pathogens and the immune system veronica leautaud, ph.d. vl2@ rice.edu keck hall 224 / 232-lab...
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Pathogens and the immune system
Veronica Leautaud, Ph.D.
vl2@ rice.eduKeck Hall 224 / 232-lab
Lecture 8BIOE 301-Bioengineering and World Health
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Review of lecture 7
• Science– “Science is the human activity of seeking
natural explanations for what we observe in the world around us.”
• Engineering– Systematic design, production and
operation of technical systems to meet practical human needs under specified constraints
– Six steps of the engineering design method
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Infectious diseases: a global health problem
(From Morens, D., et al , 2004)
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Infectious diseases: a global health problem
(MRSA)
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Infectious diseases: a global health problem
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Infectious diseases: a global health problem
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How can technology help?
1. Understanding biology: pathogens & disease immune system
2. Developing vaccines: from idea to product - vaccine design
- production - testing safety & effectiveness
3. Addressing challenges for vaccine development: - Developed vs. developing countries
- The AIDS vaccine challenge
Science
Engineering
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Lecture map
1. The players: Types of pathogens
Cells of the Immune system
2. Types of Immunity
2A. Physical barriers
2B. Innate Immunity
2C. Adaptive Immunity
MacrophagesNeutrophilsComplement proteins
B-lymphocytes: ANTIBODIEST-lymphocytes: Cell-mediatedImmunologic MEMORY
Splinter example
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Lecture map
1. The players: Types of pathogens
Cells of the Immune system
2. Types of Immunity
2A. Physical barriers
2B. Innate Immunity
2C. Adaptive Immunity
MacrophagesNeutrophilsComplement proteins
B-lymphocytes: ANTIBODIEST-lymphocytes: Cell-mediatedImmunologic MEMORY
Splinter example
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Types of pathogens
Bacteria
Mycobacterium tuberculosis Staphylococus aureusEscherichia coli O147:H7Vibrio cholera Bordetella pertussis (whooping
cough)
Viruses
SARS- Severe Acute Respiratory Syndrome
Influenza (Flu)HIV (AIDS)Hepatitis C virusEbola/ Marburg viruses
Parasites
Plasmodium sp. (Malaria)
Cryptospridium Candida albicans
Fungi
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Bacteria
DNA
- Cells with membrane and cell wall (usually)
- Can survive & reproduce outside host
- Can be killed or inhibited by antibiotics
- Responsible for >90% of hospital infections
Size ~ 1 μm
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How do bacteria cause disease?- Invade host- Reproduce- Produce toxins which disturb function of normal cells
Paralyze cilia & inhibit clearance of respiratory secretions= whooping cough
pertussis
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How do bacteria cause disease?
MRSA: Methycillin Resistant Staphylococcus aureus
http://www.npr.org/templates/story/story.php?storyId=15453093
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Viruses Nucleic acid core surrounded by protein capsid, and for some viruses an envelope
Use host intracellular machinery to reproduce
They cannot be killed with antibiotics, but antivirals may inhibit different stages
of their life cycle in the host
>50 viruses that can infect humans
Size ~ 0.1 μm = 100nm
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How do viruses cause disease?
1. Virus invades host cell
- Binds to cell membrane receptors
- Endocytosis brings virus into cell
2. Virus takes over cell
- Use viral nucleic acid and host cell resources to make new
viral nucleic acid and proteins
3. More virus is released from host cell
- Virus causes host cell to lyse OR
- Viral particles bud from host cell surface
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How do viruses cause disease?
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The Human Immunodeficiency virus (HIV)
Spikes
Viral components:
-nucleic acid core (DNA/RNA)
-protein capsid
-envelope
-Glycoproteins
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The Human Immunodeficiency virus (HIV)
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How are we protected against pathogens?
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Lecture map
1. The players: Types of pathogens
Cells of the Immune system
2. Types of Immunity
2A. Physical barriers
2B. Innate Immunity
2C. Adaptive Immunity
MacrophagesNeutrophilsComplement proteins
B-lymphocytes: ANTIBODIEST-lymphocytes: Cell-mediatedImmunologic MEMORY
Splinter example
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Cells of the immune system
Bone marrow
Blood= plasma + cells
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Cells of the immune system
Bone marrow
Blood= plasma + cells
O2 & CO2 transportClotting White Blood Cells (WBC)
(T/B)Macrophages
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Cells of the immune system
Bone marrow
Blood= plasma + cells
Phagocytosis- ‘eating pathogens’ Innate Immunity
Macrophages
Defense vs. parasitesAllergic reactions
B-lymphoctesT-lymphocytesNatural Killer Cells
Antibody productionPathogen killing Adaptive Immunity
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Cells of the immune system
Neutrophil Macrophage Lymphocyte
Phagocytosis- killingB-lymphocytesT lymphocytesNK cells
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Question:
• Based on your understanding of the characteristics of bacteria, viruses, and blood cells, identify which item best represents a bacterium, a virus and a blood cell and be able to explain why you chose each.
