57176
Malaria
- The problem of malaria
(epidemiology)
- Endemic in parts of;
- Asia
- Africa (malaria belt - subsaharan)
- Latin america
- Oceania
- 41% of the worlds population live in
regions where malaria is transmitted
- 200-500 million cases each year
- 1-2 million deaths each year
- 75% of these are kids in africa
- = 2,700 deaths each day (1 death every 30 seconds)
- 4th leading cause of death after perinatal
coditions, pneumonias and diarrhoeal diseases
- 4th leading cause of death after perinatal
coditions, pneumonias and diarrhoeal diseases
- 75% of these are kids in africa
- 1-2 million deaths each year
- 200-500 million cases each year
- Asia
- Endemic in parts of;
- Causitive agent
- Transmission
- Causitive agent is transmitted in the saliva of the female Anopheles mosquito
- During blood meal
- 30-40 different species of Anopheles
mosquito known to transmit plasmodium
(A. gambiae is the most well known)
- During blood meal
- Associated with living close to still water (mosquito breeding area)
- Puddles to swamps
- Puddles to swamps
- Causitive agent is transmitted in the saliva of the female Anopheles mosquito
- Life cycle
- In insect salivary gland: sporozoites (transmissable form)
- Enter host blood stream during blood meal
- Travel to liver and invade hepatocytes (30mins after infection)
- In hepatocyte: sporozoite nucleus divides rapidly and
asynchronously - producing a schizont (one membrane, many nuclei)
- The schizont differentiates to becomes many mononucleated merozoites
- Hepatocyte ruptures - releasing merozoites into the blood
- Infect other hepatocytes
- Infect RBCs
- Asexual cycle
- In RBC merozoite differentiates to
become a large mononucleated
trophozoite (ring stage - seen in a thin
blood slide under a microscope)
- Trophozoite divides asexually to produce a second schizont (multinucleated cell)
- The schizont differentiates to become many mononucleated merozoites
- RBC ruptures releasing merozoites into the blood stream
- Merozoites invade other RBCs
- Merozoites invade other RBCs
- RBC ruptures releasing merozoites into the blood stream
- The schizont differentiates to become many mononucleated merozoites
- Trophozoite divides asexually to produce a second schizont (multinucleated cell)
- In RBC merozoite differentiates to
become a large mononucleated
trophozoite (ring stage - seen in a thin
blood slide under a microscope)
- Sexual cycle
- Some merozoites differentiate into male
(micro-) and female (macro-) gametocytes
- RBCs containing gametocytes are taken up by a
new vector mosquito during a second blood meal
- RBC breaks down in mosquito gut
- Gametocytes become their respctive micro- (male) and macro- (female) gametes (sex cells)
- The microgamete
- Undergoes three nuclear divisions and develops flagella
- Nucleated flagella separate and fuse with the macrogamete -> zygote (diploid)
- Zygote becomes a mobile ookinete
- Ookinete crosses the insect gut epithelium into the basal side
- Ookinete undergoes meiosis in the insect's gut wall
- This forms oocysts (haploid)
- Oocysts undergo repetitive cycles of mitosis (all daughter cells still haploid)
- Daughter cells = sporozoites
- Oocyst ruptures releasing the sporozoites into the haemocoel
- Sporozoites migrate from the gut wall to the salivary gland (start of cycle)
- Sporozoites migrate from the gut wall to the salivary gland (start of cycle)
- Oocyst ruptures releasing the sporozoites into the haemocoel
- Daughter cells = sporozoites
- Oocysts undergo repetitive cycles of mitosis (all daughter cells still haploid)
- This forms oocysts (haploid)
- Ookinete undergoes meiosis in the insect's gut wall
- Ookinete crosses the insect gut epithelium into the basal side
- Zygote becomes a mobile ookinete
- Nucleated flagella separate and fuse with the macrogamete -> zygote (diploid)
- Undergoes three nuclear divisions and develops flagella
- The microgamete
- Gametocytes become their respctive micro- (male) and macro- (female) gametes (sex cells)
- RBC breaks down in mosquito gut
- RBCs containing gametocytes are taken up by a
new vector mosquito during a second blood meal
- Some merozoites differentiate into male
(micro-) and female (macro-) gametocytes
- Asexual cycle
- Infect other hepatocytes
- Hepatocyte ruptures - releasing merozoites into the blood
- The schizont differentiates to becomes many mononucleated merozoites
- In hepatocyte: sporozoite nucleus divides rapidly and
asynchronously - producing a schizont (one membrane, many nuclei)
- Travel to liver and invade hepatocytes (30mins after infection)
- Enter host blood stream during blood meal
- In insect salivary gland: sporozoites (transmissable form)
- Apicomplexan (class of protozoan)
protozoal disease caused by....
