BIOE 301 Lecture Eight

1. BIOE 301 Lecture Eight Amit Mistry Feb 6, 2007

2. BIOE 301 – Lecture 8 WARM-UP • Observation: Global average near-surface atmospheric temperature rose 1.1 ± 0.4 °Fahrenheit in the 20th century. • What is the scientific approach to this? • What is the engineering approach to it?

3. Review of Lecture 7 • Science • “Science is the human activity of seeking natural explanations for what we observe in the world around us.” • Five steps of the scientific method • Engineering • Systematic design, production and operation of technical systems to meet practical human needs under specified constraints • Six steps of the engineering design method

4. Q3: How can technology solve health care problems? CS1: Prevention of infectious disease

5. Roadmap of CS 1 • Science • Organisms that cause infectious disease • Immunity • Engineering • How to make a vaccine • Vaccines: From idea to product • Societal Impact • Health and economics • Ethics of clinical trials • Developed world/Developing world

6. Connections – First day of class • What caused the first bone marrow transplants to be rejected by recipients?

7. Bone Marrow - Pluripotent Stem Cells • Hematopoietic stem cells differentiate into: • White blood cells • Red blood cells • Platelets • Mesenchymal stem cells differentiate into: • Bone, cartilage, muscle

9. White Blood Cells Neutrophil Lymphocyte Macrophage “The Defense” “The Good Guys”

10. Pathogens How They Cause Disease “The Offense” “The Bad Guys”

11. Types of Pathogens • Bacteria • Cells with membrane and cell wall (usually) • Can survive outside host; reproduce without host • Can be killed or inhibited by antibiotics • Viruses • Nucleic acid core with protein envelope • Use host intracellular machinery to reproduce • Cannot be killed with antibiotics • >50 different viruses that can infect humans

12. Question: • Based on your understanding of the characteristics of bacteria, viruses, and blood cells, identify which item best represents each and be able to explain why you chose each. • Bacterium • Virus • Blood cell

13. Pathogens Human hair – 100,000,000 nm Red blood cell – 7,000 nm E. coli bacteria – 800 nm Virus – 100 nm www.awcommunity.org www.its.caltech.edu/~boozer

14. Bacteria

15. How do Bacteria Cause Disease? • Invade host • Reproduce • Produce toxins  disturb cell function • Examples • Escherichia Coli • Bacillus Anthracis • Microbacterium tuberculosis • Streptococcus pneumoniae http://www.cubanology.com/Articles/Virus_vs_Bacteria.htm

16. Virus

17. How do Viruses Cause Disease? • Virus invades host cell • Binds to cell membrane receptors • Endocytosis brings virus into cell • Virus takes over cell • Use viral nucleic acid and host cell resources to make new viral nucleic acid and proteins • More virus is released from host cell • Virus causes host cell to lyse OR • Viral particles bud from host cell surface

18. Virus examples: Influenza, HIV, West Nile, Hepatitis Human Papillomavirus, Viriola Major

19. Using Viruses for Good, not Evil • Gene Therapy: infect cells with beneficial DNA • Diabetes • SCID • Cancer • Sickle cell anemia • MS • Cystic fibrosis www.nih.gov

20. Pathophysiology of HIV/AIDS

21. Pathophysiology of HIV/AIDS

22. The Immune System How Are We Protected Against Pathogens?

23. Types of Immunity • Three layers of immunity: • Physical Barriers • Innate Immune System • All animals possess • Adaptive Immune System • Vertebrates possess • Keep pathogens out • Kill them if they get in

24. Types of Immunity - Defense Line of scrimmage Physical Barriers = Defensive Line Innate = Secondary Defense Adaptive = Coach

25. Types of Immunity • Physical Barriers • Skin (2 square meters) • Mucous Membranes (400 square meters) • Innate Immune System • Produces general inflammatory response when pathogens penetrate physical barriers • Adaptive Immune System • Can adapt to defend against any invader • Important when innate immune system cannot defend against attack • Provides immune system with “memory”

26. Physical Barriers

27. What happens when you get a splinter?

28. Pathogens gets past physical barrier Macrophages eat bacteria on splinter Phagocytosis Activated macrophages produce chemicals which: Increase local blood flow Increase permeability of blood vessels Recruit other phagocytes to site What happens when you get a splinter? Redness Heat Swelling Pus

29. What happens when you get a splinter? • Phagocytosis http://jcs.biologists.org/cgi/content/full/119/9/1903/DC1

31. Innate Immune System • Primarily effective against pathogens outside of cells • Two main weapons: • 1) Professional phagocytes • Cells that eat stuff • 2) The complement system • Proteins that tag stuff for destruction

32. Components of Innate Immune System • 1) Macrophages: • Sentinels that patrol periphery • If they find an invader, they become “activated” • If activated, they: • Send signals to recruit other immune system cells (Neutrophils) • Become vicious killers • Present antigen to adaptive immune system (more on this later)

33. Components of Innate Immune System • 2) Complement proteins • Present in tissues & blood • Attach to surfaces of bacteria and viruses • Target them for destruction by phagocytes • Form Membrane Attack Complexes • Recruit other immune cells from blood

34. Adaptive Immune System • Antibody-mediated: • Fight pathogens outside of cells • Cell-mediated: • Fight pathogens inside of cells

35. What is an antibody? • Bridge between: • Pathogen • Tool to kill it • Antibodies have two important regions: • Fab region: • Binds antigen • Binds surface of virus-infected cell • Fc region: • Binds macrophages and neutrophils, induces phagocytosis • Binds natural killer cell, induces killing

36. Question: • Which components of your kit are most like antibodies? • Arrange the components of the kit to demonstrate how these antibodies “bridge” a pathogen and the tool to kill it?

38. Antibodies • How are antibodies made? • B cells • Lymphocytes that make antibodies • Have B cell receptors on surface • 100 million different types of B cells, each with different surface receptors • B cell receptors are so diverse they can recognize every organic molecule • When a B cell binds antigen: • Proliferates - In one week, clone of 20,000 identical B cells • Secretes antibody

40. Adaptive Immune System • How do we kill virus once inside the cell? • Antibodies cannot get to it • Need T cells • T Cells • Recognize protein antigens • When bind antigen, undergo clonal selection • Three types of T Cells: • Killer T Cells (Cytotoxic T Lymphocytes – CTLs) • Helper T Cells (targeted by HIV) • Regulatory T Cells

41. How do T Cells ID Virus Infected Cells? • Antigen Presentation • All cells have MHC molecules on surface • When virus invades cell, fragments of viral protein are loaded onto MHC proteins • T Cells inspect MHC proteins and use this as a signal to identify infected cells

42. Question: • Using the components of the kit, demonstrate the two steps required for viral antigens to be presented on the MHC complexes on the surface of the blood cell.

44. Question: • Demonstrate how the T cell can identify a virus infected cell. • Why is this component of the adaptive immune system a significant advance over the innate immune system?

46. Immunologic Memory • First time adaptive immune system is activated by an antigen: • Build up a clone of B cells and T cells • Takes about a week • After infection is over, most die off • Some remain – memory cells • Second time adaptive immune system is activated by that antigen: • Memory cells are easier to activate • Response is much faster – no symptoms

49. Putting it all together