intracellular parasite immune evasion - T. cruzi

Question 1

infection by T. cruzi

Answer 1

• sits in host cell cytoplasm
  
  • no enclosing membrane
• Chagas disease - endemic to south america
  
  • kissing bugs (triatomines)
  • spread globally by migration of infected individuals
• invades wide range of mammals
  
  • generally any nucleated cell, and phagocytes
  • particular affinity for heart tissue

Question 2

chagas disease phases

Answer 2

• initial acute phase
  
  • fever, muscle pain, often unnoticed
• asymptomatic phase
  
  • often lasts decades if untreated
• clinical disease
  
  • occurs if immune system weakens
  • re-emerges - cardiac disorders, heart failure, sudden death

Question 3

treatment of chagas disease

Answer 3

• effective with nifurtimox or benznidazole
• no vaccine
• vector control is best

Question 4

triatomine vector

Answer 4

• endemic to south america
• likes wooden houses, straw roofs, cracks
• feed at night (people sleeping)
• bites and defecates in the same place/time
  
  • human scratches, rubs in faeces containing parasite
  • not salivary gland transmission
• also transmitted via blood transfusion, mother to new born, food

Question 5

T. cruzi lifecycle

Answer 5

• epimastigote → metacyclic trypomastigote in bug
  
  • metacyclic infective form in faeces
• invades cell → amastigote
• multiplies and cell bursts
• amastigotes reinfect host or differentiate back to metacyclic form
  
  • invade host cells or transmitted by reduvid bugs

Question 6

pathways of T. cruzi invasion

Answer 6

• lysosome-dependent entry
  
  • major pathway
• lysosome-independent entry
• both ultimately involve lysosome fusion

Question 7

lysosome-dependent entry

Answer 7

• exploits host cell’s wound repair porcess to create vacuole
• calcium ion regulated lysosome exocytosis
  
  • directional movement of lysosomes to cell sruface
• lysosomes fuse with point of parasite attachment
  
  • formation of parasitophorous vacuole
• actin remodelling may help
  
  • block actin polymerisation → impedes invasion

Question 8

lysosome-independent entry

Answer 8

• involves parasite contact wihtt he membrane and fusion with early endosomes
• initially enters plasma-membrane derived vacuole
• early endosomes fuse with the vacuole
• later on lysosomes also fuse
• host unaware of parasite in its endocytic system
• actin-independent
• LAMP-1 indicates lysosomal involvement

Question 9

parsitophorous vacuole disruption

Answer 9

• extremely acidic environment created by lysosomal fusion
  
  • can’t remodel or survive like leishmania
• parasite-mediated - breaks out of vacuole
  
  • resides in cytosol
  • access to nutrients
• replicates in the cytosol as an amastigote
  
  • nine rounds

Question 10

common features of T. cruzi invasion

Answer 10

• host cell recognition, attachment and signalling required for initiation
• parasitophorous vacuole formation and lysosome fusion
• transit of the host’s lysosomal compartment
  
  • key for getting into the cytosol and establishing infection
• acidic conditions leading to parasite release
• amastigote replication in cytoplasm
• reversible cell invasion if endosomal-lysosomal system blocked

Question 11

T. cruzi surface molecules

Answer 11

• much simpler than T. brucei/leishmania
• mucins and trans-sialidases
• disruption of C3b binding by changing surface proteins
• unknown receptors invovled in attachment (host and parasite)
  
  • probably mucins, mucin associated protein, DFG-1, GP63

Question 12

GP58-trans-sialidase

Answer 12

• bind host ECM
  
  • laminin, collagen, fibronectin
  • key for invasion
• GP58 binds:
  
  • cytokeratin-18 on host cell surface
  • intermediate filament protein vimentin
• trans-sialidase transfers sialic acid from host cell to mucins for attachment

Question 13

host immunity

Answer 13

• can control but not eliminate parasite
  
  • strong enduring T-cell mediated immunity acquired in acute infection
• innate immunity initially combats
  
  • NK cells, DCs, macrophages using PRRs

Question 14

TLR activation

Answer 14

• activated upon parasite attachment
  
  • GPILs by TLR4 (unanchored GPIs)
  • GPI-mucins by TLR2/6
  • pro-inflammatory cytokine response
• induction of host cell signalling

Question 15

acquired immunity to T. cruzi

Answer 15

• strong CD8+ T cell response
• increased IFN → infected cell lysis
• but only a few T. cruzi antigens recognised strongly
• not enough T cells to eliminate all parasites
  
  • persists in host
• classically activated macrophages and CD8+ T cells most important during chronic phase