Immunity to Infectious Micro- Organisms Anti-viral Immune Responses and Viral Evasion of Host Responses. ********** Immunity to Bacterial Diseases and Bacterial Evasion of Host Responses. ********** Emerging Infectious Diseases, Pandemic Disease, and Bioterrorism ********** Immunity to Protozoa, Multicellular Parasites, and Fungi Folder Title: MicroInfect Updated: November 20, 2013
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Immunity to Infectious Micro-Organisms Anti-viral Immune Responses and Viral Evasion of Host Responses. ********** Immunity to Bacterial Diseases and Bacterial.
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Immunity to Infectious Micro-OrganismsAnti-viral Immune Responses and Viral Evasion of Host
Responses.**********
Immunity to Bacterial Diseases and Bacterial Evasion of Host Responses.
**********
Emerging Infectious Diseases, Pandemic Disease, and Bioterrorism
**********
Immunity to Protozoa, Multicellular Parasites, and Fungi
Folder Title: MicroInfect Updated: November 20, 2013
Infectious Agents Pathogenic for Humans and for Veterinary and Farm Animals (Part 1)
Viruses• Enveloped RNA Viruses (HIV, Influenza, Hepatitis C)• Naked RNA Viruses {Polio, Hepatitis A, Rhino-viruses (common cold)}• Enveloped DNA Viruses
(Herpes Simplex, Epstein Barr – Mononucleosis, Variola major - Smallpox, Vaccinia - cowpox, Hepatitis B)
Cellular Secretions• Biochemical barriers : Enzymes (can come from innate
immune response system)• Chemical barriers: pH, oxidants (can come from innate
immune responses)
Physical BarriersElevated Temperature (Fever)
Cellular Competition: Gut flora
Innate Natural Immune Responses to Infectious Agents
Gram-positive Bacteria - Peptidoglycan (exposed)• Activates alternative complement pathway - C3b• Opsonizes Bacteria for Enhanced Host Phagocytosis
Gram-negative Bacteria - 2nd Envelope over Peptidoglycan• Bacterial Endotoxins - e.g. Lipopolysaccharide• Stimulates Cytokines (TNF, IL-1, IL-6)• From Macrophages and endothelial cells• Activates Macrophages
Interferon Stimulation by Viral Infectious Agents• Can Directly inhibit viral production• Can activate and stimulate NK Cells to attack virally infected cells• Possibly by viral effect on MHC Class I Protein Synthesis
Innate Natural Immunity and Anti-Viral Responses
Type I Interferons (IFN and IFN)• Produced by Virally-infected Cells• Also from Monocytes, Macrophages, and Fibroblasts
Mechanims of Action of IFN and IFN• Infected cell produces membrane receptors for IFN and • Activates an RNAase that cleaves viral RNA• Inactivates viral protein synthesis by effects on dsRNA-dependent protein
kinase • Induces Anti-viral response and resistance to intra-cellular viral replication
NK Cells • Activated by IFN and IFN; become cytotoxic for virally-infected cells• Also activated by IL-12 - produced in response to viral infection
Humoral Immunity & Anti-Viral ResponsesAntibody-mediated Anti-viral Responses• Prevent initial infection or reinfection• Less effective against intracellular viral infections• Less effective against viral DNA incorporated into host genome
Secretory IgA - Blocks viral binding to target cells
General Immunoglobulin Isotypes• Block Fusion Between Virus Envelop and Host Cell Membrane• Enhance phagocytosis by opsonization of viral particles
IgM - Agglutinates viral particles
IgM and IgG - Activates Complement• Opsonization by Complement Fragment C3b for phagocytosis• Lysis of virus envelop by membrane attack complex
Cell-Mediated Immunity & Anti-Viral Responses
Interferon • From TH1 Helper T-Cells or Tc• Direct Anti-viral Action
Cytoxic T-Cells (CTLs)• Kill virus-infected cells; Eliminates source of additional virus• Presentation of Viral Peptides by MHC-Class I Proteins• Virus-specific T-cell Clones; Can confer specific immunity by
passive (adoptive) transfer to unifective recipient
NK Cells and Macrophages• Antibody recognition of virus antigens on cell surface• Kill by ADCC (Antibody-dependent Cell-mediated Cytotoxicity)
Activated TH1 Cells• IFN, IL-2, TNF attack virus directly or indirectly• IFN has direct anti-viral effects• IL-2 Recruits Tc to become Effector CTL
p. 449
Mechanisms of Anti-viral Immunity
Interferon Inhibition
Of Viral Replication
In Virally-infected
Cells
Degrades RNA needed for viral replication
Shuts down protein synthesis needed for viral replication
Viral Evasion of Host Responses:Effects on Infected Cells
Block Intra-cellular Effects of IFN and IFN• Blocks intra-cellular effects on PKR - RNA-dependent protein kinase• By hepatitis C virus
Inhibition of Antigen-Presentation in Virally-infected Cells• By Herpes Simplex 1 and 2 (HSV1 and HSV2) Early Proteins• Inhibits TAP (Transporter Associated with Antigenic Protein)• Blocks delivery of Antigenic Peptide to MHC-Class I Protein• No presentation to CD8+ CTL
Down-regulation (Shutting Down) of Class I MHC Proteins• CMV (Cytomegalo Virus) and Adeno Viruses
Block Class II MHC Protein • Blocks Antigen-specific Anti-viral Helper T-Cells• By CMV, Measles, HIV
Viral Evasion: Direct Viral EffectsInhibition of Complement Pathways• Vaccinia and HSV
Antigenic Variation (Mutations in Virus Surface Proteins)• Rhino Viruses (Common Cold viruses)• Influenza• HIV
Generalized Host Immuno-Suppression• Direct Effects on Macrophages and Lymphocytes Destruction of Immune Cells Alteration of Cell function• CMV, HIV, and EBV (Epstein-Barr Virus)• Paramyxo (Mumps) Virus; Measles Virus
Cytokine-based Effects by Virus• Production of IL-10 Mimic by EBV• Suppresses TH1 Subset• Reduces Levels of TNF and IFN, and IL-2
Pathogenicity of Influenza Virus
Host Range:• Mammals, Birds• Can cross species barriers Duck influenza can infect pigs Pig influenza can infect humans• Can produce extensive antigenic reassortments - "antigenic shift"• Subject to Point Mutations in Hemagglutin (Binds to Host-Cell Sialic Acid) -
"Antigenic Drift" Host resistance based on Ab to Hemagglutin is by-passed
Influenza Pandemics• Killed 20 Million - Post World War I (1918 - 1919)• Largely Young Adults Lower prior exposure and cross-reactive immunity? More extensive exposure to infected persons?
