Basophilic polychromatic erythroblasts give rise to orthochromatic erythroblasts, which expel their nuclei to generate reticulocytes. The well-coordinated mechanism is characterized by a decreased cell size, more condensed chromatin material, progressive hemoglobinization and marked membrane organizational alterations. The role of various cytokines and chemokines in the regulation of erythropoiesis is revealed by the intimate interaction of the myeloid progenitors, macrophages and erythroblasts during RBC's production.
The erythroid hyperplasia seen in SMA excludes erythropoietin deficiency as a cause of inadequate erythropoiesis of malaria intimating that the aberrant inflammatory response mounted by the cytokine milieu as the culprit.
Associated with the hypercytokinemia is the ingestion by neutrophils, monocytes and macrophages of the inflammatory mediator hemozoin Hz, a parasite-derived polymerized heme , which is known to influence the dysregulation of inflammatory responses through synthesis of a number of cytokines with subsequent induction of SMA [ 32 ]. The engulfing of Pf Hz is a good indirect measure of sequestered parasite burden, recent schizogony, disease severity, decreased hematocrit and degree of erythropoiesis suppression in children with P.
Over-production of the innate inflammatory mediators is associated with anemia, and it has been observed that persistent macrophage activation is significantly greater in children with malarial complications through BM suppression, dyserthropoiesis and erythrophagocytosis [ 45 ].
One of the cytokines, IL-6, has been demonstrated to be increased in malaria with peripheral blood mononuclear cells PBMC being the source of the increased cytokine production during acute malaria [ 50 ]. During the erythrocytic stage, IL-6 controls parasitemia through boosting up specific immunoglobulin Ig G antibodies.
However, lack of control over parasitemia and the resulting progression toward severe disease may explain the association between elevated levels of IL-6 and enhanced pathophysiology [ 27 ]. Macrophage migration inhibitory factor MIF is a ubiquitous molecule produced by T cells, monocytes-macrophages and the anterior pituitary in response to pro-inflammatory stimuli [ 27 ].
Notably, there is a rapid mobilization and expression of large concentrations of MIF during acute inflammation as the cytokine is stored in preformed vesicles only to be released without de novo gene expression.
The pro-inflammatory properties of MIF are important for both innate and adaptive immune response in both parasitic and bacterial infections [ 27 , 51 ]. In animal models, elevated MIF concentrations have strong connexion with SMA while mice with MIF knockout gene have less anemia and higher survival chances when infected with Plasmodium chabaudi compared with the wild type [ 52 ].
Remarkably, MIF concentration in peripheral blood was not significantly inter-related to reticulocyte responses in these children. Correction for age, gender and parasitemia, however, did show that elevated levels of monocyte chemotactic protein [MCP] were significantly associated with both SMA and decreased MIF production.
Consequently, Pf Hz presence in malaria suppresses peripheral blood MIF production, thus enhancing severity of anemia. The intricacy by which Pf Hz is involved in the malarial parasite life cycle makes it the central molecule to SMA development and other malarial pathophysiologies. Therefore, Pf Hz as a heme metabolism waste product deliberately synthesized by the parasite may be regarded as a long-term strategy for its survival.
Interleukin 23 is another pro-inflammatory mediator involved in conditioning the SMA pathogenesis, which is also important in mediating anemia development in autoimmune diseases [ 54 ] and chronic inflammation [ 55 ]. The subunits making up IL are designated p19 and p40, and this cytokine shares a number of common properties with IL In cultured PBMC, hemozoin induces sustained ILp19 transcript concentrations for more than 72 h, whereas ILp40 and IL transcripts rapidly decline after reaching peak at 24 h [ 57 ].
Interleukin 12 is a heterodimer protein made up of 35 and 40 kDa subunits, which is a prototypical cytokine of type 1 immune response interfacing inflammation and immunity. The main IL secreting cells include dendritic cells, monocytes and B-cells, which can be activated by bacterial cell wall components, intracellular pathogens and the ligation of CD Reinfection with P.
The protective role of IL in malaria lies in its ability to stimulate antibody production and its ability to act as a hematopoietic growth factor. Low concentrations of IL are associated with SMA through, in part, the influence of Pf Hz phagocytosis that influences upregulation of monocyte-derived IL which in turn suppresses the ILp40 subunits [ 58 ].
