innate immune response to protozoan pathogens

Question 1

immune response to parasites

Answer 1

• depends on the parasite
  
  • e.g. free living, obligate intracellular
• first line of defence is innate response
• overlaps with adaptive immunity

Question 2

parasite recognition

Answer 2

• leukocyte PRRs recognise PAMPs to activate immune response
  
  • DCs and macrophages activate cytokine production
• TLRs, NLRs - surface or endosomal
• C-type lectins, Scavenger receptors - surface

Question 3

scavenger receptors

Answer 3

• e.g. CD36
  
  • target of PfEMP1
• modulates binding of parasite-infected RBCs to macrophages and DCs
• bind phospholipids and lipoproteins
• reduces B cell activation by DCs, but increases chance of clearance by macrophages
• parasite sustains infection but not at harmful levels
• PfEMP1 maintains binding site residues but changes all others - avoid recognition and clearance by tethering

Question 4

signalling pathways downstream of TLR ligation

Answer 4

• MAPK
  
  • TLR4 (T. cruzi)
  • TLR11 (T. gondii)
  • TLR9 (Trypanosome DNA)
• NFkB
  
  • TLR2-TLR6 (T. cruzi)
  • TLR1-TLR2 (P. falciparum)
• both lead to immune response gene activation

Question 5

role of TLR adaptors

Answer 5

• MyD88 adaptor knockout mice
  
  • lower IFN and IL-12
  • increased susceptibility to T. gondii
  • death when DCs only are lacking, not monocytes alone

Question 6

macrophage stimulation

Answer 6

• detecting parasite alone may not be enough to initiate phagocytic vacuole formation and killing
• additional stimulation by cytokines

Question 7

macrophage polarisation

Answer 7

• depends on environment surrounding monocyte upon activation
  
  • PAMP or IFN → highly phagocytic
  • regulatory cytokines (IL-10) → anti-inflammatory, non-phagocytic
  • IL-4 or IL-13 → alternatively activated macrophages
• all needed for balanced response

Question 8

alternatively activated macrophages

Answer 8

• increased expression mannose receptors and arginase
  
  • arg - leads to biosynthesis and cell proliferation
• involved in resolution of inflammation and repair

Question 9

leishmania infection

Answer 9

• in pro-inflammatory environment, argininge used in iNOS
  
  • RNS → parasite killing
• in regulatory environment, arginine used in arginase pathway
  
  • parasite growth inside macrophage using polyamine synthesis
• 2 pathways compete

Question 10

role of neutrophils

Answer 10

• phagocytosis
• cytokine production
• ROS production
• protease release
• will be counter protective during intracellular infecton by the parasite
  
  • other cells needed

Question 11

neutrophils in T. gondii infection

Answer 11

• protective role
• rapid migration to infection site
• specific reaction to free parasites
• needs to happen at early stages
• NET release

Question 12

natural killer cells

Answer 12

• directly kill stressed cells and viruses
• cytokine production
  
  • polarisation of immune response
• IFN production
  
  • stimulates killing by macrophages
• vital before adaptive immune response is active

Question 13

malaria infection

Answer 13

• monocyte/DC activation recognition
  
  • cytokine release
  • stimulate NK cells
• NK cells
  
  • protective role during liver and blood stages
  • inhibit maturation within hepatocytes
  • IFN release
  • maybe direct killing in blood
  • T cells takeover role as infection progresses