1. SITE OF REPLICATION EXTRACELLULAR Interstitial spaces Blood, lymph Bronchial, Gastrointestinal lumen Epithelial surfaces INTRACELLULAR CytoplasmicVesicular Viruses Bacteria Protozoa Fungi Worms Neisseria gonorrhoeae Worms Mycoplasma Streptococcus pneumoniae Vibrio cholerae Escherichia coli Candida albicans Helicobacter pylori Viruses Chlamydia ssp. Richettsia ssp. Listeria monocytogenes Protozoa Mycobacteria Salmonella typhimurium Seishmania spp. Listeria ssp. Trypanosoma spp. Legionella pneumophila Cryptococcus neoformans Histoplasma Yersinia pestis IgA type Antibodies Anti-microbial peptides Antibodies Complement Phagocytosis Neutralization Cytotoxic T cells NK cells T cell and NK cell- dependent macrophage activation PROTECTIVE IMMUNITY

2. PATHOGEN TYPEPROCESSINGRESPONSE Extracellular Intravesicular Cytosolic Acidic vesicles MHC II binding CD4+ T cells ANTIBODY PRODUCTION Neutralization Complement activation Phagocytosis THE SITE OF PATHOGEN DEGRADATION DETERMINES THE TYPE OF IMMUNE RESPONSES Acidic vesicles MHC II binding CD4+ T cells KILLING BACTERIA OF PARASITE IN VESICLES Intracellular killing Th1 NK Cytoplasm MHC I binding MHC II binding CD8+ T cells CD4+ T cells KILLING OF INFECTED CELL Extracellular killing ANTIBODY PRODUCTION

3. THE IMMUNE RESPONSE TO EXTRACELLULAR BACTERIA Polysaccharide capsule Exotoxins – secreted by bacteria - Cytotoxicity of various mechanisms - Inhibition of various cellular functions - Induction of cytokines  pathology, septic shock Endotoxins – released by phagocytic cells - Cell wall – Gram (-) rods LPS Gram (+) cocci glycan

4. S. pneumoniae in the lung EVASION OF THE IMMUNE RESPONSE TO STREPTOCOCCI B Lymphocyte 12 hrs Bacterium 6x10 10 Bacteria Toxin

5. Opsonization ESCAPE High carbohydrate variability Competition of strains ~90 serotypes Serotype-specific Ab response

6. Fibrin mesh in fluid with PMN's at the area of acute inflammation. It is this fluid collection that produces the "tumor" or swelling aspect of acute inflammation. The vasculitis shown here demonstrates the destruction that can accompany the acute inflammatory process and the interplay with the coagulation mechanism. The arterial wall is undergoing necrosis, and there is thrombus formation in the lumen. Edema with inflammation is not trivial at all: Marked laryngeal edema such that the airway is narrowed. This is life-threatening. Thus, fluid collections can be serious depending upon their location. A purulent exudate is seen beneath the meninges in the brain of this patient with acute meningitis from Streptococcus pneumoniae infection. The exudate obscures the sulci.

7. This tissue gram stain of an acute pneumonia demonstrates gram positive cocci that have been eaten by the numerous PMN's exuded into the alveolar space. Opsonins such as IgG and C3b facilitate the attachment of PMN's to offending agents such as bacteria so that the PMN's can phagocytose them. Neutrophilic alveolar exudate with PMN The patient had a "productive" cough because of large amounts of purulent sputum. Numerous neutrophils fill the alveoli in this case of acute bronchopneumonia in a patient with a high fever. Pseudomonas aeruginosa was cultured from sputum. Dilated capillaries in the alveolar walls from vasodilation with the acute inflammatory process. Acute bronchopneumonia of the lung

8. CONSEQUENCES OF SKIN DAMAGE INFLAMMATION IN CONNECTIVE TISSUE

9. IC THE IMMUNE RESPONSE AGAINST EXTRACELLULAR BACTERIA INNATE IMMUNITY Plasma level hours LPS TNF-α IL-1β IL-6 T-INDEPENDENT IgM/IgG antibody + Complement Complement-mediated lysis B plasma CR1 CR3 Helper T-cell activation IgM  IgG switch FcR macrophage Bacterial killing

10. MECHANISMS OF PROTECTION INNATE IMMUNITY Complement activation Gram (+)peptidoglycan  alternative pathway Gram (-)LPS  alternative pathway Mannose + MBL  lectin pathway Phagocytosis Antibody and complement mediated opsonization Inflammation LPS  TLR macrophage activation Peptidoglycan  TLR macrophage activation ACQUIRED IMMUNITY Humoral immune response Targets: cell wall antigens and toxins T-independent  cell wall polysaccharide T-dependent  bacterial protein  isotype switch  inflammation  macrophage activation ESCAPE MECHANISMS- overcome complement activation

11. ANTIBODY MEDIATED EFFECTOR FUNCTIONS SPECIFIC ANTIBODY Bacterial toxin Toxin receptor Neutralization Bacteria in interstitium Bacteria in plasma OpsonizationComplement activation PhagocytosisPhagocytosis and lysis COMPLEMENT

13. EVASION MECHANISMS OF EXTRACELLULAR BACTERIA Inhibition of complement-dependent cell lysis M-protein Str. pyogenes M-protein Sialic acid rich capsule inhibits activation of the alternative complement pathway Antigenic variants pilin Neisseria gonorrhoeae (pilin) A reaktív oxigén gyökök lekötése Katalase pozitív staphylococci Degradation of IgA antibodies Neisseria, H. influenzae Proteins to increase adhesion Bordetella pertussis Inhibition of phagocytosis S.aureus, Str. pneumoniae,

14. GENERAL SUPPRESSION OF THE IMMUNE RESPONSE

15. SUBVERSION OF THE IMMUNE SYSTEM BY EXTRACELLULAR BACTERIA Superantigens of staphylococci – staphylococcal enterotoxins (SE) – toxic shock syndrom toxin-1 (TSST-1) Simultaneous binding to MHC class II and TCR  -chain irrespective of peptide binding specificity Mimic specific antigen  Induce massive but ineffective T-cell activation and proliferation in the absence of specific peptide  2 – 20% of CD4+ T-cells, which are not specific for the bacteria but share V  get activated and develop to effector T-lymphocytes  Over production of cytokines – IL-1, IL-2, TNF-α  Systemic toxicity – sepsis/septicemia  Suppression of adaptive immunity by apoptosis PROFESSIONAL APC 11 11 22 22 T cell 

16. Sepsis/Septicemia TNF-α TNF-α→ platelet activating factor by endothelial cells→clotting, blockage restricts plasma leakage & spread of infection Infection of blood – Sepsis Sysemic edema, decreased blood volume, collapse of vessels Disseminated intravascular coagulation, multiple organ failure