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Malaria and skin
sporozoite is motile and migrates through the dermis, seeking a blood vessel
immune system reacts and destroy invading sporozoites
travel to LN where taken up by APC
antigen presentation of sporozoites
exogenous antigen processed and loaded onto MHC II and presented to TH cells
Endogenous antigens processed and loaded onto MHC 1 and presented to CTLs
how do sporozoites enter the liver
find a capillary bed and carried by blood flow
target liver and enter hepatocytes
Kupfer cells (specialised macrophages in liver) can take up sporozoites
what happens to infected hepatocyte
recognise sporozoites
release T1 interferon
signals to neighbouring hepatocytes
reduced chance of infection
increased Ag presentation
how does a CTL kill
Antigen recognition – CTLs will constantly patrol the
body, scanning surfaces for antigen-MHC class I complexes
Specific recognition triggers them to become active
The co-receptor (CD8) binds to MHC class I itself, to add stability and strengthen interaction
CTL mechanism of killing
FAS/FASL —> death receptor —> activate caspases
Perforin & Granzyme B —> pore-forming protein followed by a family of serine proteases —> apoptosis
what happens in liver?
hepatomegaly - enlargement of liver
driven by infection and inflammation
what happens to spleen
splenomegaly —> enlarged spleen
why is the spleen important
Filtration of parasitised Red Blood Cells
Immune cell activation —> Activate those T cells, and also B cell
Haematopoiesis —> in some cases, extramedullary haematopoiesis can occur, which is RBC production (erythropoiesis) outside of the Bone marrow
what is severe malaria anaemia
haemoglobin <5g/dL and parasites
hypoxia, acidosis
may need transfusion
risk peaks at 1-2 years off age
what are the mechanisms leading to less RBCs
Lysis of parasitised (p) RBCs.
2. Removal of pRBCs in the spleen.
3. Decreased and/or suppression of erythropoiesis
4. Removal of uninfected RBCs
what is hemozoin
A crystalline with a brown pigment.
• A product of haemoglobin metabolism by Plasmodia.
• Formed and sequestered to the digestive vacuole
how is Hz immunostimulatory
macrophages with Hz produce large amounts of cytokines (IL-10/IL-12,TNFa) & chemokines.
Hz acts through TLR9, presenting parasite DNA
effect of RBC deformability
spleen has small openings for filtering RBCs
parasite deformed cells get stuck
why are macrophages so important in malaria
plasmodium is an intracellular pathogen that lives in one of the only cells in the body that doesn’t express MHC 1
means no programmed apoptosis as a killing mechanisms
activated macrophages take over and phagocytose infected cells
what induces inflammation in malaria infections
rupture of RBCs releases PAMPs and DAMPs —> cytokine storm
innate immune response to blood stage parasites
fast acting and leads to inflammation, parasite killing and activation of adaptive immune system
adaptive immune response to blood stage plasmodium
requires AP and co-stimulation
leads to activation and proliferation
T cell control of innate immunity
features of naturally acquired immunity to malaria
Effective in adults after uninterrupted lifelong heavy exposure.
2. Lost upon cessation of exposure.
3. Species specific.
4. Somewhat stage specific.
5. Acquired at a rate which was dependent on exposure
what is PfEMP1
P. falciparum erythrocyte membrane protein 1 (PfEMP1)
Diverse set of ~60 proteins expressed in a single parasite
Switching PfEMP1 variant expression contributes to quick and efficient evasion of the host humoral response.
function of PfEMP1
binds to EPCR (endothelial protein C receptor), ICAM1, and CD36.
CD36 is low in the brain vascular endothelium
ICAM1 & EPCR are upregulated w/inflammation.
why is immunity hard to achieve
T regulatory 1 cells produce IL-10.
IL-10 inhibits immune cell function and thus efficient function and development of quality memory responses.