1. Problems for Intracellular Pathogens Entry into Host Cell Surviving Host Defenses Metabolism and Proliferation Preserving Host Cell Function Cell-to-Cell Transit

2. 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

3. 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

4. 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

5. TOXOPLASMA AND MACROPHAGES Joiner et al (1990) Science 249:641 tachyzoitestachyzoites + Ab invasion phagocytosis no fusion fusion PL L L Tg M parasite replicationparasite death

6. Tachyzoite invasion involves apical organelles and formation of parasititophorous vacuole devoid of host membrane proteins.

7. Ingestion of Host Cytoplasm food vacuole cytostome pinocytosis Malaria parasite ingests host erythrocyte cytoplasm.

8. The Food Vacuole A Specialized Lysosome amino- peptidase hemoglobin + heme globin fragments small fragments (6-8 amino acids) hemazoin ATP ADP ATP ADP H+H+ Fe 3+ Fe 2+ O2O2 H2O2H2O2 H 2 O + O 2 - O 2 O 2 superoxide dismutase? catalase? heme polymerase plasmepsin falcipain plasmepsin falcilysin Pfmdr-1? amino acids

9. 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

10. Problems for Intracellular Pathogens Entry into Host Cell Surviving Host Defenses Metabolism and Proliferation Preserving Host Cell Function Cell-to-Cell Transit