8. Malaria Flashcards
What is the name of the pathogen causing Malaria?
Parasite:
- Plasmodium falciparum (or P. falciparum)
- Plasmodium malariae (or P. malariae)
- Plasmodium vivax (or P. vivax)
- Plasmodium ovale (or P. ovale)
- Plasmodium knowlesi (or P. knowlesi)
What is the life cycle of Plasmodium?
Two host organisms:
- mosquito - definitive
- human - intermediate
What vessels can be infected with Plasmodium sporozoites?
Blood vessels - sporozoites into blood
Lymphatic vessels - sporozoites into lymph nodes
What APCs are used in lymph nodes for Malaria Ag presentation? What cells are activated?
DCs phagocytose sporozoites - cross-presentation - present Ag on MHC I on their surface - CTL bind - activation -> CTL migration to the liver
What are the two ways of Malaria antigen processing and presentation?
Intracellular infection - MHC I present Ag - CTL recognise
Extracellular infection - MHC II present Ag - Th recognise
Explain how do sporozzoites trigger local innate immune response in the liver
Sporozoites infect hepatocytes - infected hepatocytes recognise that they are infected - release type I IFN (cytokine) - signal neighbouring hepatocytes - reduce their chance of infection - increase Ag presentation on MHC I - better target for CTL
What are the ways of inducing apoptosis of infected hepatocytes?
Cellular immunity - CTL kill infected hepatocytes - induce apoptosis:
- CTL present Ag on TCR - FasL binds to Fas (death receptor) - signals apoptosis
- CTL present Ag on TCR - perforin and granzyme B released - form a pore in hepatocytes - triggers apoptosis
What is the problem with identifying infected hepatocytes in the liver?
Sporozoites initially infect small number of hepatocytes in liver (~10) - difficult to notice for immune system before they replicate and spread further
What are the two environments of immune response upon Plasmodium infection?
- immune response in blood
- immune response in liver cells
What is the key site for immune response to blood-stage infections?
Spleen - key site for immune response to blood-stage infections
What is the structure of spleen and what is the site of self-contained lymph nodes?
Spleen = red pulp + white pulp
White pulp - self-contained lymph nodes - checks blood for infections + provide first line of defence - macrophages
What are the components of innate recognition of blood-stage parasites?
Innate recognition components:
- PRRs - widely expressed - broad specificity - ex: TLRs
- PAMPs - hemozoin (crystals) + AT-rich DNA (diff to human genome - receptors recognise high AT)
- DAMPs - host cell released molecules recognised upon damage - damage signal sent
What event releases PAMPs and DAMPs?
Rupture of RBCs by replicated sporozoites - all RBCs burst at the same time - spikes of fever every 48h - PAMPs released from Plasmodium - DAMPs released from host => cytokine storm
What is the main goal of the first line of defence in innate immune response to Plasmodium infection?
First line of defence buys time for adaptive immunity to respond to the infection - activated macrophages in spleen when RBCs burst - secrete TNF (-> fever) + NO (-> infected RBC killing) - Th secrete IFNy (activates macrophages) + IL-10 (surpresses macrophages) => balance between IFNy and IL-10 determine macrophage activation levels
Why are macrophages very important in fighting Plasmodium infection?
Plasmodium - intracellular pathogen - inside RBCs - only cell type that does not express MHC I - can’t signal T cells that they are infected => rules out apoptosis as killing mechanism => activated macrophages phagocytose whole infected RBCs + upregulate killing mechanisms
Macropahge function can be enhanced by helper T cells (Th) + antibodies at blood-stage infection
How do T cells talk to B cells?
In germinal centres (in spleen, in lymph nodes) Th cells help activated B cells - B cells undergo affinity maturation (rearrange receptor to make it more specific) + isotype switching (specialised antibody choosing)
What is the antibody response to blood-stage parasites?
Th binds B cell - Malaria Ag showed - B cells develop into long-lived plasma cells - Ab factories - produced Malaria Ab -> bind Ag + RBCs infected with Plasmodium (Malaria antigens presented on RBC surface - allow to recognise)
How does the immune resposne to Malaria causes severe disease?
Immune response induced by Malaria can cause severe disease - severe malarial anaemia:
- destruction of infected RBCs (1x)
- destruction of uninfected RBCs (10x) - activated macrophages kill both infected and uninfected RBCs - difficult to differentiate
- suppression of erythropoiesis by TNF + IFNy - less RBCs produced in bone marrow
Destruction of uninfected RBCs + suppression of erythropoiesis - main cause of malarial anaemia - caused by immune system
How does the immune memory for Plasmodium work?
Clonal expansion - apopotosis -> more cells left than before
Why is sterilising immunity for malaria never acquired?
Because apical membrane antigen 1 - highly polymorphic - every infection slightly different -> need new Ab
Because PfEMP1 - major virulence factor has many variants - if one is attacked - switch to another
=> eventually organism doesn’t react as strongly, becomes partly resistant but still has parasite inside