- Pasmodium spp.
- Four species are pathogenic to humans
- P. falciparum
- The most clinically important
- 15% of all malarial infections...
- .... But 90% of malaria deaths
- .... But 90% of malaria deaths
- 15% of all malarial infections...
- The most clinically important
- P. vivax
- Actually the most common species
- Actually the most common species
- P. ovale
- P. malariae
- P. falciparum
- Four species are pathogenic to humans
- Pasmodium spp.
- Transmission
- Pathology and bioscience
- 1) onset
- 6-18 days after mosquito bite
parasites appear in the blood
- This is the prepatent time (i.e.
time to complete the liver stage)
- It varies with species; falciparum (6-9
days), vivax (8-12 days), ovale (10-14
days) and malariae (15-18 days)
- It varies with species; falciparum (6-9
days), vivax (8-12 days), ovale (10-14
days) and malariae (15-18 days)
- This is the prepatent time (i.e.
time to complete the liver stage)
- Incubation time is the time between
RBC infection and the start of symptoms
- This also varies between species
(from 7 days [falciparum] up to 40
days [malariae])
- This also varies between species
(from 7 days [falciparum] up to 40
days [malariae])
- Classical symptoms (last 4-8 hrs)
- Chills/rigor
- Feels cold (excessive shivering)
despite an elevated temperature
- Feels cold (excessive shivering)
despite an elevated temperature
- Fever + headache, nausea, vomiting, malaise etc
- Sweats and becomes tired
- Exhaustion -> sleep -> wake up apparently fine
- Repeated every 2/3
days (ovale and vivax = 2
days, malariae = 3 days;
falciparum = almost
continuous fever)
- Cyclic fever coinsides with RBC infection
and rupture (rupture causes fever)
- Why?
- RBC infection and development of parasites
is synchronous (all in RBCs at the same time
and all released at he same time)
- Lysis of RBC -> parasite antigens in blood ->
stimulates immune cells to produce
TNF-alpha and other cytokines -> fever
- Fever becomes less severe with
age (immunity difference with age)
- Fever becomes less severe with
age (immunity difference with age)
- RBC infection and development of parasites
is synchronous (all in RBCs at the same time
and all released at he same time)
- Why?
- Cyclic fever coinsides with RBC infection
and rupture (rupture causes fever)
- Chills/rigor
- 2) development
- Symptoms intensify
- Irregular high fever
- Anxiety, delerium and other mental manifestations
- Sweating, increased pulse rate, exhaustion
- GI symptoms
- Hepatoslenomegaly!!!
- 3) severe malaria
- Occurs in 10% of P. falciparum cases
- 50% mortality
- Several manifestation (can appear
simultaneously or sequentially)
- Nn specific fever with loss of conciousness
- Severe headache, drowsiness, neurological abormalities
- Convulsions, vomiting and coma -> death
- Drop in haematocrit (infected and non-infected RNCs
destroyed, with reduced RBC production (due to cytokines))
- Reduction in O2 supply to tissues
- Reduction in O2 supply to tissues
- Other abnormalities (renal, respiratory,
glucose levels, jaundice etc.)
