Microbes-L17-Immune Responses to Malaria

protozoal parasites

1. flagellates- African sleeping sickness

2. apicomplexans- malaria

how much bigger is malaria than mammalian cells

x5000

malaria- a global disease- stats

• half a million people die- half of them being children

• lifelong exposure rarely leads to immunity- bugs change constantly

• affects brain function in children

plasmodium falciparum- what are the hosts

• 2 hosts- transmitted by female anopheles mosquitos

• 75% of causes due to plasmodium falciparum

malaria life cycle

1. infected mosquito picks up plasmodium from a previous feed

2. gets injected into the human and enters blood to the liver

3. liver- hepatocytes and divide and make MEROZOITES and released to the blood

4. MEROZOITES can become HYPNOZOITES- ie asleep

5. MEROZOITES infect RBC- produce male and females

6. gametocytes in the blood damage RBC as they burst

7. another mosquito will ingest this gametocytes and make oocyst which burst and release sporozoites

how is malaria diagnosed and the pathology- ie symptoms

• by a blood smear- can see rings

• destruction of RBC- causes anaemia and can cause death

• causes daily fever cycles at first- leading to tertian

• kidney damage, enlarged liver, vomiting

• spleen inflammation from macrophages

• vascular inflammation due to RBC binding to endothelium- clotting and inflammatory cytokines- DEATH!!

how does malaria cause inflammation?

innate: PAMP→DAMPs→innate cell activation

• PAMPs produced by parasite- macrophages will responds and makes cytokines such as TNF- alpha, IL-6

• RBC will stick to vessel walls- which triggers neutrophils to phagocytose(too much can cause tissue, capillary damage and vascular inflammation)

• chemokines- small proteins w/ dilsufide bonds- movement of immune cells to spleen, live etc(overproduction during malaria is bad!!)

how are RBC killed in malaria?

• cytotoxic CD8 T cells

what is the target of inflammation- and consequences INDEVELOPING BABIES?

• at placenta- site of infection- immune cells localised to increase finlamattory response- PREMATURE BIRTH- multi organ failure, cerebral

adaptive immunity to malaria? why is it useless?

• mediated by inflammatory cytokines

• dendritic cells carry antigens go to the lymph and activate T cells CD8-cytoxic

• presenting MHC I molecule

T cell wasn’t enough- re-infection occurred

what is the malaria vaccine?

RTS- S/AS01- first effective vaccine after 40 years

• 36% protection

• 72% mortality reduction

• like a hep B virus like particle- fusion of p.falciparum and hep B

• antigen presented by parasite itself- doens’t make a good immune response

• when the parasite antigens are packaged in viral like particles- mimics a viral infection and better adaptive immunity

what does malaria vaccine target?

• targets sporozoites and the liver stage- immobilises parasite and prevents hepatocytes

why would parasite vaccines target the liver?

liver has a role in inflammation- local and systemic- acute phase, cytokines IL10 etc

• hepatocytes produce acute phase proteins- ie compliment protein and aid in defence

p.falciparum- multiplies silently in the liver- the liver usually suppresses immune response and parasites hide without triggering inflammation.

• targeting liver- activates immunity early

liver- what immune cells are in there?

• lots of NKs, dendritic cells, kupffer cells, myeloid and lymphoid cells

• infectious agents go here- has immunological tolerance