L27 - Malaria Flashcards
The plasmodium lifecycle
- what is the disease
- what is the parasite
- what are the hosts and their characteristics
• Malaria = disease, Plasmodium spp. = parasite
• Needs two hosts; human & Anopheles mosquito
Humans: (11-14 days)
• Skin: sporozoites enter & travel to the liver
• Liver: invasion & replication
• Blood: erythrocytic cycle = fever
Mosquito: (7-14 days)
• Gametocytes ingested and mature (sexual stages)
• Fertilisation → Ookinete → Oocyst gut wall
• Release of sporozoites → salivary gland
How does the immune system respond to sporozoite infection (e.g., malaria)?
Sporozoites are motile and must quickly migrate through the dermis to find a blood vessel—usually within ~20 minutes. During this time, some are destroyed by innate immune cells like macrophages. Others reach draining lymph nodes, where they are taken up by antigen-presenting cells, leading to priming of cytotoxic T lymphocytes (CTLs). This early activation is key for developing immunity against liver-stage infection.
How are sporozoite antigens processed and presented to T cells?
Exogenous antigen (outside the cell) is processed and loaded onto MHC class Il, and presented to a T helper cell (Th, CD4+)
Endogenous antigen (inside the cells) is processed and loaded onto MHC class I, and presented to Cytotoxic T lymphocytes (CTLs, CD8+)
Exogenous → MHCI| T helper (CD4+)
Endogenous → MHCI → CTL (CD8+)
*Cross-presentation, mediated by perforin 2, can export antigen from an endosome into the cytoplasm.
What happens after sporozite enters the blood stream?
They enter liver hepatocytes for replication
- they actively target the liver
- cross the sinusoidal barrier and enter hepatocytes
What happens to the infected hepatocyte?
Sporozites trigger a local innate response in the liver:
- release type 1 interferon
- signals neighbouring hepatocytes
- reduce chance of infection
- increases antigen presentation and class 1 MHC
How does CTL kill infected hepatocytes
- CTL constantly patrol body scanning for surfaces for antigen-MHC class 1 complexes
- CD8 binds to MHC class 1
- FAS/FASL or perforin/granzyme
What is hepatomegaly and splenomegaly
Enlargement of the liver and spleen (due to inflammation)
Why is the spleen important
- Filtration of parasitised Red Blood Cells
- Immune cell activation → Activate those T cells, and also B cells
- Haematopoiesis → in some cases, extramedullary haematopoiesis can occur, which is RBC production (erythropoiesis) outside of the Bone marrow
How is clinical malaria diverse? What is severe malarial anaemia
Diverse bc multiple types with overlapping syndromes
- Clinically - cerebral malaria, severe anaemia, respiratory distress
- Severe anaemia - haemoglobin
- Tissue hypoxia (loss of oxygen in tissues )
- Risk depends on how severe the anaemia is
SMA
- patients may need transfusion
- risk peaks at 1-2 years of age
What is the pathogenesis of malarial anaemia and what mechanism leads to less RBCs
- Lysis of parasitised (p) RBCs.
- Removal of pRBCs in the spleen.
- Decreased and/or suppression of erythropoiesis
- Removal of uninfected RBCs.
important fact
For every 1 pRBC, 12 uninfected RBCs are lost!
What happens during the egress of malaria parasites from red blood cells?
- Mature schizonts contain ~16 merozoites, which are released when the parasitophorous vacuole and RBC membrane rupture
- The RBC swells, its cytoskeleton breaks down, and lysis occurs explosively, scattering merozoites
- This process also releases PAMPs and DAMPs , parasite proteases, and toxic molecules like haemoglobin and haemozoin,
What is haemozoin
- product of haemoglobin metabolism by plasmodia
- heme is aggregated into this crystal
- following RBC rupture Hz is taken up by phagocytes of the spleen
Why do patients with severe P falciparum have reduced numbers of erythroid progenitors?
- Cytokines (TNFa and IFNg inhibits all stages)
- Hz (increased apoptosis of progenitor cells)
- EPO (impaired terminal maturation of TER119 cells)
How does RBC deformability contribute to anaemia
• Spleen is the largest filter of RBCs in the body, with very small openings (splenic slits).
• Surface to volume ratio is a predictor of deformability.
• Parasite infected and uninfected red cells have reduced deformability = stuck!
Why are macrophages important in comb acting malaria
Plasmodium is an intracelllular pathogen but it lives in cell type that doesn’t express MHC class 1 so phagocytosis is the main way to kill
Describe the innate and adaptive immune responses to blood stage parasites
Activated macrophage releases TNF leading to inflammation
Adaptive requires antigen presentation and costipulation
Th cell releases IFNy to increase macrophage
What can antibodies target in the parasite lifecycle
(1) Sporozoites; blocking trafficking to the liver.
(2) Erythrocytic Stages; targeting merozoites & infected RBCs.
(3) Gametocytes; blocking transmission to the mosquito
Immune memory to rmb malaria
Memory lymphocytes
- easier to activate
What are features of naturally acquired immmuity to malaria
Natural acquired immunity has several features:
1. 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.
Why is immunity hard to achieve
Antigenic variation
What are the key immune targets during different stages of malaria infection?
Erythrocytic (blood) stage:
• Variant Surface Antigens (VSAs) on infected RBCs:
• PfEMP1, RIFIN, STEVOR
• Merozoite surface/secreted proteins during invasion:
• MSP1, PfRH5
Liver stage:
• CSP (circumsporozoite protein)
Transmission (sexual) stage:
• Pfs230, Pfs48/45
What is PfEMP1
P falciparum erythrocyte membrane protein 1
• Diverse set of ~60 proteins expressed in a single parasite.
• Proteins express a high degree of sequence variation.
• Switching PfEMP1 variant expression contributes to quick and efficient evasion of the host humoral response.
• Function → binds to EPCR (endothelial protein C receptor), ICAM1, and CD36.
• CD36 is low in the brain vascular endothelium.
• ICAM1 & EPCR are upregulated w/inflammation.
What is the hypothesis for how people eventually become immune
- due to acquisition of a repertoire of responses to many different isolates
- development of cross protective responses to shared antigens
In regards to regulation of immune responses, why is immunity hard to achieve
Treg 1 cells produce IL-10 which inhibits immune cell function and development of quality memory responses
