Lecture 10: Immune Responses to Parasite (Malaria) Infection Flashcards
Genus Plasmodium (single celled, protozoan) P. falciparum, P vivax)
- causative agent of malaria.
- parasitic organism with mosquito and mammalian hosts.
- threatens 2.5 billion people (40% of world population)
- 500m illnesses/year with 1m deaths
- causes 20% of childhood deaths in Africa- one every 30 seconds.
Genus Anopheles
- mosquito vector for Plasmodium
- usually found in tropical and subtropical countries but starting to spread North (ex: Texas) because of global warming.
- male and female drink nectar.
- female also drinks blood for reproduction
- females are classical disease vectors, transporting pathogens from one host to another.
- vectors for yellow fever and malaria- killing millions of humans.
Principal site of infection for plasmodium?
Red blood cells
Growing parasite consumes and degrades intracellular proteins, mainly _________.
hemoglobin
Plasmodium will put up a surface antigen on the RBC. What happens after?
cryptic surface antigens are exposed and new parasite proteins are inserted in the membrane.
Infected RBCs “stick” to the lining of ________________, way of hiding from splenic processing and filtration.
small blood vessels
What is the first cell that sporozoites (infected form of Plasmodium) infect?
liver cell
Mature liver schizont
packed with plasmodium after replication
Merozoites
new form of Plasmodium
will circulate in bloodstream
can go back and infect other RBCs
Proboscis
- organ for retrieving blood meal.
- have serrated edges that minimize pain. You won’t know that it’s actually biting you.
- one tube sucks blood
- second tube injects saliva
- feed undetected up to 1.5 min.
Saliva from mosquito contains ___________ and ___________ agents which stops clotting and blocks pain response. Means you don’t get coagulation.
anti-hemostatic and anti-inflammatory agents
Mosquito injects saliva containing ___________ with blood.
sporozoites
Host defenses- Pre-liver stage
- Sporozoite sheds its coat readily and diverts antibody responses by reducing antibody-mediated complement fixation or opsonization.
- complement can some in and bind the IgM and this can lead to complement punching holes in sporozoite (becomes shriveled)
What happens when mosquito injects saliva to mammalian host?
- Mosquito injects saliva containing sporozoites with blood.
- Sporozoites rapidly (30 min.) infect liver.
Host defense: After liver stage (steps)
(This takes time and the liver infection stage is very quick)
- Parasite antigens are presented by APC to naive CD8 T cells in the spleen.
- CD8 T cells are activated, expand clonally and mature.
- Active CD8 T cells migrate to the liver.
- Infected hepatocytes present antigens and are destroyed by CD8 T cells
Parasites replicates in ________ and matures into __________, which burst out of the hepatocyte and enter blood.
hepatocytes, merozoites
Intermediate host defenses: RBC stage of infection
What are the two mechanisms?
These mutations are all common where malaria is common, an indication of the evolutionary pressure of malaria.
- Hemoglobin mutations
- Duffy (receptor) antigen mutations
Hemoglobin mutations (HbS, sickle cell trait)
cause the RBC to lyse faster after infection, disrupting parasite growth.
Duffy (receptor) antigen mutations
prevent P. vivax entry into RBC.
Variant (var) surface proteins
- used in immune avoidance
- the Plasmodium genome encodes 50-60 copies of var genes.
- Var genes cause infected RBC to adhere to endothelium
All of them have the purpose of doing sequestration of the infected RBCs in the capillaries and keeping them away from the spleen.
Every day or so, var gene expression switches and an entirely new surface antigen is formed.
Why?
These ‘new’ plasmodium replicate in RBC and making it more difficult to induce both T and B- cell dependent immunity.
Adaptive immunity takes days to develop.
Eventually by adulthood there are memory cells to all variants of var and relatively good immunity is in place.
Red Blood Cell stage of infection
- Infected RBC express parasite (var) antigens on their surface (makes it hard for T and B cell recognition)
- RBCs lack nuclei and do not express MHC I and therefore infected cells are not targets for CD8 T cells.
Splenic Filtration- CD4 T cell activation
Steps
- Merozoite antigen filtered in spleen, captured by APC and displayed on MHC class II
- Naive CD4+ T cell interacts with peptide/MHC II on APC (1st signal)
- APC delivers second signal required for T cell activation
- CD4+ T cells expands clonally and matures into helper T cell
CD4 T Cell activation promotes
antibody response
Opsonization/ Phagocytosis steps in fighting infection from plasmodium
- Anti-var antibody opsonizes (coats) microbes.
- Macrophage Fc-receptors bind opsonized microbes.
- Signals from Fcγ receptors activate phagocytosis.
- Phagocytes internalizes antibody-coated microbe.
- Phagocyte destroys internalized microbe. Peptides may be displayed on MHC II for CD4 activation.
Natural killer cells
- innate immune lymphocytes that detect and destroy infected cells.
- NK cells express receptors that recognize cell surface molecules of stressed (i.e. infected cells) or normal cells.
- NK cells degranulate on target cells, triggering apoptosis in the target.
- engagement of NK cell activating receptors can result in NK cell activation and destruction of the infected cell.
NK Cell Antibody-dependent Cell-mediated Cytotoxicity (ADCC)
- Antibodies bind antigens on the surface of target cells.
- NK cell CD16 Fc receptors recognize cell-bound antibodies.
- Cross-linking of CD16 triggers degranulation into a lytic synapse.
- Tumor cells die by apoptosis or pathogen infected cell.
Host defenses against parasites: Degranulation
- mast cells and eosinophils can recognize antibodies (IgE) opsonized on the parasite.
- activation of FceR on the surface of the cell by the antibody induces receptor activation.
- cell induces degranulation to destroy parasite directly.
