Relative sizes of infectious agents Bacteria Protozoa Viruses RBC 0.005 0.01 0.03 01 03 05 1 3 5 10 30 50 100 300 Size in microns ( µm ) - log scale
Immunity to Infection
Principle 1 Every clinical infection is a consequence of failure or subversion of innate immunity
Elements of Innate Immunity Important in Resistance to Pathogens Cells Monocytes/Macrophages NK/NKT cells Neutrophils Dendritic cells Platelets Soluble mediators Complement Defensins Cytokines
Ques%on What is complement? How is it ac%vated?
Complement opsonizes pathogens
Paneth cells secrete defensins
Significance of Differences: antimicrobial peptides hydrophobic cationic (+) defensin external leaflet cytoplasmic leaflet external leaflet cytoplasmic leaflet Zwitterionic phospholipid (+/-) Acidic phospholipid (+/-)
Ultrastructural organization Capsule Ribosomes DNA Cytoplasm Cell wall Plasma membrane Pili Flagellum
Gram Stain Gram negative Gram positive
Ques%on What is the molecular difference between gram posi%ve and gram nega%ve?
Gram (+) cell envelope structure external milieu protein lipoteichoic acid teichoic acid cell wall peptidoglycan periplasmic space plasma membrane cytoplasm
Gram (-) cell envelope structure outside cytoplasm
Infection leads to production of inducers of inflammation or dendritic cell Inflammatory mediators: Complex and many, but include: Lipids and Proteins (cytokines/chemokines) TNF Others
Principle 2 The innate and adaptive immune systems evolved to protect against infections Innate only Innate + primi%ve adap%ve Innate and adap%ve
Characteristics of Innate and Adaptive Immune Responses Innate Immunity Relatively nonspecific Not influenced by prior exposure to the same invading agent Develops rapidly, is transient Adaptive Immunity (Humoral & Cellular) Develops in response to antigenic exposure Highly specific Takes a moderate amount of time to develop, then persists for a long time Results in immunologic memory
Infection leads to production of inducers of inflammation or dendritic cell Inflammatory mediators: Complex and many, but include: Lipids and Proteins (cytokines/chemokines) TNF Others
Ques%on Why do the pathogens make the macrophages produce soluble mediators?
PRRs, PAMPs & TLRs The innate immune system initiates the immune response through pattern recognition receptors (PRRs) that recognize microbial products called pathogen-associated molecular patterns (PAMPs) Toll-like receptors (TLRs) function as important PRRs
Pathogen pattern receptors Receptor Microbial activators Ligand TLR1 Bacteria (mycobacteria, N. meningitidis) Lipopeptides, soluble factors TLR2 Bacteria, Fungi LPS, lipoteichoic acid, peptidoglycan etc. TLR3 Viruses dsrna TLR4 Bacteria LPS TLR5 Bacteria Flagellin TLR6 Bacteria, Fungi Lipoteichoic acid, Lipopeptides, zymosan TLR7 Viruses ssrna, imidazoquinolines TLR8 Viruses ssrna, imidazoquinolines TLR9 Bacteria, Viruses Unmethylated DNA (CpG) NOD1 Bacteria Peptidoglycan NOD2 Bacteria Peptidoglycan
Toll-like Receptors
What happens next? Ques%on
Human Pattern Recognition Molecules Pathogen associated molecular pattern (pamp) Toll-like receptor (TRL-X) Nucleotide oligomerization domain (NOD) external milieu TNF-a, IL-1 NF-Κb cytoplasm nucleus NF-Κb Control of gene expression of immunologic mediators
Infection leads to production of inducers of inflammation or dendritic cell Inflammatory mediators: Complex and many, but include: Lipids and Proteins (cytokines/chemokines) TNF Others
Leukocyte recruitment to sites of inflammation or DC
Pathogen Interfaces with the adaptive and innate immune system" T Peripheral tissues T Blood vessels Draining lymph nodes T Inflammatory monocytes/macrophages T T cell area Lymphocytes/NK cells Neutrophils Dendritic cells Follicle B
Principle 3 Pathogen location determines protective immune mechanisms CD8 + T cells CD4 + T cells
The source of pep=des for MHC 1 and II 33
An=gens must be processed in order to be recognised by T cells T Soluble na%ve Ag Cell surface na%ve Ag Soluble pep%des of Ag Y Cell surface pep%des of Ag Cell surface pep%des of Ag presented by cells that express MHC an%gens ANTIGEN PROCESSING No T cell response No T cell response No T cell response No T cell response T cell response
An=gen Presenta=on MHC II and CD4 T cells From Janeway, Immunobiology, 5th edi%on 35
MHC II bound pep%de ac%vates CD4+ T helper cell CD4+ cell binds to B cell presen%ng the SAME pep%de:mhc II complex
Structural features of antibodies FAb fragment Fc fragment 12. Effector functions
IgG IgM IgA IgD
Antibodies
Antibodies protect by binding and blocking
Antibodies provide protection by opsonization
Antibodies protect by activating ( fixing ) complement
Principle 4 Nonopportunistic pathogens subvert normal mechanisms of immunity Opportunistic pathogens exploit defects in immunity
Bacteria, Fungi and Protozoa
QUESTION Huge eukaryotes that cannot be engulfed by macrophages? How do we kill them?
Taenia Solium Cystercercosis: ingestion of the egg from an infected human" " Cysts form in the brain disease is caused by inflammatory response to dying parasite"
Nematodes FECAL ORAL" Enterobius vermicularis" Trichuris trichuria" Ascaris lumbricoides (lung)" SKIN INFECTION" Hookworms (lung)" Strongyloides stercoralis (lung)"
14d. Release of histamine, heparin, glycosaminoglycans, eosinophil chemotac%c factor, etc.
Ques%on? how does IgE bind to mast cells
15.
(Eosinophilia is associated with infec=on by invasive worms) 16. Eosinophil
Eosinophil inclusion bodies contain: major basic protein, eosinophil ca=onic protein, phospholipase B ( Charcot- Leyden crystals), etc 17c.
Ques%on How does IgE bind to Eosinphils?
Ques%on Pathogens that grow in the cytoplasm! How do we kill them?
Bacteria, Fungi and Protozoa
Six things a virus needs to do. 1. Attachment. 2. Entry/Penetration. 3. Uncoating. 4. Protein expression & Gene Replication. 5. Assembly. 6. Release. 3 4 2 1 5 6 Influenza virus (orthomyxovirus)
CD4 cells recognize antigen bind to MHC II MHCII = extracytoplasmic antigens CD8 cells recognize antigen bound to MHC I MHCI = Intracytoplasmic antigens CD4 + T cells CD8 + T cells
MHC I bound pep%de ac%vates CD8+ T cell
Effector func=ons of CD8 + cytotoxic T cells Primary func=on: kill infected cell Green= tubulin Red= ly%c granule Cytoplasm is reorganized: Golgi focuses towards target cell, MTOC moves to synapse,, ly%c granules move to synapse Granules fuse to T cell plasma membrane and empty into close proximity of target cell
Mechanisms of CTL-mediated lysis of target cells