Fig 1.
Variation in O2 concentration exists across and within organs of the human body.
(a) Organ-level O2 values under physiological conditions, adapted from mean and median values reported in 4 comprehensive review articles on this topic: Jagganathan et al. [7], Ortiz-Prado et al. [8], Swartz et al. [9], and Gan and Ooi [85]. Shading is indicative of level of O2 concentration, with darker shading indicating higher O2 and lighter shading indicating lower O2. (b) Placental intervillous space O2 concentration in the location where parasite sequestration takes place during placental malaria. (c) O2 gradient in the layers of the gut, as discussed in Schwerdtfeger et al. [19]. In all panels, O2 concentrations are shown as both percentages and mm Hg and were calculated using the atmospheric partial pressure of O2 equation following Dalton’s Law in Ortiz-Prado et al. [8], which is as follows: AtmPO2 = FiO2 (fraction of inspired O2) × 760 mm Hg or AtmPO2 / 760 mm Hg × 100 = %O2.
Fig 2.
Variation in the structure and biochemical pathway activity of Plasmodium’s mitochondrion exists between asexual and sexual blood stages.
Mitochondrial internal structure, glycolysis, mETC, and OXPHOS capacity variation between the (a) asexual blood stage and (b) the gametocyte stage. mETC, mitochondrial electron transport chain; OXPHOS, oxidative phosphorylation; TCA, tricarboxylic acid.
Fig 3.
Sources of reactive oxygen species (ROS) during malarial infection.
ROS generation resulting from parasites infecting RBCs and from RBC lysis (left panel, a-c) and ROS generation resulting from parasite sequestration in deep tissue and from hypoxia (top right panel, d and e). (a) P. falciparum metabolizes hemoglobin inside the RBC and converts heme to hemozoin for detoxification. Excess heme iron that escapes the conversion into hemozoin can promote production of the hydroxyl radical (·OH) inside the parasitized RBC. (b) Free heme is released into the blood plasma during the parasite-mediated lysis of RBC, where it induces ROS in a variety of cell types across the body. (c) Extracellular methemoglobin which is in the plasma of individuals with severe malaria can induce oxidative stress within uninfected RBCs causing them to externalize phosphatidylserine and aggregate. (d) Mitochondria experience changes in tissue oxygenation, resulting in ROS production. (e) Ischemia-reperfusion syndrome, which occurs as a response to reoxygenation following tissue ischemia, may lead to localized production of ROS. (f) Immune cells that have phagocytized infected RBC producing ROS as part of the oxidative burst response.
Table 1.
Compilation of studies where different O2 concentrations were tested on parasite growth.
Fig 4.
Pieces of the puzzle: possible mechanistic connections between O2 tension and P. falciparum asexual blood stage growth rate variation.
(a) Mammalian cells and other apicomplexans such as Toxoplasma perform O2 sensing through HIFs and PHDs. While Plasmodium has a putative PHD B group gene, it is not known whether the O2-sensing function is active in Plasmodium. (b) P. falciparum exhibits plasticity in energy production across its hosts, relying primarily on glucose and glycolysis in the human host but requiring O2 and mitochondrial oxidative phosphorylation in the mosquito. Whether plasticity exists within the human host but between tissue sites with varying levels of O2 and/or glucose is unknown. (c) There are numerous sources of oxidative stress during a malaria infection including release of free heme during RBC lysis, auto-oxidation of hemoglobin, immune cell induced ROS production during oxidative burst, among others. ROS production is influenced by O2 availability and oxidative stress can impact Plasmodium intraerythrocytic development. (d) Finally, given that hemoglobin is a major source of nutrients for Plasmodium, the oxygenation state of hemoglobin could impact Plasmodium’s digestion and growth. Methemoglobin, a form of hemoglobin that cannot bind O2 and forms in conditions of oxidative stress, has been shown to bind to falcipain-2 at a higher affinity than oxidized hemoglobin, potentially leading to impacts in digestion and growth rate. HIF, hypoxia induction factor; PHD, prolyl hydroxylase; RBC, red blood cell; ROS, reactive oxygen species.