problems for intracellular pathogens entry into host cell surviving host defenses metabolism and...
TRANSCRIPT
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 PhagolysosomeLeishmania:• 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
Joiner et al (1990) Science 249:641
tachyzoites tachyzoites + Ab
invasion phagocytosis
no fusion
fusion
PL
L LTg
Tg
M
parasite replication parasite death
Tachyzoite invasion involves apical organelles and formation of parasititophorous vacuole devoid of host membrane proteins.
Ingestion of Host Cytoplasm
food vacuole
cytostome
pinocytosis
Malaria parasite ingests host erythrocyte cytoplasm.
The Food VacuoleA Specialized Lysosome
amino-peptidase
hemoglobin
+hemeglobin
fragments
small fragments(6-8 amino acids)
hemazoinATP
ADP
ATP
ADP
H+
Fe3+
Fe2+
O2
H2O2
H2O + O2
-O2 O2
superoxidedismutase?
catalase?
hemepolymerase
plasmepsin
falcipain
plasmepsin
falcilysin
Pfmdr-1?
aminoacids
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