Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
83 Cards in this Set
- Front
- Back
What causes malaria?
|
Parasite: Plasmodium
|
|
What Phylum, class and group does Plasmodium fall under?
|
Phylum: Apicomplexa
Class: Sporozoea Group: Protozoa |
|
How many clinical cases is malaria responsible for?
|
300-500 million
|
|
How many ppl are killed by malaria each year?
|
1 million + ppl
|
|
How many species of malaria infect humans?
|
4
|
|
What are the 4 species of Plasmodium that infect humans?
|
P. vivax
P. falciparum P. ovale P. malariae |
|
How many hosts are involved in this parasite life cycle?
|
2
Invertebrate host: determinant host, where parasite underoges its sexual cycle Vertebrate host: parasite goes through its asexual cycle |
|
Describe the general life cycle of Plasmodium
|
Invertebrate host (insect) bites a human
Sporozoites are injected into the body (1hr) Sporozoites infect the liver (24-48 hrs) Get widespread infection in the blood, under the merozoite form (1 week) Merozoites infect RBCs where they go through their asexual cycle Some may become gametocytes and can be transmitted back to the mosquito when bitten again |
|
What secretory glands do Sporozoites have?
|
Rhoptries and micronemes
--> Important for entry |
|
What is CSP (circumsporozoite ptn)?
|
Important ptn that is expressed on the surface of all Plasmodium species
|
|
Describe CSP
|
10-15 um
Has an apical complex and an apicoplast (part of the Apicomplexa phylum) |
|
What does CSP bind?
|
Heparan sulfate proteoglycans (HSPGs) in liver sinusoids)
|
|
What is TRAP?
|
Thrombospondin related anonymous ptn (like CSP, it is a sporozoite expressed surface ptn)
|
|
What are CSP and TRAP involved in?
|
Gliding mobility of sporozoites through the hepatocytes
|
|
Where are HSPGs expressed?
|
On hepatocytes, stellate and kupffer cells (in the liver)
|
|
What happens during the liver stage?
|
Interaction between HSPGs/CS/TRAP ==> Causes arrest of sporozoites
Sporozoites cross through sinusoidal layer of the liver to the Kupffer cells Sporozoites use their gliding motility to go across several hepatocytes until the parasitophorous vacuole is formed Sporozoites multiply and form schizonts containing merozoite, within the hepatocytes Merozoites escape from the PV and mix with the host cytoplasm Form Merosomes (merozoite-filled vesicles) Merosomes mbs have a host feature and is .: not recognized by kupffer cells and DCs |
|
How does plasmodium remain dormant?
|
Sporozoites remain hypnozoites
|
|
Which Plasmodium species can remain dormant?
|
P. vivax
P. ovale |
|
What starts the erythrocytic cycle?
|
Release of merezoites (smaller than sporozoites) into the bloodstream
|
|
Describe the erythrocytic cycle
|
Merozoites infect RBCs
Go into their ring stage Develop into gametozyes or mature trophozoite Mature trophozoite becomes a schizont Schizont ruptures and releases the parasite |
|
Describe merozoites
|
Smaller than sporozoite (~2.5 um)
Have an apical comples that has 3 secretory glands Merozoites are covered by surface coat made of merozoite surface ptns (MSP) and apical mb ptn Ag (AMA-1) |
|
What are the 3 secretory glands of the merozoites apical complex?
|
Rhoptry
Microneme Dense granules |
|
What do these secretory glands do?
|
release ptns involved in the invasion of the host RBC
|
|
What are the most important ptns in the merozoite?
|
Erythocyte binding Ag (EBA-175): Located on the microneme
Duff-binding Ag (on P. vivax) |
|
What ptns does the Dense granule have?
|
Ring-infected erythrocyte surface Ag (RESA)
|
|
What kind of ptns do the Rhoptries have?
|
AMA
RAP Rhop |
|
Describe the merozoite-RBC interaction
|
Initial attachment and reorientation\Irreversible attachment and jct formation\Parasitophorous vacuole (PV) formation and invasion
|
|
What does step 1, initial attachment and reorientation, involve?
|
Use coat ptns on the merozoite
--> Need MSP and AMA-1 on the surface Surface ptns on merozoite deposited in a gradient |
|
What happens in step 2 (irreversible attachment and jct formation)?
|
Requires 2 ptns: Pf EBA-175 (P. falciparum) and Duff-binding ptn (P. vivax)
-Get the secretion of microneme ptns -High-affinity adhesion |
|
What does EBA-175 bind? (for P. falciparum)
|
Glycophorin A
|
|
What does Duff binding ptn (for P. vivax) bind?
|
Duffy ptn on the RBC
|
|
What happens during the 3rd step of merozoite-RBC interaction (PV formation and invasion)?
