Malaria

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22 Terms

1
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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

2
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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

3
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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

4
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what happens to infected hepatocyte

  • recognise sporozoites

  • release T1 interferon

  • signals to neighbouring hepatocytes

  • reduced chance of infection

  • increased Ag presentation

5
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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

6
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CTL mechanism of killing

  • FAS/FASL —> death receptor —> activate caspases

  • Perforin & Granzyme B —> pore-forming protein followed by a family of serine proteases —> apoptosis


7
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what happens in liver?

  • hepatomegaly - enlargement of liver

  • driven by infection and inflammation

8
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what happens to spleen

  • splenomegaly —> enlarged spleen

9
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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


10
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what is severe malaria anaemia

  • haemoglobin <5g/dL and parasites

  • hypoxia, acidosis

  • may need transfusion

  • risk peaks at 1-2 years off age

11
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what are the mechanisms leading to less RBCs

  1. Lysis of parasitised (p) RBCs.
    2. Removal of pRBCs in the spleen.
    3. Decreased and/or suppression of erythropoiesis
    4. Removal of uninfected RBCs

12
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what is hemozoin

  • A crystalline with a brown pigment.
    • A product of haemoglobin metabolism by Plasmodia.
    • Formed and sequestered to the digestive vacuole

13
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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


14
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effect of RBC deformability

  • spleen has small openings for filtering RBCs

  • parasite deformed cells get stuck

15
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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

16
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what induces inflammation in malaria infections

rupture of RBCs releases PAMPs and DAMPs —> cytokine storm

17
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innate immune response to blood stage parasites

  • fast acting and leads to inflammation, parasite killing and activation of adaptive immune system

18
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adaptive immune response to blood stage plasmodium

  • requires AP and co-stimulation

  • leads to activation and proliferation

  • T cell control of innate immunity

19
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features of naturally acquired immunity to malaria

  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

20
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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.

21
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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.

22
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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.