A team from the Oswaldo Cruz Foundation (Fiocruz) in Belo Horizonte, Minas Gerais, has analyzed the mechanisms by which defense cells can reverse their primary role as the body’s protectors. When these cells fight to keep protozoa of the genus Plasmodium from multiplying in the central nervous system (CNS) during a case of cerebral malaria, they trigger an intense inflammatory process that exacerbates infection, causes hemorrhaging, and often leads to death. Coordinated by immunologist Ricardo Gazzinelli, the study sheds light on the origin of one type of defense cell, called dendritic cells, which produce inflammation in the nervous system. Findings also reveal new defense routes used by the body and may provide a better understanding of the development of diseases associated with neuroinflammation, like Alzheimer’s disease and multiple sclerosis.
Using specific biomarkers, the Minas Gerais team conducted experiments on mice to clarify the origin of the dendritic cells associated with cerebral malaria and the characteristics of the intense inflammation that typically accompanies it. According to the study, the dendritic cells that trigger brain inflammation are formed from another type of white blood cell, called a monocyte, inside a secondary defense organ, the spleen. Gazzinelli explains that this is an unusual circuit because large numbers of monocytes are generated in the bone marrow and are usually recruited from there to the battlefield – or infection site – where they turn into dendritic cells. The cells then recognize the invading microorganisms and migrate to the lymph nodes, where they activate other defense cells that will likewise fight the microbes. “In the case of malaria, monocytes stored in the spleen differentiate into dendritic cells and, after that, migrate to the brain,” says the immunologist.
After breaching the blood-brain barrier, which serves to isolate the CNS and can hamper the passage of immune system cells and even drugs, dendritic cells reach the CNS and produce molecules known as chemokines CXCL9 and CXCL10, which attract another type of white blood cells, called activated T lymphocytes, or T cells. Stimulated to fight the Plasmodium inside red blood cells, which cling to blood vessel walls, the T cells trigger exacerbated inflammation, contributing to the rupturing of small vessels. Since the blood-brain barrier also breaks down, more dendritic cells and T cells migrate to CNS tissues. According to Gazzinelli, when these defense cells mobilize to combat the parasite, it intensifies the inflammatory process, prompting extensive tissue injury and clinical signs typical of this type of malaria, such as paralysis of the legs, loss of balance, seizures, and death.
“A similar inflammatory process is observed in other organs – like the lungs and, in pregnant women, the placenta – which are also affected by the infection caused by Plasmodium, but the most serious form of malaria is cerebral malaria, given the functions and sensitivity of CNS tissue,” explains physician-scientist Isabella Hirako, principal author of the study, which is described in an article published in Nature Communications in October 2016. According to biologist Marco Ataíde, who also signed the article and is currently at the University of Bonn, in Germany, the findings help explain the mechanism behind a number of infections caused by viruses and other protozoa, like Leishmaniasis, which may prompt defense cells to follow this same circuit.
By characterizing the self-destructive process that is mediated by monocyte-derived dendritic cells, the researchers believe it may be possible to further clarify the origin and evolution of degenerative diseases caused by inflammatory processes, such as Alzheimer’s disease and autoimmune disorders, like multiple sclerosis, which make the body destroy its own nervous tissue.
Potential treatment options
“If this process is confirmed in humans, it may be possible for us to interfere with the process of differentiation or migration of these monocyte-derived dendritic cells and thus enhance resistance to infectious agents or prevent a damaging inflammatory reaction, which appears to be the case with cerebral malaria and autoimmune diseases,” says Gazzinelli, who coordinates the National Institute of Science and Technology in Vaccines (INCTV) and is participating in a project to establish a branch of Fiocruz on the campus of the Ribeirão Preto School of Medicine, of the University of São Paulo (FMRP-USP).
Each year, about 200 million people are infected by P. falciparum, the most virulent species of Plasmodium, which is the parasite that causes malaria (in Brazil, the most prevalent species is P. vivax). The most serious form, cerebral malaria, accounts for approximately 570,000 deaths each year, mostly African children under the age of five; it is treated only with general drugs against Plasmodium. The Fiocruz team may have discovered potential new forms of treatment when they found that the dendritic cells that travel to the brain have a specific type of outer membrane receptor, known as C-C chemokine receptor 5 (CCR5).
In genetically modified mice that do not express CCR5, the number of dendritic cells in the brain following Plasmodium infection was dramatically lower (almost zero) than in normal animals, leading to the recruitment of fewer T cells. As a result, animals in the first group displayed less intense inflammation and were more resistant to cerebral malaria. In immune system cells, this same receptor is the gateway for HIV, the virus that causes AIDS. “Drugs that block the receptor CCR5 prevent cells from being infected with HIV and are routinely used to treat AIDS. Since they don’t have major side effects, they could be evaluated as adjuvants in the treatment of serious forms of malaria,” Gazzinelli suggests.
Biologist Maria Regina Lima, a researcher at the USP Biomedical Sciences Institute (ICB-USP) who studies the differentiation of defense cells and their role in fighting diseases like malaria, Chagas disease, and tuberculosis, says that clarifying the mechanism behind cerebral malaria may lead to a better understanding of the immune system itself, which is responsible for defending the body from tumors, microorganisms, and toxins. “The study enhances our understanding of the harmful role of defense cells, but it may also open doors for further research on the protective role of monocytes and dendritic cells and help shed light on the immune response in cerebral malaria as well as in other diseases,” she says.
HIRAKO, I. C. et al. Splenic differentiation and emergence of CCR5+ CXCL9+ CXCL10+ monocyte-derived dendritic cells in the brain during cerebral malaria. Nature Communications. V. 7, No. 13277, pp. 1-19. 2016.
GAZZINELLI, R. T. et al. Innate sensing of malaria parasites. Nature Reviews Immunology. V. 14, pp. 744-57. 2014.