Cytokine involvement in SMA induction includes influencing iron trafficking. Moreover, cytokines play a critical role in the maturation of erythroid cells. Interleukin 6 IL-6 induces hepcidin production and expression in the liver, a master regulator of iron trafficking , resulting in decreased iron availability.
This is suggestive of a critical role of these cytokines in SMA. Infection induces IL synthesis which in turn suppresses IL associated with hemozoin Hz acquisition by monocytes [ 58 , 60 ]. By preventing over-production of pro-inflammatory mediators, anti-inflammatory cytokines like IL render protection against SMA development. The later stages of the innate immune response in P. Therefore, timing of the anti-inflammatory response relative to the proinflammatory cytokines activity and concentration has a strong influence on the malarial outcomes.
Statistically significant positive association has been identified between IL in the systemic circulation and malarial pigment containing leucocytes, indicating the regulatory role of Pf Hz in the development of systemic malarial pathology when it upregulated IL production Figure 2. Chemical structure of asiatic acid. Formula C 30 H 48 C 5. MW: Redox characteristics: hydrogen bond donor HBD 7.
Chemokines or chemotactic cytokines play a critical role in immune system activation, hematopoiesis, angiogenesis and antimicrobial activities. There is a much higher concentration of IL-8 in acute malaria that is necessary for the activation of neutrophils in severe nonfatal malaria that may be associated with slow cure rate after malarial chemotherapy.
Chemokine production or suppression signal transduction depends on the phagocytosis of Pf Hz through oxidative stress-dependent and oxidative stress-independent mechanisms [ 65 ].
Growth factors play a pivotal role in the erythropoiesis cascade. A longitudinal study of malaria has shown that serum concentrations of granulocyte-colony stimulating factor G-CSF were elevated at day 0 in complicated malaria followed by a decline to within reference interval on day 7.
Significant correlation of G-CSF with procalcitonin, parasite density and erythropoietin is a common finding at the beginning of malaria [ 69 ]. G-CSF has a negative impact on erythropoiesis, and an increased concentration of the growth factor leads to SMA development.
With high parasite density associated with elevated levels of G-CSF, the increased erythropoietin is a compensatory mechanism to protect against SMA development through a mechanism driven by both hypoxia and oxidative stress common in complicated malaria [ 70 ].
In children with SMA, SCGF tends to be suppressed and positively correlated with Hb concentration, erythropoietic response suppression and high concentrations of naturally acquired monocytic Pf Hz. Genetic polymorphism of the SCGF also tends to protect against SMA development and suppression of erythropoiesis in parasitized children [ 72 ].
Relative expression of inflammatory mediators largely determines the various clinical outcome of malaria. The relative concentrations and timing of release of pro-and anti-inflammatory cytokines, chemokines and growth factors have a direct effect on cellular response as well as on the down-stream effector molecule production.
NO is both protective as it has potent parasiticidal properties limiting parasitemia and pathogenic effects as it sustained high level predispose to anemia through BM suppression, dyserythropoiesis and erythrophagocytosis. ROS appear to be both protective and pathologic in P. Increased concentrations of the free radical have observed to accompany accelerated parasitaemia clearance in Gabonese children as well as controlling of peripheral parasitaemia in children with severe malaria [ 74 ].
Severe malarial cases associated with significantly elevated markers of oxidative stress like high malondialdehyde concentrations, high protein carbonyl, high nitrite, low ascorbic acid and elevated plasma copper concentrations are suspected to have SMA [ 74 ]. Acquisition of intraleukocytic Pf Hz in placental malaria reduces mononuclear cell PGE 2 production [ 75 ]. The only treatment that has been available for SMA has been largely blood transfusion in various forms.
Erythropoietin supplementation has not been successful as most patients with SMA tend to have high concentrations of the hormone amidst a low reticulocyte count indicating a nonresponsive BM. Equally so has been the ferrous iron supplements that have proven to have worse outcomes and had to be prematurely stopped. As has been shown, SMA is a synergistic onslaught from the parasite producing Pf Hz, which is eventually taken up by activated leukocytes and breeds both pro-and anti-inflammatory mediators whose sustained synthesis results in malarial pathophysiology and derangements.
Aiming the treatment at the parasite has been successful, to some extent. However, the continued harangue of the parasite among many populations is a tacit implication that more is required to eradicate or control the malarial pandemic. Aiming malarial treatment at the pathophysiology is an avenue currently being explored with commendable results.