Over-aggressive inflammatory immune response?
Diagram of Influenza
Virus Structure Figure 17-3
Kuby- Immunology
4th Edition
p. 429
Dimensions in Cell Biology & Microbiology100 um (100 microns) • 0.1 mm• Diameter of human hair
10 um (10 microns)• Diameter of a red cell• 10 Red cell diameters = one human hair diameter
1 um (1 micron)• One-tenth the diameter of a red cell• One-hundredth the diameter of a human hair• 1000 nm (1000 nano-meters)
100 nm (0.1 um or 0.1 microns)• One-hundredth the diameter of a red cell• One-thousandth the diameter of a human hair• Size of an enveloped RNA or Enveloped DNA Virus
Structure of Influenza VirusRNA Virus• RNA Genome in nucleocapsid of Matrix proteins• 8 Different Strand of Single-Stranded (ss) RNA• RNA associated with Viral nucleoproteins and RNA polymerase• Codes of 10 different viral proteins
Enveloped RNA Virus• 100 nm Diameter (100 nano-meters - See "Dimensions" Graphic)• Host-derived plasma membrane (buds from infected host cell)• Contains Viral protein spikes Neuraminidase (for viral release from host membrane sialic acid groups) Hemagglutinin (for viral attachment to target cell)
Diagram of Influenza
Virus Structure Figure 17-3
Kuby- Immunology
4th Edition
p. 429
Host Response to Influenza Virus
Humoral Immune Response to Influenza Virus• Antibody Strain-Specific for Virus Hemagglutinin in Virus Envelop• Prevents Virus Binding to Host Target Cell• Antibodies Block Binding Cleft in HA for Host Cell Membrane Sialic Acid Antibody titer peaks within a few days after infection Decreases for six months Plateaus and persists for several years• Antigenic Shift involving entire viral single-stranded RNA's incorporation and
increase in infectivity of newly arising influenza strain.• Antigenic Drift involves point mutations in Hemagglutinin or Neuraminidase
allowing for viral escape from antibody inhibition.
Host Protection from Influenza Infection• Antibody prevents reinfection by same strain of Influenza• Antigenic drift of viral HA requires re-vaccination for newly emergent or re-
emerging strains• Serum antibody not required for recovery after infection• CTL's may play a role in responses after infection
p. 453
p. 453
p. 452
p. 453
Sequence variations in 10 different proteins in three different strains of influenza type A viruses.(HA = Hemagglutinin;NA = Neuraminidase;M = matrix protein;N and P are nucleoproteins)
The following slides are Turning Point Fill-in-the-Blank question. Please clear your desk and respond.
No talking or other kinds of consultation, please.
The 3rd leading cause of death world-wide after cardiovascular diseases (#1) and infectious diseases (#2) was listed as “neoplastic” diseases. What are neoplastic
diseases generally called? ________________
1 2 3 4 5 6
17% 17% 17%17%17%17%
Rank Responses
1
2
3
4
5
6 Other
Point mutations in hemagglutinin or neuraminidase lead to loss of recognition by antibodies. This is called antigenic _ _ _ _ _.
1 2 3 4 5 6
17% 17% 17%17%17%17%
Rank Responses
1
2
3
4
5
6 Other
Bacterial Infection and PathogenicityBacterial Entry Points (Non-immunological Barriers)• Gastro-intestinal, Respiratory, Genito-urinary epithelial linings• Epidermal Barriers - Entry by Wounding or Animal and Plant Vectors
Steps in Bacterial Infection• Attachment to Target Cells Surface Pili on Bacteria Adhesion Molecules• Proliferation• Invasion of Host Tissues• Toxin-induced Damage to Host Functions (Bacterial Exotoxins)
Pathogenicity due to host Responses• Granulomas in tuberculosis and leprosy
Granuloma(tubercule)
in pulmonary tuberculosis
Kuby -ImmunologyFigure 17-9
4th Ed., p.436
Bacterial Evasion of Host Responses
Host Responses Affecting Bacterial Attachment• Digestion of IgA - by Neisseria gonorrhoeae, and Neisseria meningitis -by hemophillus influenzae• Antigenic drift in bacterial attachment pili proteins
Responses Affecting Bacterial Proliferation and Invasion• Inactivation of complement components• Induction of apoptosis in host response cells• Escape intra-cellular destruction in lysosomes Prevent lysomal membrane fusion with phagosome Block action of lysosomal oxidative components -Listeria moncytogenes -Mycobacterium avium
p. 457
p. 467
I’m hanging in there! I’m still here and still paying attention