Materiały źródłowe

• #1 Malaria Pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5749143/

  In the mosquitohuman life cycle, the six species of malaria parasites infecting humans (Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale wallickeri, Plasmodium ovale curtisi, Plasmodium malariae, and Plasmodium knowlesi) undergo 10 or more morphological states, replicate from single to 10,000+ cells, and vary in total population from one to many more than 106 organisms. […] Human clinical disease (e.g., fever, anemia, coma) is the result of the parasite preprogrammed biology in concert with the human pathophysiological response. […] Pathogenesis, the manner of development of a disease, for a human malaria clinical illness is a complex story that has many players, settings, and potential outcomes. […] Human clinical disease is, thus, the result of the interaction of the parasite preprogrammed biology in concert with the human pathophysiological response.

• #1 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Malaria-Mechanism.aspx

  Malaria is caused by the transmission of the malaria parasite Plasmodium to humans by the bites of female Anopheles mosquitoes. […] Once within the humans, the malaria parasite undergoes two phases – an exoerythrocytic and an erythrocytic phase. […] The exoerythrocytic phase involves the maturation and development of the parasite in the liver. When an infected mosquito transmits the infection or sporozoites as it takes in a blood meal the sporozoites in the mosquito’s saliva enter the bloodstream and migrate to the liver. […] The parasite then forms thousands of merozoites within the hepatocytes. The numerous merozoites lead to the rupture of their host cells and escape into the blood. […] The involvement of the red blood cells is called the erythrocytic phase. In the RBCs the merozoites multiply further asexually and burst the RBCs as they multiply releasing the merozoites in blood. Each burst is associated with a bout of fever.

• #1 Malaria: Practice Essentials, Background, Etiology

  https://emedicine.medscape.com/article/221134-overview

  Malaria Pathogenesis […] Despite the many morphologies of the parasite in its life cycle, only a few stages cause clinical disease in humans, the most severe of which are typically P falciparum and P vivax. The initial schizont broods rupture out of the liver phase, release thousands of merozoites into the bloodstream, and attempt to establish periodicity within the erythrocytic phase (time periods vary per species) where level of parasitemia increases exponentially. […] Once the parasite concentration is high enough, a fever is mounted (pyrogenic threshold). This pyrogenic threshold may be anywhere from 0.05 to 1.25 parasites/1,000 red blood cells (0.005 – 0.125% parasitemia) immune patients may require 0.2% parasitemia to experience fever. The most theorized mechanism for the cyclic fevers is the human immune response to the hemozoin (waste product generated from Plasmodiums diet of hemoglobin) that bursts into the bloodstream during each cycle of asexual erythrocytic schizogony. Hemozoin is known to be a Plasmodium pathogen associated molecular pattern (PAMP) recognized by toll-like receptors (TLRs) that induces intense immune response. Other malarial toxins such as malaria glycophosphatidylinositol (GPI) likely are culpable through similar mechanisms. The temperature fluctuation with the human febrile response is expected to play a role in guiding the broods of parasites toward the classic paroxysmal fever-associated periodicity of schizont rupture. […] Severe malaria-associated anemia typically is seen in the young in areas of the world with poor health infrastructure and diets poor in essential vitamins. Schizont rupture from erythrocytes is an obvious mechanism of anemia; however, the more profound loss of red blood cell mass is seen in the population of uninfected erythrocytes. Their decline is thought to occur via oxidative damage of the erythrocyte membranes, eventually leading to hemolysis. Another mechanism of anemia lies within bone marrow; both insufficient production and function of erythropoietin as well as possible apoptosis induction of erythrocyte precursors lead to dyserythropoiesis. […] During acute malaria infection, the spleen serves as the main driver of infected erythrocyte clearance, immune cell activation, and extramedullary hematopoiesis. The extraordinary burden on the spleen causes the red pulp to become congested with infected and uninfected red blood cells, but splenomegaly also occurs by massive cellular expansion in both the red and white pulp. Impressively, the organ is able to revert back to a normal size after clearance of the infection (at least in mice). Because of P vivax tropism for reticulocytes (prevalent in the spleen), splenic rupture is a characteristic severe complication of P vivax, and there is evidence to suggest a separate splenic life cycle for this species. […] End-organ damage from microvascular sequestration, respiratory depression, and production of Plasmodium lactate dehydrogenase (pLDH) by the malaria parasite all lower the pH of the blood. […] Cytoadherence with thrombi formation in glomeruli is a common mechanism of acute kidney injury. If anuria or hemoglobinuria (blackwater fever) occur, it likely is secondary to an abundance of cell-free hemoglobin that results in reduced renal perfusion. Although contributing to morbidity of the acute illness, most patients do not require long-term dialysis. […] After infecting a red blood cell, P falciparum can insert adhesive proteins into the erythrocyte membrane, thus creating a cytoadherant phenotype. The ability to stick to endothelium, uninfected blood cells, and platelets causes more than 20% of brain capillaries to be filled with P falciparum parasites, resulting in vascular congestion, retinopathy, capillary leakage, thrombi, hemorrhage, axonal injury, coma, and death from cerebral malaria within 48 hours (especially in children). […] Occurring with highest incidence in Africa secondary to P falciparum due to its ability to form the cytoadherent phenotype, placental malaria is characterized by the accumulation of infected red blood cells within the intervillous space and ensuing infiltration of maternal macrophages. In severe cases, the resulting chronic intravillositis leads to decreased transplacental nutrient transport, fetal growth restriction and low birth weight babies, as well as increased risk for preterm birth and preeclampsia for the mother.

• #1 Malaria Mechanism Revealed | BNL Newsroom

  https://www.bnl.gov/newsroom/news.php?a=110354

  Malaria Mechanism Revealed […] By determining the molecular structure of a protein that enables malaria parasites to invade red blood cells, researchers have uncovered valuable clues for rational antimalarial drug design and vaccine development. […] A major pathway through which malaria parasites invade red blood cells is the binding of a protein on the surface of merozoites called EBA-175 to a receptor protein on the surface of red blood cells called glycophorin A. […] Thus, the binding of EBA-175 to glycophorin A is a prominent target for the development of therapies to control malaria. […] To explore the molecular basis of the binding of EBA-175 to glycophorin A-with the rationale that such information might reveal strategies for preventing and treating malaria-the researchers used x-ray crystallography to determine the atomic structure of a key portion of the EBA-175 protein called the RII domain.

• #1 The pathogenesis of malaria: a new perspective

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4003589/

  With 3.3 billion people at risk of infection, malaria remains one of the worlds most significant health problems. […] Increasing resistance of the main causative parasite to currently available drugs has created an urgent need to elucidate the pathogenesis of the disease in order to develop new treatments. […] The hypothesis proposed is that the parasites emerge from the liver packed with vitamin A and use retinoic acid (RA), the main biologically active metabolite of vitamin A, as a cell membrane destabilizer to invade the RBCs throughout the body. […] The characteristic hemolysis and anemia of malaria and other symptoms of the disease may thus be manifestations of an endogenous form of vitamin A intoxication associated with high concentrations of RA but low concentrations of retinol (ROL).

