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

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)

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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 Kuby Immunology, 4th Ed.

p. 426 Viral and Bacterial Viral, Bacterial and Protozoan Bacterial Protozoan Viral Viral Viral and Bacterial Bacterial Protozoan Protozoan Viral Protozoan Multi-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 Barriers Elevated 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



infected cells and IFN



; become cytotoxic for virally Also activated by IL-12 - produced in response to viral infection

Humoral Immunity & Anti-Viral Responses

• • •

Antibody-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 Effects

•

Inhibition 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 & Microbiology

• •

100 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 Virus

• • • •

RNA 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

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)

p. 453

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 3 rd leading cause of death world-wide after Rank

1

Responses was listed as “neoplastic” diseases. What are neoplastic

2

diseases generally called? ________________ 17%

3 4 5 6 Other

1 2 3 4 5 6

Point mutations in hemagglutinin or

1 2 3 4 5 6

17% 17% 17% 17% 17%

antibodies. This is called antigenic _ _ _ _ _.

17%

Other

1 2 3 4 5 6

Bacterial Infection and Pathogenicity

• •

Bacterial 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 -Immunology Figure 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

1. Yes 2. No

1 21 2 22 3 23 4 24 41 42 43 44 61 81 101 62 82 102 63 103 64 84 104 5 25 45 65 85 105 6 26 46 66 86 106 7 27 47 67 87 107 8 28 48 68 88 108 9 29 49 69 89 109 10 30 50 70 90 110 11 31 51 71 91 12 32 52 72 92 13 14 15 33 53 34 0% 54 35 55 73 74 93 Y es 94 75 95 16 36 56 76 96 17 18 19 37 57 38 0% 58 39 59 77 97 78 98 N o 79 99 20 40 60 80 100