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78 Cards in this Set
- Front
- Back
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What are the 4 plasmodium species that infect humans?
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P. vivax
P. falciparum P. ovale P. malariae |
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What are the malaria paroxysm symptoms?
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Chills/shivering
High fever Sweating |
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What is a hypnozoite?
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Dormant form of P. vivax and P. ovale within the hepatocytes
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What are hypnozoites ass't with: recrudescence or relapse?
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Hypnozoites cause relapse (have malaria months/years after apparent cure)
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What is recrudecense?
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Presence of subclinical levels of iRBC (P. falciparum and P. malariae)
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What stage of the life cycle is the most important part of malaria?
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Liver stage: this is where malaria symptoms come in
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Describe the malaria life cycle
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Infection by mosquito taking a blood meal
Sporozoites go through the blood to the liver Use CS/TRAP/HSPG to get into the liver hepatocytes Schizont formation Rupture of shchizont and release of merozoites Merozoites infect RBCs Go through asexual cycle, can develop into gametocytes or trophozoites Gametozytes can be picked up by mosquito Trophozoites can go on to mature and infect other RBCs |
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What are the 3 stages of Merozoite-RBC interaction?
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1) initial attachment and reorientation: use MSP and AMA-1
2) Irreversible attachment and jct formation: use EBA ptn (P.f) or Duff binding ptn (P. v) 3) Parasitophorous vacuole formation and invasion |
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What happens after the parasite invades a RBC?
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Develop ring stage
Mature to trophozoite Some become gametocyes Trophozoites multiply and form schizon Schizont will rupture and release merozoites that will infect mre RBCs |
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How long does the hepatocyte infection take?
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48-72 hours (tertian or quartan)
--> Only P. malariae is quartan |
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How long does paroxysm last for P. vivax/ovale?
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10hr
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How long does paroxysm last for P. malariae?
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11hr
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How long does paroxysm last for P. falciparum?
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16-36 hours
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What are the clinical characteristics ass't with P. vivax?
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Anemia: ++
CNS involvement: + Nephrotic syndrome: +/- |
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What are the clinical characteristics ass't with P. ovale?
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Anemia: +
CNS involvement: + Nephrotic syndrome: - |
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What are the clinical characteristics ass't with P. malariae?
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Anemia: ++
CNS involvement: + Nephrotic syndrome: +++ |
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What are the clinical characteristics ass't with P. falciparum?
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Anemia: ++++
CNS involvement: ++++ Nephrotic syndrome: + |
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What happens in cerebral malaria?
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Frequent cause of death
Patients have sever headache, somnolence, confusion and coma Eventual death |
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What are the 2 theories ass't with cerebral malaria (CM)?
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1) cytokines/pro-inflammatory molecules mediated
**2) Mechanical obstruction ** |
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What happens to the BBB when someone has malaria?
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BBB increases its permeability
.: increased expression of cytokines --> Causes increase Cox-2 and arachidonic acids |
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What does increased arachidonic acid cause?
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1) Inc LPO --> more leukotrienes --> inc vascular permeability and edema
2) Inc Cox-2 --> more prostaglandins --> inc fever/pain |
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What eles happens when there is increased cytokies?
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Get increased NO ---> more vasodilation
Increased HO-1: causes increased Haem --> increased biliverdin, CO, Fe ---> Increased inhibition of apoptosis (neuronal cells) |
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Describe the theory of mechanical oobstruction in cerebral malaria **
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Mechanicap obstruction: capillary obstruction, decreased blood flow, tissue hypoxia and infarction
Causes Petechial hemorrhage Can cause lumen blockage and microinfarction |
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Where can capillary obstruction take place?
What does it do? |
Takes place in different organs
Leads to an increase in their size Can be fatal if present in the brain -->Get thrombus that causes a hemorrhage The iRBCs become more sticky (cytoadherence) |
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What develops in P. falciparum infected RBCs?
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Knobs are formed
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What are knobs?
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Protuberances of the RBC mb formed by ptns made by P. falciparum (in the trophozoite-schizont stages)
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What is the knob expression specificity?
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Stage specific
Knobs are most highly expressed in the schizont stage |
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What do knobs do?