• #1 New discovery unravels malaria invasion mechanism | ScienceDaily

  https://www.sciencedaily.com/releases/2024/04/240403130556.htm

  A recent breakthrough sheds light on how the malaria parasite, Plasmodium falciparum, invades human red blood cells. […] The study reveals the role of a sugar called sialic acid in this invasion process. […] P. falciparum is known to invade human red blood cells, but the precise details of the targets that the parasite binds to has not been known to date. […] Although we know that the malaria protein, cystein-rich protective antigen (CyRPA), is essential for the invasion of red blood cells, its precise role in this process was not understood. […] The researchers discovered that a sugar called sialic acid is a key component of the red blood cell surface that is recognized by the malaria parasite, and which is essential for the invasion process. […] The CyRPA protein is highly adapted to bind to a glycan terminating with a sialic acid.

• #1 Pathogenesis of malaria – UpToDate

  https://www.uptodate.com/contents/pathogenesis-of-malaria

  Pathogenesis of malaria requires investigation of mechanisms including parasite invasion, parasite biology, and host defense. […] Pathogenesis of Plasmodium falciparum is the area of greatest study, since this species causes the most severe clinical disease. […] Issues related to the pathogenesis of malaria will be reviewed here. […] The intracellular parasites modify the erythrocyte in several ways. […] Parasites reduce red cell membrane deformability, resulting in hemolysis and accelerated splenic clearance, which may contribute to anemia. […] Alterations to uninfected red blood cells, such as the addition of P. falciparum glycosylphosphatidylinositol (GPI) to the membrane, may play a role in increased clearance of uninfected cells and contribute to anemia.

• #1 Pathogenesis of malaria – UpToDate

  https://www.uptodate.com/contents/pathogenesis-of-malaria/print

  Understanding the pathogenesis of malaria requires investigation of mechanisms including parasite invasion, parasite biology, and host defense. […] Pathogenesis of Plasmodium falciparum is the area of greatest study, since this species causes the most severe clinical disease. […] Life cycle — Human malaria occurs by transmission of Plasmodium sporozoites via a bite from an infected female anopheline mosquito. […] The intracellular parasites modify the erythrocyte in several ways. […] They derive energy from anaerobic glycolysis of glucose to lactic acid, which may contribute to clinical manifestations of hypoglycemia and lactic acidosis. […] Parasites reduce red cell membrane deformability, resulting in hemolysis and accelerated splenic clearance, which may contribute to anemia. […] Alterations to uninfected red blood cells, such as the addition of P. falciparum glycosylphosphatidylinositol (GPI) to the membrane, may play a role in increased clearance of uninfected cells and contribute to anemia.

• #1 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Malaria-Mechanism.aspx

  Plasmodium parasites exist in various forms within the liver and blood but manage to escape the immune system. This is because in most of its forms it resides within the liver and blood cells and is relatively invisible to immune surveillance. […] Infected RBCs especially those with Plasmodium falciparum escape this destruction by developing adhesive proteins on the surface of the infected blood cells, causing the blood cells to stick to the walls of small blood vessels. This leads to sequestering the parasite from passage through the general circulation and the spleen. […] These proteins are also thought to be the cause of complications caused by this type of malaria parasite. They are called PfEMP1, for Plasmodium falciparum erythrocyte membrane protein 1 and have a variety and diversity and thus cannot be targeted by the antibodies formed in the body.

• #1 Genetics of cerebral malaria: pathogenesis, biomarkers and emerging therapeutic interventions | Cell & Bioscience | Full Text

  https://cellandbioscience.biomedcentral.com/articles/10.1186/s13578-022-00830-6

  It is best described by parasite sequestration, which results in PRBC engorgement of cerebral capillaries and post-capillary venules, triggering an inflammatory cytokine response and vascular leakage. […] The host receptor Plasmodium falciparum erythrocyte membrane protein 1-Domain cassette 8 (PfEMP1-DC8) has been discovered as an endothelial cell protein C receptor (EPCR) on brain endothelial cells which interact with PRBC, as well as intercellular adhesion molecule-1 (ICAM-1), which has been demonstrated to be associated with CM development. […] This indicates a key role in the localized pathophysiology of coagulation/inflammation in CM. […] The PfEMP-1 encodes together with the var gene and communicates with numerous host receptors, for example, ICAM-1, EPCR, CD36 etc., depending on which var gene is expressed.

• #1 Malaria – Wikipedia

  https://en.wikipedia.org/wiki/Malaria

  Malaria infection develops via two phases: one that involves the liver (exoerythrocytic phase), and one that involves red blood cells, or erythrocytes (erythrocytic phase). […] The parasites multiply asexually within red blood cells, periodically breaking out to infect new ones. This repeated cycle results in synchronized waves of merozoites escaping and invading red blood cells, which cause the characteristic fever patterns. […] Many of the symptoms associated with severe malaria are caused by the tendency of P. falciparum to bind to blood vessel walls, resulting in damage to the affected vessels and surrounding tissue. […] The blockage of the microvasculature causes symptoms such as those in placental malaria. […] Sequestered red blood cells can breach the blood-brain barrier and cause cerebral malaria.

• #1 Immunological processes in malaria pathogenesis | Nature Reviews Immunology

  https://www.nature.com/articles/nri1686

  Both innate and adaptive immune mechanisms that are elicited during malaria can prevent or cause disease and fatalities. […] Common themes in malaria pathogenesis, however, include the specific properties of parasitized red blood cells, the local and systemic action of bioactive toxins, and inappropriate inflammatory cascades initiated in target organs. […] The cerebral-malaria and severe-malarial-anaemia syndromes, in particular, seem to involve dysregulation of immune responses. […] We review the molecules that are involved in recognition of the parasite by the host and the cell-cell interactions that occur during the host immune response that might underlie pathogenesis. […] The contribution of immune mechanisms to fatalities from malaria has implications for vaccine design. […] This Review article addresses the innate and adaptive immune mechanisms elicited during malaria that either cause or prevent disease and fatalities, and it considers the implications for vaccine design.

• #1 Pathology of Malaria | IntechOpen

  https://www.intechopen.com/chapters/86437

  The released merozoites infect other healthy red cells in the circulation. […] Intravascular hemolysis results in worsening anemia requiring immediate treatment and transfusion in a patient with very low hemoglobin levels (5 g/dL). […] The intravascular hemolysis results in the production of hemoglobin that causes the urine to change and appear as dark colored in the patient. […] The released products and toxic substances in ruptured red cells cause the body to release cytokines such as tumor necrosis factor (TNF) which contributes to fevers. […] The merozoite surface antigen being foreign to the body as well evokes immune responses that lead to the production of the cytokines. […] These cytokines such as TNF, Interferon-gamma, and Interleukin-1 have the potential of suppressing the red blood cell production thus reducing the restoration of hemoglobin concentration, increasing fever, stimulating reactive nitrogen species production that causes tissue damage, and inducing endothelial receptor expression of P. falciparum erythrocyte membrane protein 1 (PfEMP1) which is responsible for sequestration.

