Malaria Case Study Flashcards
Plasmodium lifecycle?
Mosquito injects motile sporozoite form into dermis
Invade blood vessel
Travel to liver and enter hepatocytes
Sporozoite matures and replicates (asexually, give rise to 100,000)
Hepatocytes burst and merozoites find and enter blood cell
Mature and replicate in blood cell over 48 hours (give rise to 20 each)
Blood cells burst and release merozoites into blood
What immune cells do plasmodium sporozoites activate?
CTL
Because sporozoites often end up in lymphatic vessels where antigens can be carted to the LN where DC present their antigens
Hepatocyte reaction to sporozoite infection?
Release Type I IFN
Signals to neighbouring hepatocytes which become infection resistant and upregulates MHC class I to increase antigen presentation (better CTL targets if they become infected)
Why is it hard for CTL to deal with sporozoites in the liver?
Very small number of sporozoites make it to liver
CTL must find them all in big liver in just a few days before their maturation/replication cycle is done
Even if they miss one infected cell it will release 100,000 parasites (merozoites?)
Disease almost always progresses last liver
Spleen function?
Key site of immune response to blood stage infection (malaria, sepsis)
Filters red blood cells passing through it
Spleen structure?
Red pulp - filters erythrocytes passing through it - traps old, damaged and senescent bliss cells
White pulp - acts similar to lymph node - lots of white cells scanning for anything suspicious to mount immune response against
Many macrophage types present (key immune sentinels)
What part of plasmodium do PRRs detect?
Hemozoin (PAMP) - waste product produced by plasmodium
ss and ds DNA motifs (PAMP) - Plasmodium is AT rich, recognised as indication of infection
Also recognises DAMPs associated with plasmodium caused damage (eg DNA in extracellular space)
What causes fever spikes in malaria?
Infected erythrocytes burst all at the same time every 48hrs when they contain about 20 parasites
Enormous synchronised release into blood
Leads to large response -> cytokine storm (red cells release lots of (P/D)AMPs when they burst)
Immune response to blood stage plasmodium?
Every 48hrs when bursting occurs lots of macrophages are activated
TNF released by macrophage, travels to hypothalamus, activates fever
Also release NO to kill parasites in red cells
Inflammation
Fever
Parasite killing
Activation of adaptive response
Importance of macrophages in plasmodium infection?
Plasmodium merozoites infect erythrocytes
Non-nucleated so don’t express class I MHC (CTL can’t interact)
Need macrophage to phagocytose them
Reason why macrophages are important in spleen
Adaptive response to plasmodium?
Ag presented on MHC class II
Activates Th cells (along with danger signal costimulation)
Release cytokine IFN-gamma - activated macrophages
Th cells also signal to B cells - antibody response (neutralisation?, opsonisation)
Where do Th cells communicate with B cells?
Germinal centres:
-Lymph nodes
-Spleen (blood stage infections)
Antibody response to blood stage merozoites?
IgG:
-neutralises parasite to inhibit cell invasion
-opsonises parasite to increase phagocytosis
Immune pathology of malaria?
Severe Anaemia
-both healthy and infected erythrocytes are phagocytosed and destroyed (antibodies help specificity but not fully)(for every one infected destroyed ten healthy ones are)
-erythropoiesis is suppressed - less of them produced (caused by cytokines)
-most common in children <2yrs
How is massive immune response to plasmodium regulated?
Th cells balance activation (IFN-gamma) and shut down (IL-10) signals
Allows tuning of macrophage activation to just right level
