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Malaria

The problem of malaria (epidemiology)
1. Endemic in parts of;
  1. Asia
  2. Africa (malaria belt - subsaharan)
  3. Latin america
  4. Oceania
  5. 41% of the worlds population live in regions where malaria is transmitted
    1. 200-500 million cases each year
      1. 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
Causitive agent
1. Transmission
  1. Causitive agent is transmitted in the saliva of the female Anopheles mosquito
    1. During blood meal
    2. 30-40 different species of Anopheles mosquito known to transmit plasmodium (A. gambiae is the most well known)
  2. Associated with living close to still water (mosquito breeding area)
    1. Puddles to swamps
2. Life cycle
  1. In insect salivary gland: sporozoites (transmissable form)
    1. Enter host blood stream during blood meal
      1. 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
        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)
3. Apicomplexan (class of protozoan) protozoal disease caused by....
  1. Pasmodium spp.
    1. Four species are pathogenic to humans
      1. P. falciparum
        The most clinically important
        15% of all malarial infections...
        .... But 90% of malaria deaths
      2. P. vivax
        Actually the most common species
      3. P. ovale
      4. P. malariae
Pathology and bioscience
1. 1) onset
  1. 6-18 days after mosquito bite parasites appear in the blood
    1. This is the prepatent time (i.e. time to complete the liver stage)
      1. It varies with species; falciparum (6-9 days), vivax (8-12 days), ovale (10-14 days) and malariae (15-18 days)
  2. Incubation time is the time between RBC infection and the start of symptoms
    1. This also varies between species (from 7 days [falciparum] up to 40 days [malariae])
  3. Classical symptoms (last 4-8 hrs)
    1. Chills/rigor
      1. Feels cold (excessive shivering) despite an elevated temperature
    2. Fever + headache, nausea, vomiting, malaise etc
    3. Sweats and becomes tired
    4. Exhaustion -> sleep -> wake up apparently fine
    5. Repeated every 2/3 days (ovale and vivax = 2 days, malariae = 3 days; falciparum = almost continuous fever)
      1. 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)
  4. 2) development
    1. Symptoms intensify
    2. Irregular high fever
    3. Anxiety, delerium and other mental manifestations
    4. Sweating, increased pulse rate, exhaustion
    5. GI symptoms
    6. Hepatoslenomegaly!!!
    7. 3) severe malaria
      1. Occurs in 10% of P. falciparum cases
      2. 50% mortality
      3. 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
        Other abnormalities (renal, respiratory, glucose levels, jaundice etc.)
2. Sequestration/cytoadherence
  1. Sequestration
    1. Infections with P. falciparum - only the ring trophozoite can be seen (in RBCs) in ther peripheral blood
      1. 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
  2. Cytoadherence
    1. RBCs containing schizonts become sticky
      1. 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)
      2. 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
        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
        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
        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
        About 60 VAR egens
Acquired immunity
1. People living in endemic areas acquire immunity through natural exposure to the parasite
  1. Acquired (or natural) immunity occurs only after copntinued exposure from multiple infections over time
    1. Acquired immunity limits high-density parasitaemia; however it does not lead to sterile protection
      1. Clinical immunity gives protection gives prtoection against severe effects of malaria but fails to provide strong protection against infection

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Malaria

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	Created by maisie_oj over 11 years ago