• #1 CDC – DPDx – Malaria

  https://www.cdc.gov/dpdx/malaria/index.html

  Blood stage parasites are responsible for the clinical manifestations of the disease. […] The clinical presentation can vary substantially depending on the infecting species, the level of parasitemia, and the immune status of the patient. […] Infections caused by P. falciparum are the most likely to progress to severe, potentially fatal forms with central nervous system involvement (cerebral malaria), acute renal failure, severe anemia, or acute respiratory distress syndrome. […] Complications of P. vivax malaria include splenomegaly (with, rarely, splenic rupture), and those of P. malariae include nephrotic syndrome. […] The symptoms of uncomplicated malaria can be rather non-specific and the diagnosis can be missed if health providers are not alert to the possibility of this disease.

• #1 Pathology of Malaria | IntechOpen

  https://www.intechopen.com/chapters/86437

  The development of cerebral malaria following infection with P. falciparum occurs in cases of high parasitemia. […] It is thought that infected red cells are sequestrated through the attachment on the endothelium that causes occlusion of the cerebral capillaries. […] This coupled with sequestration of the parasites cause reduction in blood circulation in the microvasculature resulting in a decreased supply of nutrients and oxygen. […] The obstruction of the blood flow shuts down energy production which is needed to maintain the blood-brain barrier. […] As a result, ischemia ensues and there is a neuronal alteration that causes cerebral swelling and increased the cerebral intracranial pressure. […] Cytokines and chemokine are also described as through a complex role in protecting and posing harmful effects in the pathogenesis of cerebral malaria. […] Cerebral malaria is fatal and without treatment, the mortality rates increase exponentially.

• #1 Malaria Pathogenesis: Anemia and Cerebral Malaria – ISGLOBAL

  https://www.isglobal.org/en/-/malaria-pathogenesis-anemia-and-cerebral-malaria

  Although the development of severe malaria anemia and cerebral malaria are major causes of death in patients, the pathogenesis of these syndromes are not well understood. […] Our research work in cerebral malaria has uncovered that Plasmodium falciparum weakens brain endothelial cell junctions through the activation of beta-catenin, a protein that is present in the junctions but also activates transcription in these cells. […] We observed that this process is regulated by angiotensin receptors (AT1 and AT2) that can inhibit the activation of beta-catenin and preserve the integrity of the endothelium. […] Results in mice experimental models confirm these findings and suggest that angiotensin receptor modulators, which are approved for use in humans, can be used as adjunctive treatment for cerebral malaria.

• #1 Pathogenesis of Cerebral Malarialogo-32logo-40logo-60NEJM Journal WatchnejmJW_1L_RGB-b

  https://www.jwatch.org/na33355/2014/01/13/pathogenesis-cerebral-malaria

  Cerebral malaria is usually caused by Plasmodium falciparum infection and is often fatal. Autopsy studies show that infected erythrocytes adhere to and occlude cerebral vessels and that fibrin deposition occurs. To clarify the pathogenesis of cerebral malaria, investigators analyzed recent studies and noted the following: […] Erythrocytes infected by malarial parasites expose specific membrane proteins that mediate binding to the endothelial receptors in the various vascular beds. […] Infected erythrocytes bind to the endothelial protein C receptor (EPCR) of cerebral vessels. […] EPCR bound by infected erythrocytes is unable to activate protein C; activated protein C (APC) normally limits thrombin generation and fibrin deposition. […] APC also has cytoprotective effects, including anti-inflammatory, anti-apoptotic, and maintenance of endothelial barrier function that are impaired in cerebral malaria. […] This summary of recent research suggests that the endothelial protein C receptor on cerebral vessels is a principal target of P. falciparum and accounts for many of the pathologic findings in cerebral malaria.

• #1 Pathology of Malaria | IntechOpen

  https://www.intechopen.com/chapters/86437

  The infected red cells appear sticky and adhered to the blood vessels causing obstruction of the blood flow and causing ischemia in the affected areas and organs. […] The sticky red cells as well clump together forming a rosette that if large enough have the potential to obstruct blood flow in major blood vessels. […] The sequestration of the red cells in the blood vessel endothelium and the ability of the body to take away damaged red cells mostly occur in the spleen contributing to splenomegaly in some patients. […] Sequestration of the red cells, and destruction of the red cells leading to anemia coupled with obstruction of blood flow results in the reduction of tissue perfusion causing fatigue, general body weakness, and ischemia. […] P. falciparum is responsible for most malarial cases, especially in the WHO African region.

• #1 Pathology of Malaria | IntechOpen

  https://www.intechopen.com/chapters/86437

  The parasite can infect red blood cells of all ages thus resulting in high parasitemia as compared to P. ovale and P. vivax which infect only young red cells. […] High parasitemia results in severe hemolysis that causes hemoglobinuria which has the potential of damaging the kidneys and causing renal failure worsening the prognosis. […] Infection with P. falciparum has the specific property of sequestration. […] The organisms exhibit adherence properties that result in sequestration of the parasites in small post-capillary vessels. […] Through sequestration of the parasite, the patient may develop an altered mental state and even a coma. […] Infection with P. falciparum is associated with a high burden of cytokines released by the body which in addition to high parasitemia resulting in end-organ failures.

• #1 Malaria | Nature Reviews Disease Primers

  https://www.nature.com/articles/nrdp201750

  Malaria is caused in humans by five species of single-celled eukaryotic Plasmodium parasites (mainly Plasmodium falciparum and Plasmodium vivax) that are transmitted by the bite of Anopheles spp. mosquitoes. […] Advances in our understanding of the underlying molecular basis of pathogenesis have fuelled the development of new diagnostics, drugs and insecticides. […] Several new combination therapies are in clinical development that have efficacy against drug-resistant parasites and the potential to be used in single-dose regimens to improve compliance. […] However, despite these achievements, a well-coordinated global effort on multiple fronts is needed if malaria elimination is to be achieved. […] Investigating the pathogenesis of severe malaria: a multidisciplinary and cross-geographical approach.

• #1 The pathogenesis of malaria: a new perspective

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4003589/

  If the hypothesis is correct, compounds that alter the metabolism of RA or block its expression may be effective as treatments, not only by attacking the parasite and its nutrition but by blocking the toxic effects of RA released by P. falciparum and other Plasmodium species on the human host. […] The fact that RA and TTNPB trigger phosphatididylserine exposure and cell shrinkage of erythrocytes, which are typical features of suicidal erythrocyte death or eryptosis, supports the present hypothesis that the malarial parasite itself uses RA accumulated in the host liver to invade erythrocytes. […] Other signs and symptoms may be similarly caused by generalized and localized endogenous forms of host- and parasite-generated vitamin A poisoning in the affected tissues.

