Microvesicle from malaria-infected erythrocyte fuses with NK cell membrane. Green is NK cell membrane. Red is microvesicle. When they fuse they become yellow/orange. Credit: Ye Weijian, et al. (2018) Microvesicles from malariainfected red blood cells activate natural killer cells via MDA5 pathway.

At least 250 million people are infected with malaria every year, and about half a million of those die from the disease. A new study from MIT offers a possible explanation for why some people are more likely to experience a more severe, and potentially fatal, form of the disease.

The researchers found that in some patients, called (NK ) fail to turn on the genes necessary to effectively destroy malaria-infected .

The researchers also showed that they could stimulate NK cells to do a better job of killing infected red cells grown in a lab dish. This suggests a possible approach for developing treatments that could help reduce the severity of malaria infections in some people, especially children, says Jianzhu Chen, one of the study's senior authors.

"This is one approach to that problem," says Chen, an MIT professor of biology and a member of MIT's Koch Institute for Integrative Cancer Research. "Most of the malaria patients who die are children under the age of 5, and their immune system has not completely formed yet."

Peter Preiser, a professor at Nanyang Technical University (NTU) in Singapore, is also a senior author of the study, which appears in the journal PLOS Pathogens on Oct. 4. The paper's lead authors are NTU and Singapore-MIT Alliance for Research and Technology (SMART) graduate students Weijian Ye and Marvin Chew.

First line of defense

In 2010, Chen and his colleagues engineered strains of that produce several types of and red blood cells. These "humanized" mice can be used to study the human immune response to pathogens that don't normally infect mice, such Plasmodium falciparum, the parasite that causes malaria.

A few years later, the researchers used those mice to investigate the roles of NK cells and macrophages in malaria infection. These two cell types are key players in the innate immune system, a nonspecific response that acts as the first line of defense against many microbes. Chen and his colleagues found that when they removed human NK cells from the mice and infected them with malaria, the quantity of parasites in the blood was much greater than in mice with NK cells. This did not happen when they removed human macrophages, suggesting that NK cells are the most important first-line defenders against malaria.

In that study, the researchers also found that in about 25 percent of the human blood samples they used, the NK cells did not respond to malaria at all. In the new paper, they set out to try to find out why that was the case. To do that, they sequenced the RNA of NK cells before and after they encountered malaria-infected red blood cells. This allowed the researchers to identify a small number of genes that get turned on in malaria-responsive NK cells but not in nonresponsive cells.

Among these genes was one that codes for a protein called MDA5, which was already known to be involved in helping immune cells such as NK cells and macrophages recognize foreign RNA. Further studies revealed that malaria-infected red blood cells secrete tiny bubbles called microvesicles that carry pieces of RNA from the parasite. The studies also showed that NK cells absorb these microvesicles. If MDA5 is present, the NK cell is activated to kill the infected blood cell.

Nonresponsive NK cells, which have lower levels of MDA5, fail to recognize and kill the . NK cells are also responsible for secreting cytokines that summon T cells and other immune cells, so their failure to activate also hinders other elements of the immune response.

Boosting immunity

Chen and his colleagues also showed that they could activate the nonresponsive NK cells by treating them with a synthetic molecule called poly I:C, which is structurally similar to double-stranded RNA. For poly I:C to be effective, the researchers had to package it into tiny spheres called liposomes, which allow it to enter cells just like the RNA-carrying microvesicles do.

The researchers also found a correlation between the levels of MDA5 in the NK cells and the disease severity experienced by the patients who donated the blood samples. Next, they hope to take cells from human patients and use them to further examine this correlation in humanized mice, and also to explore whether treating the mice with poly I:C would have the same beneficial effect they saw in cells grown in a lab dish.

Explore further: New understanding of the way chikungunya virus protects mice against malaria could lead to improved patient care

More information: Weijian Ye et al. Microvesicles from malaria-infected red blood cells activate natural killer cells via MDA5 pathway, PLOS Pathogens (2018). journals.plos.org/plospathogen … journal.ppat.1007298

Related Stories

New understanding of the way chikungunya virus protects mice against malaria could lead to improved patient care

June 25, 2018
Chikungunya virus (CHIKV) infection may reduce the severity of malaria, according to a discovery by A*STAR scientists, which could lead to the development of new malaria treatments.

A new approach to developing a vaccine against vivax malaria

September 21, 2018
A novel study reports an innovative approach for developing a vaccine against Plasmodium vivax, the most prevalent human malaria parasite outside sub-Saharan Africa. The study led by Hernando A. del Portillo and Carmen Fernandez-Becerra, ...

How the immune system fights off malaria

January 13, 2014
The parasites that cause malaria are exquisitely adapted to the various hosts they infect—so studying the disease in mice doesn't necessarily reveal information that could lead to drugs effective against human disease.

Researchers identify target for novel malaria vaccine

July 13, 2018
A Yale-led team of researchers have created a vaccine that protects against malaria infection in mouse models, paving the way for the development of a human vaccine that works by targeting the specific protein that parasites ...

New clue to how mosquitoes fend off malaria

January 24, 2017
(Medical Xpress)—A team of researchers at the National Institutes of Health has found another part of the process that allows mosquitoes to keep from getting malaria even as they carry the parasite responsible for the disease ...

Recommended for you

Researchers discover unique immune cell likely drives chronic inflammation

December 11, 2018
For the first time, researchers have identified that an immune cell subset called gamma delta T cells that may be causing and/or perpetuating the systemic inflammation found in normal aging in the general geriatric population ...

New light-based technology reveals how cells communicate in human disease

December 11, 2018
Scientists at the University of York have developed a new technique that uses light to understand how cells communicate in human disease.

Macrophage cells key to helping heart repair—and potentially regenerate, new study finds

December 11, 2018
Scientists at the Peter Munk Cardiac Centre have identified the type of cell key to helping the heart repair and potentially regenerate following a heart attack.

Immune cells sacrifice themselves to protect us from invading bacteria

December 11, 2018
Immune systems are working overtime as winter approaches. Stomach flu can turn the strongest individual into a bedridden convalescent. Viruses are spreading in kindergartens. This year's flu is approaching in full swing. ...

Study identifies a key cellular mechanism that triggers pneumonia in humans

December 11, 2018
The relationship between influenza and pneumonia has long been observed by health workers. Its genetic and cellular mechanisms have now been investigated in depth by scientists in a study involving volunteers and conducted ...

Roadmap reveals shortcut to recreate key HIV antibody for vaccines

December 11, 2018
HIV evades the body's immune defenses through a multitude of mutations, and antibodies produced by the host's immune system to fight HIV also follow convoluted evolutionary pathways that have been challenging to track.

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.