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Cold Spring Harbor Perspectives in... Jan 2018In the mosquito-human life cycle, the six species of malaria parasites infecting humans (, , , , , and ) undergo 10 or more morphological states, replicate from single... (Review)
Review
In the mosquito-human life cycle, the six species of malaria parasites infecting humans (, , , , , and ) undergo 10 or more morphological states, replicate from single to 10,000+ cells, and vary in total population from one to many more than 10 organisms. In the human host, only a small number of these morphological stages lead to clinical disease and the vast majority of all malaria-infected patients in the world produce few (if any) symptoms in the human. Human clinical disease (e.g., fever, anemia, coma) is the result of the parasite preprogrammed biology in concert with the human pathophysiological response. Caveats and corollaries that add variation to this host-parasite interaction include parasite genetic diversity of key proteins, coinfections, comorbidities, delays in treatment, human polymorphisms, and environmental determinants.
Topics: Female; Humans; Malaria; Malaria, Cerebral; Placenta; Plasmodium; Pregnancy; Species Specificity; Virulence Factors
PubMed: 28533315
DOI: 10.1101/cshperspect.a025569 -
Frontiers in Cellular and Infection... 2022Cerebral malaria (CM) caused by is a fatal neurological complication of malaria, resulting in coma and death, and even survivors may suffer long-term neurological... (Review)
Review
Cerebral malaria (CM) caused by is a fatal neurological complication of malaria, resulting in coma and death, and even survivors may suffer long-term neurological sequelae. In sub-Saharan Africa, CM occurs mainly in children under five years of age. Although intravenous artesunate is considered the preferred treatment for CM, the clinical efficacy is still far from satisfactory. The neurological damage induced by CM is irreversible and lethal, and it is therefore of great significance to unravel the exact etiology of CM, which may be beneficial for the effective management of this severe disease. Here, we review the clinical characteristics, pathogenesis, diagnosis, and clinical therapy of CM, with the aim of providing insights into the development of novel tools for improved CM treatments.
Topics: Child; Child, Preschool; Humans; Malaria, Cerebral; Malaria, Falciparum; Plasmodium falciparum
PubMed: 35959375
DOI: 10.3389/fcimb.2022.939532 -
Current Neurology and Neuroscience... Aug 2022To discuss the neurological complications and pathophysiology of organ damage following malaria infection. (Review)
Review
PURPOSE OF REVIEW
To discuss the neurological complications and pathophysiology of organ damage following malaria infection.
RECENT FINDINGS
The principal advancement made in malaria research has been a better understanding of the pathogenesis of cerebral malaria (CM), the most dreaded neurological complication generally caused by Plasmodium falciparum infection. However, no definitive treatment has yet been evolved other than the use of antimalarial drugs and supportive care. The development of severe cerebral edema in CM results from two distinct pathophysiologic mechanisms. First, the development of "sticky" red blood cells (RBCs) leads to cytoadherence, where red blood cells (RBCs) get stuck to the endothelial walls and between themselves, resulting in clogging of the brain microvasculature with resultant hypoxemia and cerebral edema. In addition, the P. falciparum-infected erythrocyte membrane protein 1 (PfEMP1) molecules protrude from the raised knob structures on the RBCs walls and are in themselves made of a combination of human and parasite proteins in a tight complex. Antibodies to surfins, rifins, and stevors from the parasite are also located in the RBC membrane. On the human microvascular side, a range of molecules involved in host-parasite interactions, including CD36 and intracellular adhesion molecule 1, is activated during interaction with other molecules such as endothelial protein C receptor and thrombospondin. As a result, an inflammatory response occurs with the dysregulated release of cytokines (TNF, interleukins 1 and 10) which damage the blood-brain barrier (BBB), causing plasma leakage and brain edema. This second mechanism of CNS injury often involves multiple organs in adult patients in endemic areas but remains localized only to the central nervous system (CNS) among African children. Neurological sequelae may follow both P. falciparum and P. vivax infections. The major brain pathology of CM is brain edema with diffuse brain swelling resulting from the combined effects of reduced perfusion and hypoxemia of cerebral neurons due to blockage of the microvasculature by parasitized RBCs as well as the neurotoxic effect of released cytokines from a hyper-acute immune host reaction. A plethora of additional neurological manifestations have been associated with malaria, including posterior reversible encephalopathy syndrome (PRES), reversible cerebral vasoconstriction syndrome (RCVS), malarial retinopathy, post-malarial neurological syndrome (PMNS), acute disseminated encephalomyelitis (ADEM), Guillain-Barré syndrome (GBS), and cerebellar ataxia. Lastly, the impact of the COVID-19 pandemic on worldwide malaria control programs and the possible threat from co-infections is briefly discussed.