• #1 Scientists identify mechanism behind drug resistance in malaria parasite | MIT News | Massachusetts Institute of Technology

  https://news.mit.edu/2024/scientists-identify-mechanism-behind-drug-resistance-malaria-parasite-0529

  SMART researchers find a cellular process called transfer ribonucleic acid (tRNA) modification influences the malaria parasites ability to develop resistance. […] This breakthrough discovery advances the understanding of how malaria parasites respond to drug-induced stress and develop resistance, and paves the way for the development of new drugs to combat resistance. […] A change in a single tRNA, a small RNA molecule that is involved in translating genetic information from RNA to protein, provides the malaria parasite with the ability to overcome drug stress. […] The study describes how tRNA modification can alter the parasites response to ART and help it survive ART-induced stress by changing its protein expression profile, making the parasite more resistant to the drug. […] Our research, the first of its kind, shows how tRNA modification directly influences the parasites resistance to ART, highlighting the potential impact of RNA modifications on both disease and health.

• #1 Opsonic phagocytosis of Plasmodium falciparummerozoites: mechanism in human immunity and a correlate of protection against malaria | BMC Medicine | Full Text

  https://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-108

  An understanding of the mechanisms mediating protective immunity against malaria in humans is currently lacking, but critically important to advance the development of highly efficacious vaccines. […] Antibodies promoting opsonic phagocytosis of merozoites were cytophilic immunoglobulins (IgG1 and IgG3), induced monocyte activation and production of pro-inflammatory cytokines, and were directed against major merozoite surface proteins (MSPs). […] Opsonic phagocytosis of merozoites appears to be an important mechanism contributing to protective immunity in humans. […] We demonstrate that human antibodies against MSP2 and MSP3 that are strongly associated with protection in this population are effective in opsonic phagocytosis of merozoites, providing a functional link between these antigen-specific responses and protection for the first time.

• #1 Investigating the Pathogenesis of Severe Malaria: A Multidisciplinary and Cross-Geographical Approach | smo

  https://www.severemalaria.org/investigating-the-pathogenesis-of-severe-malaria-a-multidisciplinary-and-cross-geographical-approach

  More than a century after the discovery of Plasmodium spp. parasites, the pathogenesis of severe malaria is still not well understood. […] Insights into its complex pathophysiology are emerging through a combination of autopsy, neuroimaging, parasite binding, and endothelial characterizations. […] Shedding light on the underlying disease mechanisms will be necessary to implement effective diagnostic tools for identifying and classifying severe malaria syndromes and developing new therapeutic approaches for severe disease. […] This review highlights progress and outstanding questions in severe malaria pathophysiology and summarizes key areas of pathogenesis research within the International Centers of Excellence for Malaria Research program.

• #2 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Malaria-Mechanism.aspx

  Malaria is caused by the transmission of the malaria parasite Plasmodium to humans by the bites of female Anopheles mosquitoes. […] Once within the humans, the malaria parasite undergoes two phases – an exoerythrocytic and an erythrocytic phase. […] The exoerythrocytic phase involves the maturation and development of the parasite in the liver. When an infected mosquito transmits the infection or sporozoites as it takes in a blood meal the sporozoites in the mosquito’s saliva enter the bloodstream and migrate to the liver. […] The parasite then forms thousands of merozoites within the hepatocytes. The numerous merozoites lead to the rupture of their host cells and escape into the blood. […] The involvement of the red blood cells is called the erythrocytic phase. In the RBCs the merozoites multiply further asexually and burst the RBCs as they multiply releasing the merozoites in blood. Each burst is associated with a bout of fever.

• #2 Pathogenesis of malaria – UpToDate

  https://www.uptodate.com/contents/pathogenesis-of-malaria/print

  Understanding the pathogenesis of malaria requires investigation of mechanisms including parasite invasion, parasite biology, and host defense. […] Pathogenesis of Plasmodium falciparum is the area of greatest study, since this species causes the most severe clinical disease. […] Life cycle — Human malaria occurs by transmission of Plasmodium sporozoites via a bite from an infected female anopheline mosquito. […] The intracellular parasites modify the erythrocyte in several ways. […] They derive energy from anaerobic glycolysis of glucose to lactic acid, which may contribute to clinical manifestations of hypoglycemia and lactic acidosis. […] Parasites reduce red cell membrane deformability, resulting in hemolysis and accelerated splenic clearance, which may contribute to anemia. […] Alterations to uninfected red blood cells, such as the addition of P. falciparum glycosylphosphatidylinositol (GPI) to the membrane, may play a role in increased clearance of uninfected cells and contribute to anemia.

• #2 Malaria – Wikipedia

  https://en.wikipedia.org/wiki/Malaria

  Malaria infection develops via two phases: one that involves the liver (exoerythrocytic phase), and one that involves red blood cells, or erythrocytes (erythrocytic phase). […] The parasites multiply asexually within red blood cells, periodically breaking out to infect new ones. This repeated cycle results in synchronized waves of merozoites escaping and invading red blood cells, which cause the characteristic fever patterns. […] Many of the symptoms associated with severe malaria are caused by the tendency of P. falciparum to bind to blood vessel walls, resulting in damage to the affected vessels and surrounding tissue. […] The blockage of the microvasculature causes symptoms such as those in placental malaria. […] Sequestered red blood cells can breach the blood-brain barrier and cause cerebral malaria.

• #2 The pathogenesis of malaria: a new perspective

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4003589/

  It is believed that the balance between pro-inflammatory and anti-inflammatory cytokines, chemokines, growth factors, and effector molecules determines disease severity. […] This paper presents a new theory on the pathogenesis of malaria, suggesting that an endogenous form of hypervitaminosis A induced by the parasite contributes significantly to the signs and symptoms of the disease. […] Here it is proposed that malarial symptoms are caused by an endogenous form of vitamin A intoxication induced by the parasites following their egress from the liver. […] On this hypothesis, the parasites emerge from the liver packed with vitamin A and use RA as a cell membrane destabilizer to invade the red blood cells (RBCs), causing hemolysis and anemia. […] Other symptoms of the disease e.g., fever, headache, muscle aches, gastrointestinal symptoms, seizures, coma, respiratory distress, and retinopathy may similarly reflect parasite-induced vitamin A toxicity in the brain and other organs, following the transport of RBCs throughout the body and the release of RA (or RAs) into the circulation.

