Tissue-specific immunopathology during malaria infection

Abstract

Systemic inflammation mediated by Plasmodium parasites is central to malaria disease and its complications. Plasmodium parasites reside in erythrocytes and can theoretically reach all host tissues via the circulation. However, actual interactions between parasitized erythrocytes and host tissues, along with the consequent damage and pathological changes, are limited locally to specific tissue sites. Such tissue specificity of the parasite can alter the outcome of malaria disease, determining whether acute or chronic complications occur. Here, we give an overview of the recent progress that has been made in understanding tissue-specific immunopathology during Plasmodium infection. As knowledge on tissue-specific host-parasite interactions accumulates, better treatment modalities and targets may emerge for intervention in malaria disease.

Figure 1. Outcomes of Plasmodium infection of red blood cells in the bloodstream.

Following the release of Plasmodium merozoites from infected hepatocytes into the bloodstream, repetitive erythrocyte-invasion cycles occur in the blood. This leads to the release of several parasite by-products, such as haemozoin, and the parasites themselves into the bloodstream. The blood-stage cycle of Plasmodium infection causes various pathologies, such as anaemia, toxic haem release, immune cell activation (modulation of platelets, neutrophils, monocytes, macrophages, T cells and B cells) and can cause a cytokine and chemokine storm. In blood tissue, infected red blood cells (iRBCs) and their products may interact with other infected and uninfected RBCs (causing rosetting), or they may interact with immune cell populations (causing a cytokine storm) or with the endothelial cells of blood vessels (causing RBC sequestration and microhaemorrhage). These cell–cell interactions have organ specificity and thus take place in specific tissue environments, resulting in specific immunopathologies. PowerPoint slide

Figure 2. Interaction of Plasmodium-infected red blood cells with various blood vessels and lymphatics.

a | Infected red blood cells (iRBCs) circulate in blood vessels, which vary in size from large arteries to veins, with blood flow running from arteries, arterioles, capillaries and post-capillary venules (PCVs) to venules and veins, providing controlled blood pressure and velocity in organs. The speed of blood flow is lowest in capillaries and PCVs. In various organs, these capillary beds are mostly near lymphatic vessels, through which interstitial fluid and materials coming from blood vessels drain the lymph nodes and finally return to veins. iRBCs and iRBC-mediated immune responses, therefore, may have profound effects on these smaller vascular beds in each organ. b | Capillaries have only an endothelial cell wall and no smooth muscle; therefore, they are in close contact with iRBCs. c | Two capillaries fuse and form PCVs, which may have some smooth muscle and where leukocyte rolling can occur. d | Capillaries and PCVs in the brain are additionally surrounded by pericytes, astrocyte end-feet and microglia; iRBC-related events in capillaries are sensed immediately. PowerPoint slide

Figure 3. Infected red blood cells in close proximity with brain components.

a | Small arteries on the pial surface of the brain penetrate into the brain parenchyma and further divide into arterioles; these are surrounded by perivascular space (PVS) which is filled with interstitial fluid (ISF) that has drained from the brain parenchyma. Arterioles become capillaries, venules then veins, which finally drain into dural venous sinuses, and each of these areas potentially contain abundant infected red blood cells (iRBCs), as well as lymphocytes such as CD8⁺ T cells. Lymphatic vessels located in the dura carry immune cells and cerebrospinal fluid (CSF) into deep cervical lymph nodes. b | The retina is rich in photoreceptors (cones, bipolar cells and ganglions), nerve cells and complex blood vessels, especially capillary structures surrounded by Müller cells, a retina-specific astrocyte-like cell. The optic nerve serves as a connector between the retinal nervous tissue and the brain, where meningeal membranes, dura lymphatics and CSF cover the optic nerve up to the retina border. This area may contain abundant iRBCs. c | The olfactory bulb is surrounded by meninges of brain dura and arachnoid and pial layers. CSF similarly runs throughout the bulb and reaches the cribriform plate area. Olfactory nerves originate from the nasal mucosa and terminate in the olfactory bulb through the cribriform plate, which is also the route of the blood vessels surrounding the olfactory nerves. These olfactory nerves project any signal for smell to the olfactory bulb and the brain. Inside the olfactory bulb, very dense blood capillaries are oriented in different directions (radially and tangentially), with thin astrocyte end-feet surrounding the vessels, and sense iRBC-related events and secrete several cytokines and/or chemokines including CC-chemokine ligand 21 (CCL21). Blood capillaries easily bleed during cerebral malaria. PCV, post-capillary venule. PowerPoint slide

Figure 4. Infected red blood cells in gut and bone marrow niches.

a | The intestinal tract is made up of several tissue layers. The villous mucosa is covered by mucus that is secreted by the goblet cells of the epithelium. It lies on a connective tissue, the lamina propria, which is an environment rich in blood vessels, lymphatics, nerves and immune cells. It also contains Peyer's patches and is lined by smooth muscle tissue (muscularis mucosa). Blood capillaries that are carrying infected red blood cells (iRBCs) reach the lamina propria of the intestinal tract and can come into close proximity with lacteals at this location. b | Bone tissue supports the whole body and is home to bone cells, blood vessels, nerves and endothelium, as well as containing the bone marrow niches. The bone marrow is composed of haematopoetic and mesenchymal stem cells that are involved in both haematopoiesis and bone remodelling, such as osteoclasts and osteoblasts. Cells and iRBCs pass through the circulation and bone marrow via specialized venules called bone marrow sinusoids. Plasmodium parasites can invade erythroblasts, the erythrocyte precursors, and preferentially form gametocytes in the bone marrow erythroblastic niche. Released Plasmodium products including haemozoin can be engulfed by osteoclasts and activate osteoblasts and osteoclast precursors. HSC, haematopoietic stem cell; MSC, mesenchymal stem cell; OSB, osteoblast. PowerPoint slide