Targeting innate immunity in malaria

WORCESTER, Mass. – Scientists at the University of Massachusetts Medical School have uncovered a novel DNA-sensing pathway important to the triggering of an innate immune response for malaria. Activation of this pathway appears to stimulate production of an overabundance of type-1 interferon by the immune system that may contribute to inflammation and fever in malaria patients and could play a part in susceptibility for the most common and lethal form of malaria known as plasmodium falciparum. Published online by Immunity this week, the study offers the first evidence that recognition of parasite DNA by the innate immune system may play a key role in malaria.

Caused by a parasite transmitted through mosquitoes, malaria is often characterized by successive waves of high fevers, which contribute to the lethalness of the disease and cause many of its complications. The disease initially incubates in liver cells where it can gestate and multiple for up to 30 days. In the second stage, the parasite infects blood cells where it continues to multiply. Invisible to the immune system while inside the blood cells, the malaria parasite periodically bursts through to infect new cells and further multiply. Once the malaria parasite is outside of the blood cells, the immune system is able to detect its presence and attempts to mount a defensive response. It is this response and the corresponding inflammation that accounts for the periodic and deadly waves of fever experienced by malaria patients.

"Traditionally, immunologists have investigated how the adaptive immune system responds to foreign bodies such as virus, bacteria and parasites. It's only over the last 10 to 15 years that we've begun to understand the complex and important role the innate immune system plays in responding to all different classes of pathogens," said Katherine A. Fitzgerald, PhD, associate professor of medicine at UMMS and one of the lead authors of the Immunity study. "In this study, we set out to understand what role the innate immune system plays in this fever response, the dominate symptom found in malaria patients."

Looking at blood samples from febrile malaria patients, Fitzgerald and colleagues found the typical genetic signs expected from patients infected by a pathogen. What they weren't expecting to find, however, were elevated levels of interferon-expressing genes. Typically produced when a virus is detected, interferon triggers the protective defenses of the immune system that can eradicate viruses or tumors. "What we saw when we looked at the samples from malaria patients was a type 1 interferon signature in the immune cells that were responding to the malaria," said Fitzgerald. "This surprised us at the time because traditionally we thought of interferon only in the context of virus infections"

Working with Douglas T. Golenbock, MD, chief of the Division of Infectious Diseases and Immunology at UMMS, Dr. Fitzgerald and colleagues set out to find what was triggering the innate immune response and what effect that response was having on the host cells. What they found was a part of the malaria genome containing a dense portion of the nucleic acids adenine and thymine, two of the building blocks in DNA, which were responsible for activating a novel signaling pathway, including STING, TBK1 and IRF3-IRF7, in the host that enabled innate immune cells to produce type 1 interferon.

When Fitzgerald and colleagues proceeded to test the importance of this pathway to the progression of the disease in small animal models they found another surprise. Those which expressed the normal STING, TBK1 and IRF3-IRF7 pathway all succumbed to the infection within 12 days. However, those that lacked some or all of these genes survived the infection, suggesting that this novel DNA-sensing pathway that leads to type 1 interferon production may play a vital role in the progression of malaria in the host.

"Normally interferon works to eradicate viruses from our body," said Fitzgerald. "In malaria it appears that the interferon response produced by the innate immune system might actually be harmful to the host rather than beneficial. It's not clear yet how or why this occurs but these findings suggest that immune system recognition of DNA and the corresponding production of interferon may play an important role in the parasite's pathogenesis."

Fitzgerald also theorizes that these finding will have broader implications for other infectious and autoimmune diseases. It's possible that with other infectious agents dense portions of the nucleic acids adenine and thymine might also alert the innate immune response to the presence of infection. Additionally, some forms of autoimmunity are associated with overproduction of interferon and it's possible that pathways like those defined here in the context of malaria may be involved in exacerbating these diseases. "More work needs to be done to fully understand these issues" she said.

The University of Massachusetts Medical School (UMMS), one of the fastest growing academic health centers in the country, has built a reputation as a world-class research institution, consistently producing noteworthy advances in clinical and basic research. UMMS attracts more than $255 million in research funding annually, 80 percent of which comes from federal funding sources. The mission of UMMS is to advance the health and well-being of the people of the commonwealth and the world through pioneering education, research, public service and health care delivery with its clinical partner, UMass Memorial Health Care. For more information, visit www.umassmed.edu.