• #2 New discovery unravels malaria invasion mechanism

  https://phys.org/news/2024-04-discovery-unravels-malaria-invasion-mechanism.html

  A recent breakthrough sheds light on how the malaria parasite, Plasmodium falciparum, invades human red blood cells. The study, led by the Swiss Tropical and Public Health Institute (Swiss TPH) and Griffith University’s Institute for Glycomics, reveals the role of a sugar called sialic acid in this invasion process. […] The malaria parasite Plasmodium falciparum is the leading cause of severe malaria and is responsible for the largest portion of malaria deaths. All clinical symptoms of malaria are caused by the multiplication of malaria parasites in the red blood cells. […] Although we know that the malaria protein, cystein-rich protective antigen (CyRPA), is essential for the invasion of red blood cells, its precise role in this process was not understood. […] The researchers discovered that a sugar called sialic acid is a key component of the red blood cell surface that is recognized by the malaria parasite, and which is essential for the invasion process.

• #2

  https://link.springer.com/article/10.1007/s00018-002-8421-y

  Malaria results in up to 2.5 million deaths annually, with young children and pregnant women at greatest risk. The great majority of severe disease is caused by Plasmodium falciparum. A characteristic feature of infection with P. falciparum is the accumulation or sequestration of parasite-infected red blood cells (RBCs) in various organs, such as the brain, lung and placenta, and together with other factors is important in the pathogenesis of severe forms of malaria. Sequestration results from adhesive interactions between parasite-derived proteins expressed on the surface of infected RBCs and a number of host molecules on the surface of endothelial cells, placental cells and uninfected RBCs. Some receptors for parasite adhesion have been implicated in particular malaria syndromes, such as intercellular adhesion molecule 1 in cerebral malaria and chondroitin sulfate A and hyaluronic acid in placental infection. The principal parasite ligand and antigen on the RBC surface, P. falciparum erythrocyte membrane protein 1 encoded by a multigene family termed var, is clonally variant, enabling evasion of specific immune responses. An understanding of these host-parasite interactions in the context of clinical disease and immunity may reveal potential targets to prevent or treat severe forms of malaria.

• #2 Pathology of Malaria | IntechOpen

  https://www.intechopen.com/chapters/86437

  The infected red cells appear sticky and adhered to the blood vessels causing obstruction of the blood flow and causing ischemia in the affected areas and organs. […] The sticky red cells as well clump together forming a rosette that if large enough have the potential to obstruct blood flow in major blood vessels. […] The sequestration of the red cells in the blood vessel endothelium and the ability of the body to take away damaged red cells mostly occur in the spleen contributing to splenomegaly in some patients. […] Sequestration of the red cells, and destruction of the red cells leading to anemia coupled with obstruction of blood flow results in the reduction of tissue perfusion causing fatigue, general body weakness, and ischemia. […] P. falciparum is responsible for most malarial cases, especially in the WHO African region.

• #2 Pathology of Malaria | IntechOpen

  https://www.intechopen.com/chapters/86437

  The released merozoites infect other healthy red cells in the circulation. […] Intravascular hemolysis results in worsening anemia requiring immediate treatment and transfusion in a patient with very low hemoglobin levels (5 g/dL). […] The intravascular hemolysis results in the production of hemoglobin that causes the urine to change and appear as dark colored in the patient. […] The released products and toxic substances in ruptured red cells cause the body to release cytokines such as tumor necrosis factor (TNF) which contributes to fevers. […] The merozoite surface antigen being foreign to the body as well evokes immune responses that lead to the production of the cytokines. […] These cytokines such as TNF, Interferon-gamma, and Interleukin-1 have the potential of suppressing the red blood cell production thus reducing the restoration of hemoglobin concentration, increasing fever, stimulating reactive nitrogen species production that causes tissue damage, and inducing endothelial receptor expression of P. falciparum erythrocyte membrane protein 1 (PfEMP1) which is responsible for sequestration.

• #2 Pathophysiology of Cerebral Malaria: Implications of MSCs as A Regenerative Medicinal Tool

  https://www.mdpi.com/2306-5354/9/6/263

  The activation of endothelial cells is regulated by cytokines such as Tumour Necrosis Factor alpha (TNF-α), Tumour Necrosis Factor beta (TNF-β), and interferon-γ. […] The upregulation of TNF cytokine was observed in the blood and the brain cells of human and murine models of cerebral malaria. […] Malaria parasite during infection suppresses erythropoiesis in the bone marrow, and hemozoin deposition in the tissues are mostly responsible for malarial anemia. […] The proliferation of erythroid progenitor cells is challenged during malaria infection due to decreased expression of erythroid-specific transcription factors such as GATA-1 and GATA-2. […] Platelets are considered as critical contributors to CM by providing an alternate, indirect mechanism for infected RBCs adhesion. […] Platelet-induced in vitro clumping experiments revealed the occurrence of infected RBCs clumping after incubation with Platelet-rich plasma.

• #2 Malaria – Wikipedia

  https://en.wikipedia.org/wiki/Malaria

  The liver infection causes no symptoms; all symptoms of malaria result from the infection of red blood cells. […] The parasite is relatively protected from attack by the body’s immune system because for most of its human life cycle it resides within the liver and blood cells and is relatively invisible to immune surveillance.

• #2 PATHOGENESIS OF MALARIA IN TISSUES AND BLOOD | Mediterranean Journal of Hematology and Infectious Diseases

  https://www.mjhid.org/mjhid/article/view/2012.061

  The clinical manifestations of severe malaria are several and occur in different anatomical sites. Both parasite- and host-related factors contribute to the pathogenicity of the severe forms of the disease. Cytoadherence of infected red blood cells to the vascular endothelium of different organs and rosetting are unique features of malaria parasites which are likely to contribute to the vascular damage and the consequent excessive inflammatory/immune response of the host. […] In addition to cerebral malaria or severe anaemia, which are quite common manifestation of severe malaria, clinical evidences of thrombocytopenia, acute respiratory distress syndrome (ARDS), liver and kidney disease, are reported. […] In primigravidae from endemic areas, life threatening placental malaria may also be present.

• #2 Pathophysiology of Cerebral Malaria: Implications of MSCs as A Regenerative Medicinal Tool

  https://www.mdpi.com/2306-5354/9/6/263

  The severe form of malaria, i.e., cerebral malaria caused by Plasmodium falciparum, is a complex neurological syndrome. […] The adhesion and accumulation of infected RBCs, platelets, and leucocytes (macrophages, CD4+ and CD8+ T cells, and monocytes) in the brain microvessels play an essential role in disease progression. […] Micro-vascular hindrance by coagulation and endothelial dysfunction contributes to neurological damage and the severity of the disease. […] Recent studies in human cerebral malaria and the murine model of cerebral malaria indicate that different pathogens as well as host-derived factors are involved in brain microvessel adhesion and coagulation that induces changes in vascular permeability and impairment of the blood-brain barrier. […] Understanding the mechanism of brain injury and loss of the BBB is vital for further developments of therapeutic approaches.

