Lecture 10: Immune Responses to Parasite (Malaria) Infection

Question 1

Genus Plasmodium (single celled, protozoan) P. falciparum, P vivax)

Answer 1

• 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.

Question 2

Genus Anopheles

Answer 2

• 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.

Question 3

Principal site of infection for plasmodium?

Answer 3

Red blood cells

Question 4

Growing parasite consumes and degrades intracellular proteins, mainly _________.

Answer 4

hemoglobin

Question 5

Plasmodium will put up a surface antigen on the RBC. What happens after?

Answer 5

cryptic surface antigens are exposed and new parasite proteins are inserted in the membrane.

Question 6

Infected RBCs “stick” to the lining of ________________, way of hiding from splenic processing and filtration.

Answer 6

small blood vessels

Question 7

What is the first cell that sporozoites (infected form of Plasmodium) infect?

Answer 7

liver cell

Question 8

Mature liver schizont

Answer 8

packed with plasmodium after replication

Question 9

Merozoites

Answer 9

new form of Plasmodium

will circulate in bloodstream

can go back and infect other RBCs

Question 10

Proboscis

Answer 10

• 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.

Question 11

Saliva from mosquito contains ___________ and ___________ agents which stops clotting and blocks pain response. Means you don’t get coagulation.

Answer 11

anti-hemostatic and anti-inflammatory agents

Question 12

Mosquito injects saliva containing ___________ with blood.

Answer 12

sporozoites

Question 13

Host defenses- Pre-liver stage

Answer 13

• 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)

Question 14

What happens when mosquito injects saliva to mammalian host?

Answer 14

1. Mosquito injects saliva containing sporozoites with blood.
2. Sporozoites rapidly (30 min.) infect liver.

Question 15

Host defense: After liver stage (steps)

(This takes time and the liver infection stage is very quick)

Answer 15

1. Parasite antigens are presented by APC to naive CD8 T cells in the spleen.
2. CD8 T cells are activated, expand clonally and mature.
3. Active CD8 T cells migrate to the liver.
4. Infected hepatocytes present antigens and are destroyed by CD8 T cells

Question 16

Parasites replicates in ________ and matures into __________, which burst out of the hepatocyte and enter blood.

Answer 16

hepatocytes, merozoites

Question 17

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.

Answer 17

1. Hemoglobin mutations
2. Duffy (receptor) antigen mutations

Question 18

Hemoglobin mutations (HbS, sickle cell trait)

Answer 18

cause the RBC to lyse faster after infection, disrupting parasite growth.

Question 19

Duffy (receptor) antigen mutations

Answer 19

prevent P. vivax entry into RBC.

Question 20

Variant (var) surface proteins

Answer 20

• 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.

Question 21

Every day or so, var gene expression switches and an entirely new surface antigen is formed.
Why?

Answer 21

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.

Question 22

Red Blood Cell stage of infection

Answer 22

• 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.

Question 23

Splenic Filtration- CD4 T cell activation

Steps

Answer 23

1. Merozoite antigen filtered in spleen, captured by APC and displayed on MHC class II
2. Naive CD4+ T cell interacts with peptide/MHC II on APC (1st signal)
3. APC delivers second signal required for T cell activation
4. CD4+ T cells expands clonally and matures into helper T cell

Question 24

CD4 T Cell activation promotes

Answer 24

antibody response

Question 25

Opsonization/ Phagocytosis steps in fighting infection from plasmodium

Answer 25

1. Anti-var antibody opsonizes (coats) microbes.
2. Macrophage Fc-receptors bind opsonized microbes.
3. Signals from Fcγ receptors activate phagocytosis.
4. Phagocytes internalizes antibody-coated microbe.
5. Phagocyte destroys internalized microbe. Peptides may be displayed on MHC II for CD4 activation.

Question 26

Natural killer cells

Answer 26

• 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.

Question 27

NK Cell Antibody-dependent Cell-mediated Cytotoxicity (ADCC)

Answer 27

1. Antibodies bind antigens on the surface of target cells.
2. NK cell CD16 Fc receptors recognize cell-bound antibodies.
3. Cross-linking of CD16 triggers degranulation into a lytic synapse.
4. Tumor cells die by apoptosis or pathogen infected cell.

Question 28

Host defenses against parasites: Degranulation

Answer 28

• 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.