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Make the schizont more sticky
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Describe the trafficking of P. falciparum secreted ptns that are bound to knobs
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P.f. produced ptns (like EMP1: adhesin) are exported, trafficked through the PV and Mauerer's cleft and deposited in the iRBC mb
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What are the parasite-secreted Ags used to form knobs?
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Cytoplasmic scaffold
PfEMP1 |
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Describe the cytoplasmic scaffold
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Pf erythrocyte mb ptn (PfEMP)-3
Knob-ass't histidine rich ptns (KAHRP) 1 or 2 These 2 ptns anchor PfEMP-1 |
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Describe PfEMP1
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Encoded by Var (variation) genes
Involved in the escape from the host Ab response by one variant expressed at the time and by switching its surface expression |
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What is important abotu PfEMP1?
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Can be expressed by different ptns
.: can't be recognized by the immune response formed by the host |
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How does the iRBC adhere to the capillary endothelium?
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Ligand-receptor mediated event
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What is the ligand of the iRBC-endothelium interaction?
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P. falciparum antigens
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What are the receptors of this interaction in endothelial cells?
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Adhesion molec:
CD36, ICAM-1, VCAM-1, Thrombospondin, E-selectin, P-selectin etc |
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What are the receptors of this interaction in RBCs?
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Complement receptor 1
CD36 ABO blood gp Heparan sulfate |
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What are the receptors of this interaction in the placenta?
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Hyaluronic acid (HA)
Chondroitin sulfate A (CSA) |
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What are the receptors of this interaction in cerebral malaria?
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Intercellular adhesion molec 1 (ICAM-1)
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Describe the infection pathology of cerbral malaria
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Capillary lumen obstruction (multi-organ)
Decrease in blood flow Tissue anoxia Local endothelium infarction |
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What does Cerebral malaria do to non-immune adults?
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Course rapid, acute and fatal within 2 weeks of untreated cases
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What is the mortality of CM among malnourished children under age 5?
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20-50% with incompetent immune mechanisms
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How prevalent is CM in adults/pre-adults?
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Rare or non-existent (in semi-immune populations with sufficient anti-malarial immunity => premunition)
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What kind of a disease is cM?
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sudden onset
Initial symptoms meningitis-like, rapidly progressing, severe headache, somnolence, confusion and coma |
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What is the treatment for CM?
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Intravenmous quinine, passive transfer of anti-TNF or anti-P.f Abs from human subjects
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What causes anemia?
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Heavy parasite load
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What is blackwater fever?
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Caused by hemolysis, which causes hemoglobin in the urine (hemoglobulinuria) and plasma (hemoglobulinemia)
Results in brown-black color |
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What are the 2 criteria that define anemia?
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Low hematocrit lvl: below 21% (normal= 42%)
Low Hg concentration: below 13g/100ml (5g/100ml results in severe malarial anemia in non-immune individuals) |
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What does severe anemia result in?
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Reduced oxygen
Tissue hypoxia Metabolic acidosis |
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How is the hematocrit lvl determined?
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In the lab, heparinized blood is centrifuged in a graduated Wintrobe hematocrit or capillar glass tube
Get a separation: at the top: 100% heparinized blood in the middle: ~42% normal adult hematocrit at the bottom: low hematocrit (~21%) clinical anemia |
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What is the etiology of anemia and blackwater fever in Pf infection?
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Multifactorial pathologic process
Decreased RBC production Increased RBC lysis |
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What happens to the BM in anemia and blackwater fever?
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BM dyserythropoiesis
Hemozoin increase Increase in TNF, IFN-y and MIF which blocks BM hematopoiesis |
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What happens in endemic areas where ppopulations produce less MIF?
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They are more resistant to anemia because the have an increased RBC #
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What happens if there is increased splenic removal of Pf-iRBC or Ab-opsonized non-infected RBC (with anti-GPI, anti-RAP)?
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Can lead to tropical splenomegal (big spleen syndrome)
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What happens when there is a high lvl of parasitemia in Pf infection?
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Increased RBC rupture
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What does treatment with quinine do?
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Increases Hemolysis in ppl with G6P dehydrogenase deficiency
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What happens if there is an autoimmune mechanism?
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Anti-RBC IgM + C' can lead to intravasculat RBC lysis
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What evidence was found for an autoimmune mechanism ass't with malaria caused anemia?