• #2 Malaria Pathogenesis: Anemia and Cerebral Malaria – ISGLOBAL

  https://www.isglobal.org/-/malaria-pathogenesis-anemia-and-cerebral-malaria

  Ana Rodrguez, Associated Professor of the Department of Microbiology at the New York University, will give an open seminar on 'Malaria pathogenesis: anemia and cerebral malaria’ on 14 May, 2019. […] A main interest of her laboratory is the study of malaria-induced inflammatory pathology. They also study cerebral malaria, a complication of severe malaria that frequently leads to coma and death. […] Although the development of severe malaria anemia and cerebral malaria are major causes of death in patients, the pathogenesis of these syndromes are not well understood. Our research work in cerebral malaria has uncovered that Plasmodium falciparum weakens brain endothelial cell junctions through the activation of beta-catenin, a protein that is present in the junctions but also activates transcription in these cells.

• #2

  https://haematologica.org/article/view/haematol.2021.280450

  Accumulating data suggest that hemostatic dysfunction contributes to Plasmodium falciparum malaria pathogenesis. […] In addition, specific mechanisms through which the protein C pathway modulates P. falciparum pathogenesis have been described. […] In keeping with findings in patients with severe P. falciparum malaria, we observed that dysregulated thrombin generation and protein C pathway dysfunction were both late features of ECM. […] All together, these findings confirm that hemostatic and protein C pathway dysfunction are both consistent features in human and ECM, and demonstrate for the first time a role for recombinant APC in reducing clinical progression and mortality in ECM. […] Significant coagulation cascade activation including elevations in levels of fibrin degradation products (FDP) and thrombin-antithrombin (TAT) complexes are common in patients with P. falciparum infection.

• #2 Malaria: Practice Essentials, Background, Etiology

  https://emedicine.medscape.com/article/221134-overview

  Malaria Pathogenesis […] Despite the many morphologies of the parasite in its life cycle, only a few stages cause clinical disease in humans, the most severe of which are typically P falciparum and P vivax. The initial schizont broods rupture out of the liver phase, release thousands of merozoites into the bloodstream, and attempt to establish periodicity within the erythrocytic phase (time periods vary per species) where level of parasitemia increases exponentially. […] Once the parasite concentration is high enough, a fever is mounted (pyrogenic threshold). This pyrogenic threshold may be anywhere from 0.05 to 1.25 parasites/1,000 red blood cells (0.005 – 0.125% parasitemia) immune patients may require 0.2% parasitemia to experience fever. The most theorized mechanism for the cyclic fevers is the human immune response to the hemozoin (waste product generated from Plasmodiums diet of hemoglobin) that bursts into the bloodstream during each cycle of asexual erythrocytic schizogony. Hemozoin is known to be a Plasmodium pathogen associated molecular pattern (PAMP) recognized by toll-like receptors (TLRs) that induces intense immune response. Other malarial toxins such as malaria glycophosphatidylinositol (GPI) likely are culpable through similar mechanisms. The temperature fluctuation with the human febrile response is expected to play a role in guiding the broods of parasites toward the classic paroxysmal fever-associated periodicity of schizont rupture. […] Severe malaria-associated anemia typically is seen in the young in areas of the world with poor health infrastructure and diets poor in essential vitamins. Schizont rupture from erythrocytes is an obvious mechanism of anemia; however, the more profound loss of red blood cell mass is seen in the population of uninfected erythrocytes. Their decline is thought to occur via oxidative damage of the erythrocyte membranes, eventually leading to hemolysis. Another mechanism of anemia lies within bone marrow; both insufficient production and function of erythropoietin as well as possible apoptosis induction of erythrocyte precursors lead to dyserythropoiesis. […] During acute malaria infection, the spleen serves as the main driver of infected erythrocyte clearance, immune cell activation, and extramedullary hematopoiesis. The extraordinary burden on the spleen causes the red pulp to become congested with infected and uninfected red blood cells, but splenomegaly also occurs by massive cellular expansion in both the red and white pulp. Impressively, the organ is able to revert back to a normal size after clearance of the infection (at least in mice). Because of P vivax tropism for reticulocytes (prevalent in the spleen), splenic rupture is a characteristic severe complication of P vivax, and there is evidence to suggest a separate splenic life cycle for this species. […] End-organ damage from microvascular sequestration, respiratory depression, and production of Plasmodium lactate dehydrogenase (pLDH) by the malaria parasite all lower the pH of the blood. […] Cytoadherence with thrombi formation in glomeruli is a common mechanism of acute kidney injury. If anuria or hemoglobinuria (blackwater fever) occur, it likely is secondary to an abundance of cell-free hemoglobin that results in reduced renal perfusion. Although contributing to morbidity of the acute illness, most patients do not require long-term dialysis. […] After infecting a red blood cell, P falciparum can insert adhesive proteins into the erythrocyte membrane, thus creating a cytoadherant phenotype. The ability to stick to endothelium, uninfected blood cells, and platelets causes more than 20% of brain capillaries to be filled with P falciparum parasites, resulting in vascular congestion, retinopathy, capillary leakage, thrombi, hemorrhage, axonal injury, coma, and death from cerebral malaria within 48 hours (especially in children). […] Occurring with highest incidence in Africa secondary to P falciparum due to its ability to form the cytoadherent phenotype, placental malaria is characterized by the accumulation of infected red blood cells within the intervillous space and ensuing infiltration of maternal macrophages. In severe cases, the resulting chronic intravillositis leads to decreased transplacental nutrient transport, fetal growth restriction and low birth weight babies, as well as increased risk for preterm birth and preeclampsia for the mother.

• #2 CDC – DPDx – Malaria

  https://www.cdc.gov/dpdx/malaria/index.html

  Blood stage parasites are responsible for the clinical manifestations of the disease. […] The clinical presentation can vary substantially depending on the infecting species, the level of parasitemia, and the immune status of the patient. […] Infections caused by P. falciparum are the most likely to progress to severe, potentially fatal forms with central nervous system involvement (cerebral malaria), acute renal failure, severe anemia, or acute respiratory distress syndrome. […] Complications of P. vivax malaria include splenomegaly (with, rarely, splenic rupture), and those of P. malariae include nephrotic syndrome. […] The symptoms of uncomplicated malaria can be rather non-specific and the diagnosis can be missed if health providers are not alert to the possibility of this disease.

• #2 Pathology of Malaria | IntechOpen

  https://www.intechopen.com/chapters/86437

  The parasite can infect red blood cells of all ages thus resulting in high parasitemia as compared to P. ovale and P. vivax which infect only young red cells. […] High parasitemia results in severe hemolysis that causes hemoglobinuria which has the potential of damaging the kidneys and causing renal failure worsening the prognosis. […] Infection with P. falciparum has the specific property of sequestration. […] The organisms exhibit adherence properties that result in sequestration of the parasites in small post-capillary vessels. […] Through sequestration of the parasite, the patient may develop an altered mental state and even a coma. […] Infection with P. falciparum is associated with a high burden of cytokines released by the body which in addition to high parasitemia resulting in end-organ failures.

