Unraveling the implications of red blood cell half-life imbalance and homeostatic autoimmunity in the development of malarial anemia

The number of red blood cells present in the blood at any given moment must be finely regulated to ensure an adequate supply of oxygen to the tissues. This regulation arises from the balance between cell destruction and production. Every second, millions of red blood cells are destroyed in the liver and spleen and are replaced by new cells that are continually formed in the bone marrow. Red blood cell production is regulated by erythropoietin (EPO), a hormone produced in the liver in response to changing oxygen levels in the blood. If these levels drop, the concentration of EPO in the blood increases, which accelerates RBC production in the bone marrow. Regarding their destruction, RBCs lack the intracellular machinery necessary for apoptosis, so they must be eliminated by macrophages residing in the sinusoids of the liver and spleen. These macrophages phagocytose RBCs that have reached a critical age (120 days in humans and 60 in mice). This observation has led to the idea that the lifespan of RBCs is fixed and characteristic of each species. Apparently, the control of RBC production by EPO and this fixed duration are sufficient to explain RBC homeostasis. In fact, the current paradigm relies on these two hypotheses.
By combining experimental work with mathematical modeling, the researchers have shown in previous articles that such a mechanism would be an inefficient solution to the problem of regulating RBC numbers. Effective control requires a variable RBC duration. The team have also shown that the duration is indeed variable and regulated by EPO. The paradigm that emerges from this observation is radically different from the current one, and deepening the understanding of it is the objective of this proposal. This line of research and the paradigm shift it implies are of great interest in a wide variety of research areas, ranging from sports medicine to spaceflight physiology. In this project, the new paradigm will be used to understand the causes of anemia in malaria patients. Anemia is one of the most critical consequences of malaria and is responsible for most deaths caused by this disease. Contrary to what might be expected, anemia is not caused by the destruction of red blood cells by the parasite. Most of the red blood cells that are destroyed are not infected, and the problem persists even after the parasite has been eliminated from the blood. Currently, there is no satisfactory explanation for this paradoxical phenomenon. In this project, it is proposed that anemia is caused by interference by the parasite with the host’s homeostatic mechanisms. Preliminary results point to a malfunction of these mechanisms in the context of infection. This project has a marked interdisciplinary nature, as it is located at the intersection of physiology, immunology, and malaria. Furthermore, its implementation requires a multidisciplinary approach in which data provided by cell biology and physiology are integrated with systems analysis and theoretical and mathematical biology. The intention of this project is to create a new research group focused on understanding how RBC homeostasis is regulated under normal conditions and how its imbalance can cause diseases.

Project details

Basic Science
Immunology
Modeling

Jan 2022

$157,712

Spain