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3 serum parameters were correlated with the hematocrit:
-Total IgM -Total C3 -Total mean anti-RBC titer |
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What happens if there is longer parasite infection?
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Higher IgM
Lower C3 Higher anti-RBC |
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What effect did low hematocrit have on these parameters?
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Same as with prolonged parasite infection
Higher IgM Lower C3 Higher anti-RBC |
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What is a possible mechanism of the autoimmune role in anemia?
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Polyclonal activation of peripheral B cell populations by P.f Ags/Pf pyrogen
This triggers the generation of auto-reactive B-cells that generate anti-RBC IgM Ab |
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AutoAB production is related to anemia, but how does it also help host protection?
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AutoAb anti-parasite Ag (like GPI, phospholipid, nuclear or cytoskeleton) direct parasiticide activity by splenic removing iRBC from the blood
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What is an ex of how malaria infection can give protection vs pathogenic autoimmunity?
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When P.falciparum was removed in an areaa in Italy, got an increase in the incidence of multiple sclerosis, because the macs became more susceptible to infection
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Which plasmodium species can cause malaria related glomerulonephritis (Gnpt)?
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P. malariae
P. falciparum |
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What kind of Gnpt does Pm cause?
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Immune complex mediated Gnpt
Occurs in children <5y No response to drug therapy .: probably a genetic or autoimmune disorder |
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What kind of Gnpt does Pf cause?
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Acute febrile Gnpt
Immune complex mediate or due to the deposition of Hb and hemozoin in glomerulus-urinary tubules |
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What is clinically distinct between Pm and Pf Gnpt?
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Pm is chronic and severe
Pf is transient and acute (can respond with drug therapy) |
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Describe the mechanism of glomerulonephritis (2)
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1) Complex formation: Ab combines with Ag, forms the IC. If joined with C' (C3a/C5a can be ingested by basophils and other PMNs, goes to vasoactive amines, causes ---> INC vascular permeability
2) IC formed, get platelet aggregation, microthromb formation on the endothelium or IC deposition of the endothelium or enz release from PMNs to the endothelium ---> gets to the basement mb and increases its permeability |
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What is the basic mechanism of Gnpt?
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1) Immune complex formation
2) Increased vascular permeability |
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Summarize the mechanisms of Gnpt
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Generation of circulating large and small IC
Binding of IC to kidney endothelium and IC deposition at the basement mb Generation of C3a and C5a Local accumulation of PMNs and macs IC mediateed activation of the leukocytes NO and ROS + exocytosis of hydrolytic enz by leukocytes Local necrosis- hemoglobinuria/albumenuria Sclerosis of kidney glomeruli - renal failure- death |
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How is placental malaria caused?
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Accumulation of iRBC in the placenta (Pf variant VAR2CSA/chondroitin sulfate A interaction)
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What happens in primagravida (1st pregnancy) infection without treatment?
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Can progress to severe mmalaria (premunition in endemic regions does not give protection as it does in repeated pregnancies --> might need to develop anti-VAR2CSA)
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Which species causes the most placental malaria?
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Pf > Pv
-->Causs anemia, low birth weight, premature birth and spontaneous abortion |
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What happens in iRBC sequestration?
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Get placental monocyte infiltration and increased levels of pro-inflammatory cytokines (TNFa, IL-2)
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What are some othe problems ass't with malaria?
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-Tropical splenomegaly --> hyperplasia of RE cells, susceptible to rupture
-Immunosuppression: mal-toxin-mediated polyclonal activation of B/T cells --> as consequence patients respond poorly to vaccine and do not effectively control other intercurrent bacterial/viral/parasitic infections |
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What are the main reasons for why P. falciparum is responsible for almost 90% of malaria-specific mortality?
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-Induces high level of iRBC-lysis (by infecting mature/immature RBC) and iRBC phagocytosis, acute hemolytic anemia, dyserythropoiesis
-iRBC sequestered in deep soft tissues: cerebral malaria, acute transient nephritis |
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What ensures persistence of iRBC?
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Ag variation causes a persistence of iRBC, chronicity and a source of mosquito inffection
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What does P.falciparum pyrogen (GPI glycolipid) do?
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Induces immunosuppression of polyclonal activation of B and T cells and suggested generation of anti-RBC Abs, causing anemia
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