• #2 Clinical Features of Malaria | Malaria | CDC

  https://www.cdc.gov/malaria/hcp/clinical-features/index.html

  Progression to severe malaria occurs when infections are complicated by serious organ failures or abnormalities in the patient’s blood or metabolism, usually following delays in diagnosis and treatment. […] In P. vivax and P. ovale infections, patients having recovered from the first episode of illness may suffer several additional attacks („relapses”) after months or even years without symptoms. […] Relapses occur because P. vivax and P. ovale have dormant liver stage parasites („hypnozoites”) that may reactivate, infect peripheral erythrocytes, and begin a new symptomatic episode of malaria. […] Hyperreactive malarial splenomegaly (also called „tropical splenomegaly syndrome”) occurs infrequently and is attributed to an abnormal immune response to repeated malarial infections.

• #2 The pathogenesis of malaria: a new perspective

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4003589/

  If the hypothesis is correct, compounds that alter the metabolism of RA or block its expression may be effective as treatments, not only by attacking the parasite and its nutrition but by blocking the toxic effects of RA released by P. falciparum and other Plasmodium species on the human host. […] The fact that RA and TTNPB trigger phosphatididylserine exposure and cell shrinkage of erythrocytes, which are typical features of suicidal erythrocyte death or eryptosis, supports the present hypothesis that the malarial parasite itself uses RA accumulated in the host liver to invade erythrocytes. […] Other signs and symptoms may be similarly caused by generalized and localized endogenous forms of host- and parasite-generated vitamin A poisoning in the affected tissues.

• #2 New discovery unravels malaria invasion mechanism | ScienceDaily

  https://www.sciencedaily.com/releases/2024/04/240403130556.htm

  The discovery of the key function of CyRPA in host cell invasion provides an explanation for the parasite inhibitory activity of CyRPA-specific antibodies. […] In this study, we show that the human form of sialic acid, Neu5Ac, is strongly preferred by the human-specific malaria parasite P. falciparum, and may explain the adaptation of this parasite to humans. […] The discovery of the key function of CyRPA in host cell invasion strongly supports the concept to clinically test CyRPA as a blood stage vaccine target. […] The essential binding activity of CyRPA to a specific glycan also validates CyRPA as drug target, and we demonstrate that small molecule inhibitors that interfered with this function can inhibit malaria replication in our study.

• #2 Scientists identify mechanism behind drug resistance in malaria parasite | MIT News | Massachusetts Institute of Technology

  https://news.mit.edu/2024/scientists-identify-mechanism-behind-drug-resistance-malaria-parasite-0529

  We found that the parasites ability to survive a lethal dose of artemisinin is linked to the downregulation of a specific tRNA modification. […] This discovery reveals how drug-resistant parasites exploit epitranscriptomic stress response mechanisms for survival, which is particularly important for understanding parasite biology. […] The research sets the foundation for the development of better tools to study RNA modifications and their role in resistance while simultaneously opening new avenues for drug development. […] By hindering the parasites ability to manipulate these modifications, drug resistance can be prevented from arising.

• #2 Opsonic phagocytosis of Plasmodium falciparummerozoites: mechanism in human immunity and a correlate of protection against malaria | BMC Medicine | Full Text

  https://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-108

  Opsonic phagocytosis was strongly associated with a reduced risk of clinical malaria in longitudinal studies in children with current or recent infections. […] In multivariate analyses including several antibody responses, opsonic phagocytosis remained significantly associated with protection against malaria, highlighting its potential as a correlate of immunity. […] We investigated the role of antibody-mediated opsonic phagocytosis of Plasmodium falciparum merozoites by monocytes. […] Opsonic phagocytosis by monocytes may also stimulate the release of cytokines or other mediators that subsequently promote parasite killing. […] We found that opsonic phagocytosis was only weakly correlated with the ability of the same purified IgG to inhibit parasite growth in a standard GIA. […] We demonstrate that opsonic phagocytosis of merozoites is mediated by IgG, primarily through cytophilic IgG1 and IgG3 antibodies to merozoite surface antigens, and leads to activation of monocytes with subsequent release of pro-inflammatory cytokines that could further enhance parasite clearance in vivo.

• #2 Malaria | Nature Reviews Disease Primers

  https://www.nature.com/articles/nrdp201750

  Malaria is caused in humans by five species of single-celled eukaryotic Plasmodium parasites (mainly Plasmodium falciparum and Plasmodium vivax) that are transmitted by the bite of Anopheles spp. mosquitoes. […] Advances in our understanding of the underlying molecular basis of pathogenesis have fuelled the development of new diagnostics, drugs and insecticides. […] Several new combination therapies are in clinical development that have efficacy against drug-resistant parasites and the potential to be used in single-dose regimens to improve compliance. […] However, despite these achievements, a well-coordinated global effort on multiple fronts is needed if malaria elimination is to be achieved. […] Investigating the pathogenesis of severe malaria: a multidisciplinary and cross-geographical approach.

• #3 Clinical Features of Malaria | Malaria | CDC

  https://www.cdc.gov/malaria/hcp/clinical-features/index.html

  All the clinical symptoms associated with malaria are caused by the asexual erythrocytic or blood stage parasites. […] When the parasite develops in the erythrocyte, numerous known and unknown waste substances such as hemozoin pigment and other toxic factors accumulate in the infected red blood cell. […] The hemozoin and other toxic factors such as glucose phosphate isomerase (GPI) stimulate macrophages and other cells to produce cytokines and other soluble factors which act to produce fever and rigors and probably influence other severe pathophysiology associated with malaria. […] When this sequestration of infected erythrocytes occurs in the vessels of the brain it is believed to be a factor in causing the severe disease syndrome known as cerebral malaria, which is associated with high mortality.

• #3 Pathophysiology of Cerebral Malaria: Implications of MSCs as A Regenerative Medicinal Tool

  https://www.mdpi.com/2306-5354/9/6/263

  The binding of infected RBCs to the brain endothelium cells causes sequestering of infected RBCs in brain microvessels, leading to inflammation and cerebral swelling. […] The loss of the BBB facilitates Plasmodium falciparum plasma protein and fluid leakage into parenchymal and perivascular space, leading to cerebral vasogenic edema. […] Moreover, adhesion of infected RBCs to endothelial cells obstructs blood vessels, leading to sudden swelling in the brain and may result in death due to respiratory failure. […] Targeting BBB disruption may be an optional therapeutic approach to reduce brain swelling and edema. […] Several hypotheses have been reported to explain the mechanism of cerebral malaria development. […] One such hypothesis affirms that infected RBCs adherence to brain endothelium leads to blockage in microvessels, causing nutrient deprivation and hypoxia in nearby brain tissue.