|
Secretion of rhoptry ptns and lipids
Inwards motion driven by actomyosin motor Proteolytic processing/cleavage of parasite surface ptns (MSP & AMA-1) Localized reorganization of host cell mb and cytoskeleton |
|
Describe the erythrocyte cycle of P. falciparum
|
~5 minutes for merozoite to enter RBC
After ~12 hours, have ring formation, start seeing clefts ~24 hours: Trophozoite -> see cleft and loop structures and knobs with the parasite adhesin Pf-EMP1 (makes RBCs stick more to the blood vessel). --> Also see food vacuole with hemozoin in it. -->Has a larger cytoplasm ~36 hours: start formaing merozoites ~40 hours: develop schizont ~48 hours: Schizont ruptures and RBCs release merozoites |
|
Describe gametocytes
|
Formed from merozoites (not entirely sure how)
Takes a dew days to appear in broad circulation can be taken up by mosquito -->Goes into the invertebrate cycle |
|
Describe the plasmodium life cycle in invertebrates (Anophole mosquitoes)
|
Insect ingests the gametocytes
Female and male gametes combine and fertilization takes place (in the stomach) Ookinete can penetrate the stomach lining Oocysts end up below the stomahc lining Sporogeny takes place Sporozoites develop into oocysts and migrate to the salivary glands of the insect (from there, they can be injected into the human host when the bug takes a blood meal) |
|
Which Plasmodium species infect the most?
|
P. falciparum (50%) > P. vivax (43%) >>> P malariae (7%) >> P. ovale (rare)
|
|
What kind of paroxysm does P. vivax cause?
|
Benign tertian
|
|
What kind of paroxysm does P. falciparum cause?
|
Malignant tertian
|
|
What kind of paroxysm does P. ovale cause?
|
Bening tertian
|
|
What kind of paroxysm does P. malariae cause?
|
Benign quartan
|
|
What's the difference between being benign and malignant?
|
Benign: not complicated, host doesn't die
Malignant: host dies |
|
For P. vivax, describe the
Periodicity Hepatic cycle Prepatent (amt of merozoites) Relapse or Recrudescense |
Periodicy: 48 hrs
Hepatic cycle: 8-27 days Prepatent: 10, 000 mz Relapse up to 8 years (have hypnozoites) |
|
For P. falciparum describe the
Periodicity Hepatic cycle Prepatent (amt of merozoites) Relapse or Recrudescense |
Periodicity: 36- 48 hours
Hepatic cycle: 8-25 days Prepatent: 30, 000 mz** Recrudescence 1 yr RBC |
|
For P. ovale, describe the
Periodicity Hepatic cycle Prepatent (amt of merozoites) Relapse or Recrudescense |
Periodicity: 48 hours
Hepatic cycle: 9-17 days Prepatnet: 15, 000 mz Relapse up to 8 years, hypnozoites |
|
For P. malariae, describe the
Periodicity Hepatic cycle Prepatent (amt of merozoites) Relapse or Recrudescense |
Periodicity: 72 hrs **
Hepatic cycle: 15-30 dyass Prepatent: 2,000 mz Recrudescence up to 53 years iRNC without symptoms |
|
Why is the relapse of a disease important?
|
Some parasites develop into hypnozoites (P. ovale and P. vivax)
These parasites might come back years later |
|
What is recrudescence?
|
After treatment, there are no more symptomsm but the parasite is still subdividing
Parasite is still there in RBCs, but they can't be seen This can increase the incidence of transmission (i.i through blood donor) These ppl still have the disease, but it cannot be observed |
|
What are the 3 pathognomonic cardinal signs of malarial paroxysm?
|
Chills and vigorous shivering (host and parasite-derived factors)
Pyrexia or spiking high fever Profuse sweating |
|
What are some other non-specific symptoms of malarial paroxysm?
|
Headache
Muscle aches Tiredness Nausea Vomiting Diarrhea Flu may be included |
|
What do malarial paroxysm episodes vary with?
|
Dpeneds on the Plasmodium species
|
|
Describe the malarial paroxysm (MP) according to P. vivax/ovale
|
Benign tertian
Schizont ruptures the first day: corresponds to MP Schizonts rupture again on the 3rd day Fever and other MP symptoms decrease after the spike on the 1st and 3rd days |
|
Describe the malarial paroxysm (MP) according to P. falciparum
|
Malignant tertian
Schizont ruptures on the 1st day but fever stays high until end of 2nd day, then goes down and spikes up again on the 3rd day (also a 48 hour cycle) |
|
Describe the malarial paroxysm (MP) according to P. malariae
|
Benign quatern
Schizont ruptures day 1 and get spike of fever Symptoms of MP decrease and stay low until day 4**, when fever peaks again =>3 day cycle |
|
How does paroxysm occur?
|
Starts with rupture of the schizont, release of merozoites, cellular devris and metabolic waste (hemozoin)
|
|
What hapens when a merozoite infects and RBC?
|
Merozoite surface coat ptns are cleaved
MSP or GPI-MSP are cleaved and shed continuously into the blood |
|
How many domains does MSP-1 have?
