Discovery reveals potential loophole in immune response
A team of scientists led by Katherine A. Fitzgerald, PhD, associate professor of medicine, and Douglas T. Golenbock, MD, chief of the Division of Infectious Diseases and Immunology, have uncovered a potential loophole in the body’s innate immune response for malaria. In the most common and deadly form of malaria, known as plasmodium falciparum, the immune response appears to stimulate overproduction of the protein interferon that may contribute to inflammation and fever in patients and could play a part in vulnerability to the disease. The study was published online by the journal Immunity. Caused by a parasite transmitted through mosquitoes, malaria is often characterized by successive waves of high fevers, which contribute to the deadliness of the disease and many of its complications. The disease initially incubates in liver cells 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 viruses, 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 Dr. Fitzgerald. “In this study, we set out to understand what role the innate immune system plays in this fever response, the dominant symptom found in malaria patients.” Looking at blood samples from malaria patients with fever, 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 the interferon-expressing genes. These are typically produced when a virus is detected and they trigger the protective responses of the immune system that can wipe out 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.” Fitzgerald, Dr. Golenbock 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 is that the presence of malaria DNA was causing an innate immune response that contributed to inflammation and fever in the host that are the hallmarks of malaria infection – giving rise to the possibility that the immune system is doing more harm than good. “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 findings will have broader implications for other infectious and autoimmune diseases. “More work needs to be done to fully understand these issues” she said.
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EXPERTS’ CORNER: Malaria immune response may do more harm than good