Immunity to Infectious Micro-OrganismsAnti-viral Immune Responses and Viral Evasion of Host

Responses.**********

Immunity to Bacterial Diseases and Bacterial Evasion of Host Responses.

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Emerging Infectious Diseases, Pandemic Disease, and Bioterrorism

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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)

• Naked DNA Viruses (Adeno-viruses; SV40 Virus; Polyoma viruses)“Envelop” = lipid bilayer membrane, host-derived;

Contains proteins and glycoproteins derived from pathogen or from the host.

Bacteria• Gram Positive (No 2nd cell envelop) - Anthrax, Staphylococci, Streptococci• Gram Negative (2nd Cell envelop with membrane endotoxins) - E coli• Extra-cellular (i.e. pathogen is outside of host cells):

Neisseria gonorrhoeae; Streptococcal pneumonia• Intracellular (i.e. pathogen gets inside of host cells):

Listeria Monocytogenes; Tuberculosis; Typhus (rickettsia)• Exotoxin Producers: Diptheria, Anthrax, Botulism, Tetanus, Yersinia pestis

Infectious Agents Pathogenic for Humans and for Veterinary and Farm Animals (Part 2)

Protozoans• Plasmodium falciparum - Malaria• Trypanosoma brucei - Sleeping Sickness• Trypanosoma cruzei - Chagas Disease

Fungal (Yeast) Diseases• Ring-worm; Athletes feet• Candidiasis• Oral "Thrush"; Other opportunistic fungal pathogens

Multi-Cellular Parasitic Diseases• Parasitic Worms - (Helminths)• Schistosomiasis (worm pathogen transmitted by snails

Pathogenicity of Infectious Diseases in Humans

1 Billion Infected World-Wide

15 Million Deaths per Year

Greatest Impact in Third-World Countries

• No Economic Incentive to Develop Treatments

• Potential Liabilities in Testing and from Failures

Significance of the "Global Village”

• Emergence of resistance to Tuberculosis

• Emigration of cholera and leishmaniasis

• Disease survival in susceptible patient pools – polio; measles

• Pandemic Influenza

Infectious Diseases in

1996

From KubyImmunology, 4th Ed.p. 426Viral and BacterialViral, Bacterial and ProtozoanBacterialProtozoanViralViralViral and BacterialBacterialProtozoan

ProtozoanViralProtozoanMulti-cellular (Helminth)Multi-cellular (Helminth)Viral Multi-cellular (Helminth)

Infect1996

p. 448

Causes of Death - Worldwide

Non-Immunological Host Barriers to Infection

Epithelial Surfaces• Gastrointestinal, respiratory, genito-urinary linings• Ciliated epithelium and mucous secretions• Epidermal barriers

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)

Bacterial Pathogenicity• Bacterial Cell Wall Endotoxins• Bacterial Exotoxins• Pathological Host Responses• Bacterial Mimics of Host Antigens• Intra-cellular Bacterial Infections and Damaging Host Responses

Host Response to Extra-cellular Bacterial Challenge & Infection

Blocking Bacterial Attachment to Target Cells• Secretory Antibody (IgA)

Removal of Bacteria• Complement Pathways - Direct destruction of Bacterium, or Attracts

PMN's for Anti-bacterial action, or Targets bacterium for Phagocytosis Antibody-dependent "Classical" Complement Response -Opsonization and phagocytosis - Inflammatory mediators (PMN Attraction and degranulation) - Bacterial Membrane lysis Antibody-independent "Alternative" Complement Pathway - Opsonization and phagocytosis; - Inflammatory mediators (PMN Attraction and degranulation)• Agglutination of bacteria by poly-valent antibody• Antibody-dependent phagocytosis of bacteria

Neutralization of Bacterial Exotoxins• Antibodies to bacterial exotoxins

p. 456

Host Response to Intra-cellular Bacterial Challenge & Infection

T-Cell Mediated DTH (Delayed-type Hypersensitivity)• Cytokines• Inflammatory mediators• PMN and Macrophage responses

NK Cell Cytotoxicity of Bacterially-Infected Cell

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

Yes N

o

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1. Yes

2. No

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