Administration of the phytochemical triterpenes, asiatic acid and other triterpenoids has been shown to have antiparasitic effects and reduction of SMA development in murine malaria.
Addressing the pathophysiology of malaria while eradicating parasitemia seems to provide a provocative approach that encompasses inflammation, immunoreactivity, glucose homeostasis, renal failure and other aspects, which commonly complicates malaria in humans.
Hypothetically, drugs that may inhibit or reverse malarial pathophysiology or the disease components have a higher chance of controlling malaria even without parasite eradication. This may include targeting SMA, which is an independent malarial mortality predictor in pregnant women and children [ 80 ]. The concept of malarial pathophysiology being referred to as malarial disease and its management being denoted as antidisease in malaria is a novel term in malaria handling terminology introduced to differentiate this approach from the antiparasitic treatment [ 80 ].
Triterpenes with antidisease properties in other conditions similar to malaria, like inflammation in sepsis and hypoxia in anemia are able to eradicate the Plasmodium parasite as well as resolve the ensuing pathophysiology. Triterpenes with pleiotropic functions, sufficient to be antidisease as well as antiparasitic, have been reported.
Betulinic acid BA , ursolic acid UA , maslinic acid MA and oleanolic acid [OA] have been shown to have moderate activity in vitro against the chloroquine-insensitive K1 and chloroquine-sensitive T P. MA, a possible multitargeting antimalarial, effectively inhibits proteolytic processing of the malarial merozoite surface protein [MSP1] complex, inhibits the metalloproteases and has several putative binding sites for the parasite antigens [ 81 ].
This multitarget phenomenon suppresses the parasitemia in more than one way. Furthermore, the age-old preoccupation with targeting single process of the parasite infective cycle which is mutation prone is avoided, and host-related responses potentiating antidisease and antiresistance outcomes are involved [ 80 ].
Asiatic acid AA , an amphiphilic triterpene Figure 2 , has known for its antioxidant and pro-oxidant capacity, anti-inflammatory and antinociception activity in mice [ 82 ], calcium release-associated apoptosis induction [ 83 , 84 ] and a potent immunomodulator.
Targeting the pathophysiology of malaria, SMA, as well as the parasite provides new mechanisms for combating malaria.
Noteworthy is that AA is known to attenuate, inhibit or ameliorate the above factors in other diseases, which formulate the bedrock of malarial disease and its sequelae. Immunity against severe malaria is partly antiparasitic and partly antitoxic toxic effects in response to parasite factors [ 85 ].
The majority of the adults in malarial endemic areas have resistance to severe malaria and subsequently to SMA. The induction of innate pro-inflammatory cytokine responses is mediated by germline-encoded pattern-recognition receptors, such as toll-like receptors TLR , which recognize conserved microbial structures, i. While GPI structure is conserved among Plasmodium species, human and Plasmodium GPI differ considerably but provide potential therapeutic points [ 88 ].
Several functionally important parasite proteins, including MSP-1, MSP-2 and MSP-4, are anchored to the cell membranes through GPI moieties and are also abundantly present free of protein attachment in membranes of pathogenic protozoa [ 89 ]. AA modulates immunity by selective induction of mitochondria-dependent apoptosis of activated lymphocytes in the prevention of murine fulminant hepatitis [ 91 ], a mechanism that may be extendable to malaria.
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Fleming AF. Tropical obstetrics and gynaecology. Anaemia in pregnancy in tropical Africa. Download references. Materials and Methods 2. Study Population The study population included children of both sexes aged 1—14 years, who presented themselves at the Regional Hospital Annex-Buea for consultation during the period of study. Study Design This cross-sectional hospital based study was carried out during the peak malaria transmission season from the month of May to August , in the Regional Hospital Annex-Buea.
Clinical Evaluation For each child a general clinical evaluation was carried out by the medical personnel in charge. Questionnaire A structured questionnaire was administered to parent or guardian of the child in order to obtain information on demography, socioeconomic status SES , type of accommodation, health-seeking behaviour, access to health facilities, malaria control measures, knowledge on the signs of anaemia, and feeding practices.
Results 3. Characteristics of Participants The consent of children at presentation to the general outpatient department in the Regional Hospital Annex-Buea was sought for their participation in the study of the burden of malaria, M d SA, and M d SMA. Table 1. Sociodemographic, altitude, and clinical characteristics of the participants by age and sex. Figure 1. Prevalence of malaria parasite as affected by the status of fever, malnutrition, and splenomegaly.
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