Macrophages formed in the bone marrow can only assume the function of embryonal phagocytes, or "scavenger cells," to a certain degree according to a study by the University of Bonn and the Peter Doherty Institute for Infection and Immunity at the University of Melbourne. The researchers have demonstrated that malaria infection causes permanent damage to resident CD163 macrophages in the spleen, which are responsible for cleaning the blood, recycling iron and communicating with other cells involved in the body's immune response. Their findings could harbor potential not only for more effective malaria vaccines but also for developing drugs and treatments to combat other infectious diseases. The paper is to be published in the journal "Immunity" but can already be accessed online.
Macrophages are an important component in our immune system. As part of our nonspecific defenses, these "big eaters" serve as our body's "cleanup crew," tracking down pathogens, removing dead cells and digesting foreign substances to make them harmless. "Macrophages essentially come in two different kinds: resident ones, which develop in the embryo, and recruited ones, which can be newly formed at any time," explains Professor Elvira Mass, head of the Developmental Biology of the Immune System working group at the University of Bonn's Life & Medical Sciences Institute (LIMES).
Resident macrophages regenerate through cell division. If many of them are destroyed as a result of a severe infection or injury, they cannot divide quickly enough to keep up. In that case, their role is assumed by white blood cells, which are created in the bone marrow and which then develop into macrophages. "People used to assume that this replacement was virtually 1:1, but our latest research shows this not to be the case," Mass explains.
Malaria infection causes lasting damage to macrophage population
In a joint study together with Dr. Lynette Beattie's working group at the Peter Doherty Institute for Infection and Immunity in Melbourne, Mass's group investigated the long-term impact of malaria infection on resident macrophages in the spleen. "The spleen is home to a large population of macrophages that eat dead red blood cells, recycling iron in the process. They possess a receptor called CD163, hence the name 'CD163 macrophages,'" says Mass, who is also Speaker for the University of Bonn's Life and Health Transdisciplinary Research Area and a member of its ImmunoSensation3 Cluster of Excellence.
By running experiments on genetically altered mice, the researchers were able to show that the presence of the malaria parasites, which live in and cause lysis of red blood cells, results in a long-lasting loss of the CD163 macrophages during the "blood stage" of the infection i.e. the phase in which the characteristic bouts of fever occur. Even months after the infection had subsided, the CD163 population had not recovered. "Their places are taken by new cells originating in the bone marrow, although these cells don't attain the same degree of specialization as the originals," Mass explains. This is a problem because CD163 macrophages also control parts of the immune response in addition to their scavenging role. Specifically, they use a signaling molecule to communicate with macrophages in the marginal zone (an important structural component of the spleen). "This structure helps to make sure that the immune cells in the spleen can get the signals that they need to fight bacteria and viruses, and we found that this structure and the associated communication network is persistently damaged by malaria" said Dr Beattie, the co-lead of the study.
A series of follow-up experiments confirmed that eliminating the signaling molecule is enough to shrink the macrophage population in the marginal zone. If the CD163 macrophages are depleted, a malaria infection will be more severe, releasing more malaria-causing parasites into the bloodstream and making anemia last longer. And, because this damage is not just temporary, the prognosis for repeat infections is also significantly worse.
Findings can be applied to human beings
Given that CD163 macrophages are also present in our own spleen, the researchers believe that malaria causes a permanent change in the human macrophage architecture too. "Our results indicate that a single malaria episode can leave a lasting impression on the immunological memory, particle filtering and the spleen's iron metabolism," Mass reveals. "This could be relevant for vaccine effectiveness, especially in parts of the world where malaria infections occur repeatedly."
The study also does much to improve our understanding of how resident and recruited macrophages are formed, work and interact. In an ideal scenario, this could accelerate the development of drugs and treatments not only for malaria but also for other diseases.
Institutions involved and funding secured
Alongside the University of Bonn and the Doherty Institute in Melbourne, the study also involved the University of New South Wales (Sydney, Australia), the Gulbenkian Institute for Molecular Medicine (Lisbon, Portugal), the Gustave Roussy Cancer Campus (Villejuif, France), the Shanghai Institute of Immunology (Shanghai, China), the Singapore Immunology Network and the Translational Immunology Institute (both Singapore). The project was funded by the Boehringer Ingelheim Foundation, the ImmunoSensation3 Cluster of Excellence at the University of Bonn, the IRTG 2168 Research Training Group and a Global Fund at the TRA Life and Health.
The University of Bonn—Excellence with Impact
As a leading European university and one of the world's most prestigious academic institutions, we are devising solutions to the global challenges of the 21st century. From our home in Bonn—Germany's city of the United Nations—we bring together top-level research, excellent teaching and an unshakable commitment to diversity. We promote talented individuals at all stages of their careers, inspire the next generation of leaders and generate knowledge that is accelerating progress in society and technology.
About the Peter Doherty Institute for Infection and Immunity
Finding solutions to prevent, treat and cure infectious diseases and understanding the complexities of the immune system requires innovative approaches and concentrated effort. This is why The University of Melbourne – a world leader in education, teaching and research excellence – and The Royal Melbourne Hospital – an internationally renowned institution providing outstanding care, treatment and medical research – have partnered to create the Peter Doherty Institute for Infection and Immunity (Doherty Institute); a centre of excellence where leading scientists and clinicians collaborate to improve human health globally.
doherty.edu.au
