Transcript No Slide Title

Problems for
Intracellular Pathogens
•
•
•
•
•
Entry into Host Cell
Surviving Host Defenses
Metabolism and Proliferation
Preserving Host Cell Function
Cell-to-Cell Transit
Entry into the Host Cell
• specialized structures
• apical complex (Apicomplexa)
• polar tube (Microsporidia)
• phagocytosis (endocytosis)
• ie, macrophages
Macrophages as host cells?
• detect, ingest, and destroy
infectious agents
• antigen presentation
• secrete pro-inflammatory
cytokines
Survival in the Phagolysosome
Leishmania:
• has proton pump to maintain
intraparasite pH
• amastigote surface resistant
to proteases
• degrades host hydrolases
• down regulates oxidative
burst and cytokine response
Invasion by T. cruzi
• phagocytosis followed by
escape from phagolysosome
• parasite replicates in host
cytoplasm
Tc-TOX:
• T. cruzi protein with
hemolytic activity
• pH 5.5 optimum
•  pH of phagolysosome
blocks escape
• C9 antibodies cross-react
Andrews et al (1990) Cell 61:1277
TOXOPLASMA AND MACROPHAGES
tachyzoites

Tg
tachyzoites + Ab

invasion
Tg
L
MF
no fusion
parasite replication

phagocytosis
L
 fusion
PL
parasite death
Joiner et al (1990) Science 249:641
Tachyzoite invasion involves apical organelles and formation of
parasititophorous vacuole devoid of host membrane proteins.
Ingestion of Host Cytoplasm
cytostome
Malaria parasite ingests host
erythrocyte cytoplasm.
food vacuole
pinocytosis
The Food Vacuole
A Specialized Lysosome
ATP
hemoglobin
Fe2+
O2
Fe3+
-O
2
O
2
superoxide
dismutase?
H2O2
H+
plasmepsin
globin
heme + fragments
heme
polymerase
falcipain
plasmepsin
hemazoin
falcilysin
amino
acids
aminopeptidase
ATP
catalase?
H2O + O2
ADP
small fragments Pfmdr-1?
(6-8 amino acids)
ADP
Natural Resistance
to Malaria
• inherited erythrocyte disorders associated
with protection against malaria:
• sickle-cell anemia
• thalassemia
• G6PD deficiency
• all 3 may make the erythrocyte more
sensitive to oxidative stress
Problems for
Intracellular Pathogens
•
•
•
•
•
Entry into Host Cell
Surviving Host Defenses
Metabolism and Proliferation
Preserving Host Cell Function
Cell-to-Cell Transit