Topics: Adult; Brain Edema; COVID-19; Child; Cytokines; Humans; Hypoxia; Malaria, Cerebral; Malaria, Falciparum; Pandemics; Plasmodium falciparum; Posterior Leukoencephalopathy Syndrome
PubMed: 35699901
DOI: 10.1007/s11910-022-01214-6 -
Frontiers in Immunology 2022This review focuses on current clinical and immunological aspects of cerebral malaria induced by infection. Albeit many issues concerning the inflammatory responses... (Review)
Review
This review focuses on current clinical and immunological aspects of cerebral malaria induced by infection. Albeit many issues concerning the inflammatory responses remain unresolved and need further investigations, current knowledge of the underlying molecular mechanisms is highlighted. Furthermore, and in the light of significant limitations in preventative diagnosis and treatment of cerebral malaria, this review mainly discusses our understanding of immune mechanisms in the light of the most recent research findings. Remarkably, the newly proposed CD8+ T cell-driven pathophysiological aspects within the central nervous system are summarized, giving first rational insights into encouraging studies with immune-modulating adjunctive therapies that protect from symptomatic cerebral participation of infection.
Topics: CD8-Positive T-Lymphocytes; Humans; Malaria, Cerebral; Malaria, Falciparum; Plasmodium falciparum
PubMed: 35514965
DOI: 10.3389/fimmu.2022.863568 -
Journal of Neurology, Neurosurgery, and... Oct 2000Cerebral malaria may be the most common non-traumatic encephalopathy in the world. The pathogenesis is heterogeneous and the neurological complications are often part of... (Review)
Review
Cerebral malaria may be the most common non-traumatic encephalopathy in the world. The pathogenesis is heterogeneous and the neurological complications are often part of a multisystem dysfunction. The clinical presentation and pathophysiology differs between adults and children. Recent studies have elucidated the molecular mechanisms of pathogenesis and raised possible interventions. Antimalarial drugs, however, remain the only intervention that unequivocally affects outcome, although increasing resistance to the established antimalarial drugs is of grave concern. Artemisinin derivatives have made an impact on treatment, but other drugs may be required. With appropriate antimalarial drugs, the prognosis of cerebral malaria often depends on the management of other complications-for example, renal failure and acidosis. Neurological sequelae are increasingly recognised, but further research on the pathogenesis of coma and neurological damage is required to develop other ancillary treatments.
Topics: Adult; Child; Humans; Malaria, Cerebral
PubMed: 10990500
DOI: 10.1136/jnnp.69.4.433 -
Frontiers in Cellular and Infection... 2017Cerebral malaria is among the major causes of malaria-associated mortality and effective adjunctive therapeutic strategies are currently lacking. Central... (Review)
Review
Cerebral malaria is among the major causes of malaria-associated mortality and effective adjunctive therapeutic strategies are currently lacking. Central pathophysiological processes involved in the development of cerebral malaria include an imbalance of pro- and anti-inflammatory responses to infection, endothelial cell activation, and loss of blood-brain barrier integrity. However, the sequence of events, which initiates these pathophysiological processes as well as the contribution of their complex interplay to the development of cerebral malaria remain incompletely understood. Several cytokines and chemokines have repeatedly been associated with cerebral malaria severity. Increased levels of these inflammatory mediators could account for the sequestration of leukocytes in the cerebral microvasculature present during cerebral malaria, thereby contributing to an amplification of local inflammation and promoting cerebral malaria pathogenesis. Herein, we highlight the current knowledge on the contribution of cytokines and chemokines to the pathogenesis of cerebral malaria with particular emphasis on their roles in endothelial activation and leukocyte recruitment, as well as their implication in the progression to blood-brain barrier permeability and neuroinflammation, in both human cerebral malaria and in the murine experimental cerebral malaria model. A better molecular understanding of these processes could provide the basis for evidence-based development of adjunct therapies and the definition of diagnostic markers of disease progression.
Topics: Animals; Blood-Brain Barrier; Cytokines; Disease Models, Animal; Endothelial Cells; Host-Pathogen Interactions; Leukocytes; Malaria, Cerebral; Mice; Permeability; Plasmodium
PubMed: 28775960
DOI: 10.3389/fcimb.2017.00324 -
Frontiers in Cellular and Infection... 2014There are two theories that seek to explain the pathogenesis of cerebral malaria, the mechanical obstruction hypothesis and the immunopathology hypothesis. Evidence... (Review)
Review
There are two theories that seek to explain the pathogenesis of cerebral malaria, the mechanical obstruction hypothesis and the immunopathology hypothesis. Evidence consistent with both ideas has accumulated from studies of the human disease and experimental models. Thus, some combination of these concepts seems necessary to explain the very complex pattern of changes seen in cerebral malaria. The interactions between malaria parasites, erythrocytes, the cerebral microvascular endothelium, brain parenchymal cells, platelets and microparticles need to be considered. One factor that seems able to knit together much of this complexity is the cytokine interferon-gamma (IFN-γ). In this review we consider findings from the clinical disease, in vitro models and the murine counterpart of human cerebral malaria in order to evaluate the roles played by IFN-γ in the pathogenesis of this often fatal and debilitating condition.