- Nn specific fever with loss of conciousness
- Occurs in 10% of P. falciparum cases
- Symptoms intensify
- 6-18 days after mosquito bite
parasites appear in the blood
- Sequestration/cytoadherence
- Sequestration
- Infections with P. falciparum - only the ring trophozoite
can be seen (in RBCs) in ther peripheral blood
- The schizonts cause the RBCs to become 'sticky'
(cytoadherence) this causes them to attach to the
endothelium of venules (= sequestration)
- P. falciparum infected RBCs are sequestered
in many organs; heart, lungs, kidneys, brain,
adipose, intestines, liver, spleen and placenta
- P. falciparum infected RBCs are sequestered
in many organs; heart, lungs, kidneys, brain,
adipose, intestines, liver, spleen and placenta
- The schizonts cause the RBCs to become 'sticky'
(cytoadherence) this causes them to attach to the
endothelium of venules (= sequestration)
- Infections with P. falciparum - only the ring trophozoite
can be seen (in RBCs) in ther peripheral blood
- Cytoadherence
- RBCs containing schizonts become sticky
- Stick to other RBCs (and endothelial cells)
- Infected cell binding to non-infected cells =
rosetting (organised rosettes of healthy RBCs
arranged around a central infected RBC)
- Infected cells binding to other infected cells
= clumping (irregular clumps of infected cells
which have lost their structure [shperocytes])
- Seen in 50% of cases
(correlates with
disease severity)
- Sticky cells clog-up blood
vessels and cause haemorrhage
(especially seen in cerebral
malaria)
- Sticky cells clog-up blood
vessels and cause haemorrhage
(especially seen in cerebral
malaria)
- Infected cell binding to non-infected cells =
rosetting (organised rosettes of healthy RBCs
arranged around a central infected RBC)
- Rosetting/clumping is caused by PfEMP1
(P.falciparum erythrocyte membrane protein)
- Multidomain protein produced by the parasite
that are transferred to the RBC cell surface
- Forms structures called 'knobs'
on the membrane of the RBC
- Forms structures called 'knobs'
on the membrane of the RBC
- Allows infected cells to bind other
infected/non-infected cells and endothelial cells
(which are expressing cell adhesion molecules)
- Cell adhesion molecules expressed by
venule endothelium due to inflammatory
IFN-gamma and TNF-alpha
- Cell adhesion molecules expressed
(can bind PfEMPs) = CD36 and ICAM1
- Cell adhesion molecules expressed
(can bind PfEMPs) = CD36 and ICAM1
- Cell adhesion molecules expressed by
venule endothelium due to inflammatory
IFN-gamma and TNF-alpha
- PfEMP1 structure
- NH2-multiple cysteine-rich domains (feature duffy binding-like (DBL) and cysteine-rich interdomain regions (CIDR))-transmembrane domain-COOH
- Number and arrangement of DBLs and
CIDRs vary between different PfEMPs
- Number and arrangement of DBLs and
CIDRs vary between different PfEMPs
- Extremely antigenic (elicits a strong immune response)
- However, PfEMPs are encoded by a large multi-gene family (VAR genes)
- Parasites are able to switch between PfEMP gene expression (antigenic variation)
- One one gene is expressed at any one time (like
Trypanosoma antigenic variation [VSG]) - allelic exclusion
- Deopends on the VAR promoter
- Swithching VAR gene may result in a new adhesion phenotype
- 2% of the parasite population switch VAR genes per cycle
- 2% of the parasite population switch VAR genes per cycle
- Swithching VAR gene may result in a new adhesion phenotype
- Deopends on the VAR promoter
- One one gene is expressed at any one time (like
Trypanosoma antigenic variation [VSG]) - allelic exclusion
- About 60 VAR egens
- Parasites are able to switch between PfEMP gene expression (antigenic variation)
- However, PfEMPs are encoded by a large multi-gene family (VAR genes)
- NH2-multiple cysteine-rich domains (feature duffy binding-like (DBL) and cysteine-rich interdomain regions (CIDR))-transmembrane domain-COOH
- Multidomain protein produced by the parasite
that are transferred to the RBC cell surface
- Stick to other RBCs (and endothelial cells)
- RBCs containing schizonts become sticky
- Sequestration
- 1) onset
- Acquired immunity
- People living in endemic areas acquire immunity
through natural exposure to the parasite
- Acquired (or natural) immunity occurs only after
copntinued exposure from multiple infections over time
- Acquired immunity limits high-density parasitaemia; however it does not lead to sterile protection
- Clinical immunity gives protection gives prtoection against severe effects
of malaria but fails to provide strong protection against infection
- Clinical immunity gives protection gives prtoection against severe effects
of malaria but fails to provide strong protection against infection
- Acquired immunity limits high-density parasitaemia; however it does not lead to sterile protection
- Acquired (or natural) immunity occurs only after
copntinued exposure from multiple infections over time
- People living in endemic areas acquire immunity
through natural exposure to the parasite
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