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Lecture map
1. The players: Types of pathogens
Cells of the Immune system
2. Types of Immunity
2A. Physical barriers
2B. Innate Immunity
2C. Adaptive Immunity
MacrophagesNeutrophilsComplement proteins
B-lymphocytes: ANTIBODIEST-lymphocytes: Cell-mediatedImmunologic MEMORY
Splinter example
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Types of Immunity
Physical Barriers - skin (2 square meters!)
- mucose membranes (400 square meters!)
Innate Immune System- General inflammatory response
against pathogens outside of the cell
Adaptive Immune System- Can adapt to defend against any
specific invader inside or outside of the cell
- Important when innate immunity cannot defend against the attack
-Provides ‘Immune Memory’
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What happens when you get a splinter?
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What happens when you get a splinter?
• Pathogen makes it past a physical barrier
• Symptoms?– Red, swollen, hot, pus
• What causes these symptoms?– The Innate immune system is kicking into gear!
• Usually innate immune system can take care of it
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The Innate Immune System: 3 main weapons
-Activated Macrophages
Phagocyte (‘eat’) invading pathogensProduce chemicals that:
- increase blood flow (redness & heat)
- cause ‘fuild leaking’ (swelling)
- recruit neutrophils (pus)
Present antigen to adaptive immune system
-Complement proteins Present in tissue and blood
Attach to surface of bacteria and viruses targeting them for phagocytosis
Recruit other immune cells from blood
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What happens when you get a splinter?
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Macrophage attacking E.coli SEM x 8,800 ©Denis Kunkel
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Question:
• Based on your understanding of the innate immune system, represent a macrophage during phagocytosis
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Lecture map
1. The players: Types of pathogens
Cells of the Immune system
2. Types of Immunity
2A. Physical barriers
2B. Innate Immunity
2C. Adaptive Immunity
MacrophagesNeutrophilsComplement proteins
B-lymphocytes: ANTIBODIEST-lymphocytes: Cell-mediatedImmunologic MEMORY
Splinter example
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Recognizes antigens (molecular signatures) specific for each pathogen
Effective against both intra- and extracellular pathogens
Two main components:
The Adaptive Immune System
Humoral immunity - Relies on Antibodies produced by B-lymphocytes- Fights pathogens outside of cells
Cell-mediated Immunity- Relies on specific receptors on the surface of T-lymphocytes- Fights pathogens inside of cells
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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
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1. Neutralization: Blocking the biological activity of toxin or pathogen ie. Blocking access
2. Bridge: Bringing together pathogens and phagocytes
The Adaptive Immune response: humoral immunity
How do antibodies work?
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1. Neutralization
2. Bridge: pathogen-phagocyte
Target cell
Target cell
Macrophage
The Adaptive Immune response: humoral immunity
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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?
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The Adaptive Immune response: humoral immunity
• 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
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(proliferation)
Clonal selection and proliferation
B cells
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The Adaptive Immune response: cell-mediated immunity
• 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 (orchestrate adaptive immune
response)• Regulatory T Cells
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• All cells have Major Histocompatibility Complex (MHC) molecules on surface
How do T Cells recognize Virus-Infected Cells?
• When virus invades target cell, fragments of viral protein are loaded onto MHC proteins
• ‘Profesional’ Antigen Presentation Cells (APCs= phagocytes of innate immunity)
• T Cells inspect MHC proteins and use this as a signal to identify infected cells
Antigens (bits of pathogens) get loaded into MHC molecules:
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Antigen presentation and cellular immunity
T Helper Cell (CD4+)
Macrophage Strengthen antibody response
Killer T-cell (CD8+)
Strengthen Killer T cell response
MHC
TCR
Infected cell
MHC
TCR
Macrophage
Infected cell
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Question:
• Demonstrate how the T cell can identify a virus infected cell: antigen presentation
• Why is this component of the adaptive immune system a significant advance over the innate immune system?
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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
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Immunologic Memory
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The adaptive Immune Response
Putting it together…
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The Adaptive immune response
B cell: antibodies(neutralize & bridge)
T-helper cell
Killer T cell
Antigen presentation
Antigen presentation
macrophage
macrophage
infected cell
1. Cellular Immunity:
2. Humoral Immunity:
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Summary of lecture 8
• Pathogens: Bacteria and Virus
• Levels of Immunity:– Barriers First line of defense
– Innate Inflammation• Phagocytes• Complement
– Adaptive Immunologic memory• Antibody mediated immunity• Cell mediated immunity Pathogens within
cells• Diversity to recognize 100 million antigens
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Next time
• How do vaccines work?
• Vaccine development:• Design• Production• Testing safety & efficacy
• Challenges of vaccine development
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Assignments Due Next Time
• Homework 5- Reading: ‘Polio: an end in sight’. Toby Reynolds - Questions 1-3
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The end.