Topics: Animals; Disease Models, Animal; Endothelial Cells; Humans; Interferon-gamma; Malaria, Cerebral; Signal Transduction
PubMed: 25177551
DOI: 10.3389/fcimb.2014.00113 -
Brain Pathology (Zurich, Switzerland) Jan 1997Malaria infection of the Central Nervous System (CNS) can cause a severe neurological syndrome termed Cerebral Malaria (CM). The central neuropathological feature of CM... (Review)
Review
Malaria infection of the Central Nervous System (CNS) can cause a severe neurological syndrome termed Cerebral Malaria (CM). The central neuropathological feature of CM is the preferential sequestration of parasitised red blood cells (PRBC) in the cerebral microvasculature. The level of sequestration is related to the incidence of cerebral symptoms in severe malaria. Other neuropathological features of CM include petechial hemorrhages in the brain parenchyma, ring hemorrhages and Dürck's granuloma's. Immunohisto-chemical and electron microscopy studies have shown widespread cerebral endothelial cell activation and morphological changes occur in CM, as well as focal endothelial cell damage and necrosis. The immune cell response to intravascular sequestration appears to be limited, although activation of pigment-phagocytosing monocytes is a late feature. The mechanisms by which PRBC cause coma in malaria remain unclear. In vitro parasitised erythrocytes bind to endothelial cells by specific, receptor mediated interactions with host adhesion molecules such as ICAM-1, whose expression on cerebral endothelial cells is increased during CM as part of a systemic endothelial activation. Induction of local neuro-active mediators such as nitric oxide and systemic cytokines like TNF alpha may be responsible for the rapidly reversible symptoms of the coma of CM. The recent cloning of the parasite ligand PfEMP-1, thought to mediate binding to host sequestration receptors, promises further insight into the relationship between patterns of sequestration and the incidence and pathogenesis of coma in cerebral malaria.
Topics: Brain; Brain Edema; Cell Count; Cerebral Hemorrhage; Humans; Ischemic Attack, Transient; Malaria, Cerebral; Neurons; Syndrome
PubMed: 9034566
DOI: 10.1111/j.1750-3639.1997.tb01075.x -
Malaria Journal Jul 2020Cerebral malaria (CM), results from Plasmodium falciparum infection, and has a high mortality rate. CM survivors can retain life-long post CM sequelae, including... (Review)
Review
Cerebral malaria (CM), results from Plasmodium falciparum infection, and has a high mortality rate. CM survivors can retain life-long post CM sequelae, including seizures and neurocognitive deficits profoundly affecting their quality of life. As the Plasmodium parasite does not enter the brain, but resides inside erythrocytes and are confined to the lumen of the brain's vasculature, the neuropathogenesis leading to these neurologic sequelae is unclear and under-investigated. Interestingly, postmortem CM pathology differs in brain regions, such as the appearance of haemorragic punctae in white versus gray matter. Various host and parasite factors contribute to the risk of CM, including exposure at a young age, parasite- and host-related genetics, parasite sequestration and the extent of host inflammatory responses. Thus far, several proposed adjunctive treatments have not been successful in the treatment of CM but are highly needed. The region-specific CM neuro-pathogenesis leading to neurologic sequelae is intriguing, but not sufficiently addressed in research. More attention to this may lead to the development of effective adjunctive treatments to address CM neurologic sequelae.
Topics: Erythrocytes; Humans; Malaria, Cerebral; Malaria, Falciparum; Plasmodium falciparum; Quality of Life
PubMed: 32703204
DOI: 10.1186/s12936-020-03336-z -
Nature Communications Jul 2022Heme-biosynthetic pathway of malaria parasite is dispensable for asexual stages, but essential for mosquito and liver stages. Despite having backup mechanisms to acquire...
Heme-biosynthetic pathway of malaria parasite is dispensable for asexual stages, but essential for mosquito and liver stages. Despite having backup mechanisms to acquire hemoglobin-heme, pathway intermediates and/or enzymes from the host, asexual parasites express heme pathway enzymes and synthesize heme. Here we show heme synthesized in asexual stages promotes cerebral pathogenesis by enhancing hemozoin formation. Hemozoin is a parasite molecule associated with inflammation, aberrant host-immune responses, disease severity and cerebral pathogenesis. The heme pathway knockout parasites synthesize less hemozoin, and mice infected with knockout parasites are protected from cerebral malaria and death due to anemia is delayed. Biosynthetic heme regulates food vacuole integrity and the food vacuoles from knockout parasites are compromised in pH, lipid unsaturation and proteins, essential for hemozoin formation. Targeting parasite heme synthesis by griseofulvin-a FDA-approved antifungal drug, prevents cerebral malaria in mice and provides an adjunct therapeutic option for cerebral and severe malaria.
Topics: Animals; Griseofulvin; Heme; Hemoglobins; Malaria, Cerebral; Mice; Parasites
PubMed: 35821013
DOI: 10.1038/s41467-022-31431-z