|
5
|
|
How is MSP1 anchored?
|
through GPI (glycosylphosphatidylinositols)
|
|
How can the parasite Ag be detected?
|
By ELISA
|
|
What is the role of hemozoin in the paroxysm?
|
Hemozoin interacts with many cells of the immune system and induces proinflammatory mediators (IL-1, TNF)
|
|
What is the role of MSP in paroxysm?
|
MSP-2 can stimulate macs to make cytokines (TNF, IL-1a/B, IL-6)
When MSP is in the presence of GPI, production of these cytokines is increased |
|
Through which receptors does GPI stimulate macrophages?
|
TLR2/1 or 6
GPI, MSP and Hemozoin cause an increase in the produciton of inflammatory cytokines |
|
What is the evidence that TNF-a is a critical mediator of MP?
|
1) TNF changes correspond with changes in body T and MP in P. vivax infecte children (in Gambia)
2) Peak TNF level preceded fever peak (30-60 min) 3) Passive transfer of anti-TNF Ab decreases fever |
|
Summary of malarial paroxysm
|
Rupture of RBC-schizonts/merozoites infection
Release of malarial toxin (Hz/GPI-exogenous pyrogen) Activation of RE cells, such as macrophages Release of TNF, IL-1α, IL-1, IL-6 (endogenous pyrogens-EP) EP interaction with hypothalamic endothelial vessels Increased level of prostaglandin E2 in hypothalamus Elevation in core temperature set point |
|
What are factors affecting the course and severity of malaria?
|
1) Species of plasmodium infection (P. falciparum is the most virulent)
2) Immature/incompetent immune mechanisms 3) Host genetic factors 4) Frequency of infected mosquito bites |
|
What are the immature/incompetent immune mechanisms due to?
|
Age: children under 5 have 80% mortality rate in sub-Saharan Africa
Primigravida (1st preganancy) and nutritional states --> malnutrition |
|
How do the host genetic factors influence the severity of the disease?
|
Renders refractory to infection or if infected, develop mild disease
1) Duffy blood gp: expressed because of alleles Fy-a/b that are codominant, which produce a ptn rec'z by P. vivax Ppl who don't have these allese are protected vs P. vivax malaria 2) G6P-dehydrogenase deficiency: these ppl protected vs malaria 3) Rigid RBCs (sickle cell trait or HgAS): protected vs malaria |
|
What does repeated exposure to malaria, due to the frequency of infected mosquito bites, lead to?
|
Premunition
|
|
What is premunition?
|
Takes place in hyperendemic areas because the ppl have been continuously exposed to infection
Takes years to develop Very easy to lose (1 year without infection) Not a sterilizing type of immunity because infected RBCs persist at subclinical level |
|
What are the mechanisms of premunition?
|
1) Ag polymorphism: Pf-EMP-1 present in knob structure encoded by gene Var, ~150 genes that provide ~2.4% rate switching/generation
2) Lower response to malarial Ags (higher CD8+ cells and suppressor T cells) |
|
What mediates the premunition response?
|
IgG/IgM
-->Ab dependent cellular inhibition (ADCI) |
|
Where is premunition seen?
|
Pre-adults/Adults (not seen in children under the age of 5)
|
|
Who does premunition benefit?
|
Both partners\Parasite can still be transmitted and host doesn't get as badly hurt
|
|
What kind of a disease is malaria?
|
Tropical disease (caused by 4 plasmodium species that infect humans)
|
|
Which P. species have worldwide distribution?
|
PV and PF
|
|
Which species is responsible for 90% of malaria caused deaths?
|
PF (can cause serious complications)
|
|
What insect is responsible for malaria transmission?
|
Anopheles species mosquito
|
|
What happens when sporozoites are injected into the blood from the mosquito?
|
Sporozoites migrate to the liver (HSPG/CS/TRAM iunteraction)
Cross via Kuppfer cells\Infect hepatocytes Merozoites are released from liver schizont via merosome formation |
|
How do hepatocyte-derived merozoites infect RBCs?
|
Use MSP/AMA-1 dependent reorientation, tight jct (through EBA and Duff-binding Ag) and the Parasitophorus vacuole)
|
|
What happens once merozoites enter the RBC?
|
Differentiate into:
Ring stage Trophozoite stage Schizont stage Merozoites than released into the blood and infect new RBCs |
|
What is paroxysm ass't with?
|
Rupture of the schizont stage
|
|
What happens when the schizont is ruptured?
|
Hemozoin and GPI are released, which stimulated monocytoid cells to release endogenous pyrogen (IL-1, TNF-a)
This affects the T receptors in the hypothalamus, initiating MP |
|
What does the course and severity of malaria depend on?
|
Plasmodium species
Immature/incompetent immune system Host genetic factors Development of premunition |
|
How can malaria be diagnosed?
|
Microscopic examination of Giemsa stained blood film
|