• #3

  https://jmsronline.com/archive-article/disease-pathogenesis-host-response-endemic-malaria

  The blood stage of infection is associated with all malarial disease symptoms, whereas the liver stage of infection is known to be asymptomatic, or clinically silent. […] Because of this, malarial species have developed various mechanisms to elude the hosts immune response so that the parasite is able to establish a sustainable state of pathogenesis. […] In order for the liver stage of infection to be established, the parasite must avoid being phagocytosed by Kupffer cells (KCs), the resident macrophages of the liver. […] Once the parasite successfully establishes liver stage infection, it must evade subsequent host immune defenses as it progresses to the blood stage; these mechanisms may vary between species. […] These immune evasion strategies are momentous in regard to the parasites ability to implement a sustainable infection.

• #3 Cerebral Malaria Pathogenesis

  https://www.medscape.com/viewarticle/758869

  Cerebral malaria is one of a number of clinical syndromes associated with infection by human malaria parasites of the genus Plasmodium. The etiology of cerebral malaria derives from sequestration of parasitized red cells in brain microvasculature and is thought to be enhanced by the proinflammatory status of the host and virulence characteristics of the infecting parasite variant. […] The mechanisms of pathology are not fully known but are thought to be related to the ability of infected erythrocytes (IE) to bind to vascular endothelium and to the inflammation seen both systemically and highly localized to areas of IE recruitment. […] A range of cytoadherence interactions exist for IE involving a broad array of host receptors and the parasite variant surface antigen PfEMP1. […] Intravascular immunopathology can be caused by a range of cell types, including leukocytes and endothelium itself, and recently platelets (as well as microparticles derived from these cells as well as others) have also been implicated in disease pathogenesis. […] The pathogenesis of CM is likely to be multifactorial, which has made understanding the mechanisms underpinning this syndrome difficult and has contributed to our lack of development of effective adjunct treatments for CM.

• #3 Malaria Pathogenesis: Anemia and Cerebral Malaria – ISGLOBAL

  https://www.isglobal.org/en/-/malaria-pathogenesis-anemia-and-cerebral-malaria

  Severe anemia is another common complication of malaria, which is caused mainly by the loss of uninfected erythrocytes during infection. […] We have observed that high levels of autoimmune antibodies that are induced by Plasmodium infection. […] During malaria, autoimmune antibodies recognizing the lipid phosphatidylserine bind to the surface of uninfected erythrocytes facilitating clearance and contributing to anemia. […] These autoimmune antibodies are generated by an atypical subclass of B cells that is found to be elevated in the blood of malaria patients and also in patients with classic autoimmune disorders. […] Activation of these B cells does not require T cells and is mediated by three specific signals that are provided during infection: crosslinking of the B cell receptor (by Plasmodium antigens), TLR9 (by parasite DNA) and interferon-gamma (general inflammatory response).

• #3 PATHOGENESIS OF MALARIA IN TISSUES AND BLOOD | Mediterranean Journal of Hematology and Infectious Diseases

  https://www.mjhid.org/mjhid/article/view/2012.061

  The clinical manifestations of severe malaria are several and occur in different anatomical sites. Both parasite- and host-related factors contribute to the pathogenicity of the severe forms of the disease. Cytoadherence of infected red blood cells to the vascular endothelium of different organs and rosetting are unique features of malaria parasites which are likely to contribute to the vascular damage and the consequent excessive inflammatory/immune response of the host. […] In addition to cerebral malaria or severe anaemia, which are quite common manifestation of severe malaria, clinical evidences of thrombocytopenia, acute respiratory distress syndrome (ARDS), liver and kidney disease, are reported. […] In primigravidae from endemic areas, life threatening placental malaria may also be present.

• #3 CDC – DPDx – Malaria

  https://www.cdc.gov/dpdx/malaria/index.html

  Blood stage parasites are responsible for the clinical manifestations of the disease. […] The clinical presentation can vary substantially depending on the infecting species, the level of parasitemia, and the immune status of the patient. […] Infections caused by P. falciparum are the most likely to progress to severe, potentially fatal forms with central nervous system involvement (cerebral malaria), acute renal failure, severe anemia, or acute respiratory distress syndrome. […] Complications of P. vivax malaria include splenomegaly (with, rarely, splenic rupture), and those of P. malariae include nephrotic syndrome. […] The symptoms of uncomplicated malaria can be rather non-specific and the diagnosis can be missed if health providers are not alert to the possibility of this disease.

• #3 Scientists identify mechanism behind drug resistance in malaria parasite | MIT News | Massachusetts Institute of Technology

  https://news.mit.edu/2024/scientists-identify-mechanism-behind-drug-resistance-malaria-parasite-0529

  SMART researchers find a cellular process called transfer ribonucleic acid (tRNA) modification influences the malaria parasites ability to develop resistance. […] This breakthrough discovery advances the understanding of how malaria parasites respond to drug-induced stress and develop resistance, and paves the way for the development of new drugs to combat resistance. […] A change in a single tRNA, a small RNA molecule that is involved in translating genetic information from RNA to protein, provides the malaria parasite with the ability to overcome drug stress. […] The study describes how tRNA modification can alter the parasites response to ART and help it survive ART-induced stress by changing its protein expression profile, making the parasite more resistant to the drug. […] Our research, the first of its kind, shows how tRNA modification directly influences the parasites resistance to ART, highlighting the potential impact of RNA modifications on both disease and health.

• #3 Opsonic phagocytosis of Plasmodium falciparummerozoites: mechanism in human immunity and a correlate of protection against malaria | BMC Medicine | Full Text

  https://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-108

  The finding that antibodies to some, but not all, merozoite antigens were associated with protection from malaria supports the argument that only a subset of antigens may be key targets for protective immunity. […] This study provides major new advances in our understanding of mechanisms underlying acquired immunity and establishes the OPA as an important biomarker of blood-stage immunity for accelerating the development and evaluation of malaria vaccines.

• #4 Cerebral malaria: insight into pathogenesis, complications and molecul | IDR

  https://www.dovepress.com/cerebral-malaria-insight-into-pathogenesis-complications-and-molecular-peer-reviewed-fulltext-article-IDR

  Cerebral malaria is a medical emergency. […] Pathogenesis of cerebral malaria is due to damaged vascular endothelium by parasite sequestration, inflammatory cytokine production and vascular leakage, which result in brain hypoxia, as indicated by increased lactate and alanine concentrations. […] Pathogenesis of cerebral malaria is due to damaged vascular endothelium by parasite sequestration, inflammatory cytokine production and vascular leakage. The basic underlying defect seems to be clogging of the cerebral microcirculation by the parasitized red cells as a result of increased cytoadherent properties due to which the parasites sequester in these deeper blood vessels. […] The association with hypoxia, as well as the cytokine expression to play a role in its evolvement, especially interferon- and lymphotoxin-, and the chemokine CXCL10 are essential for the development of cerebral malaria.

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