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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)
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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
tachyzoites tachyzoites + Ab ò ò phagocytosis invasion L Tg L Tg å F æ M fusion no fusion PL parasite replication parasite death TOXOPLASMA AND MACROPHAGES 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
ATP hemoglobin H+ plasmepsin Fe2+ O2 ADP globin fragments Fe3+ heme + amino acids -O2 O2 heme polymerase falcipain plasmepsin falcilysin superoxide dismutase? H2O2 hemazoin ATP catalase? small fragments (6-8 amino acids) Pfmdr-1? H2O + O2 ADP The Food VacuoleA Specialized Lysosome amino- peptidase
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