Relative sizes of infectious agents

Transcription

1 Relative sizes of infectious agents Bacteria Protozoa Viruses RBC Size in microns ( µm ) - log scale

2 Immunity to Infection

3 Principle 1 Every clinical infection is a consequence of failure or subversion of innate immunity

4 Elements of Innate Immunity Important in Resistance to Pathogens Cells Monocytes/Macrophages NK/NKT cells Neutrophils Dendritic cells Platelets Soluble mediators Complement Defensins Cytokines

5 Ques%on What is complement? How is it ac%vated?

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7 Complement opsonizes pathogens

8 Paneth cells secrete defensins

9 Significance of Differences: antimicrobial peptides hydrophobic cationic (+) defensin external leaflet cytoplasmic leaflet external leaflet cytoplasmic leaflet Zwitterionic phospholipid (+/-) Acidic phospholipid (+/-)

10 Ultrastructural organization Capsule Ribosomes DNA Cytoplasm Cell wall Plasma membrane Pili Flagellum

11 Gram Stain Gram negative Gram positive

12 Ques%on What is the molecular difference between gram posi%ve and gram nega%ve?

13 Gram (+) cell envelope structure external milieu protein lipoteichoic acid teichoic acid cell wall peptidoglycan periplasmic space plasma membrane cytoplasm

14 Gram (-) cell envelope structure outside cytoplasm

15 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

16 Principle 2 The innate and adaptive immune systems evolved to protect against infections Innate only Innate + primi%ve adap%ve Innate and adap%ve

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18 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

19 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

20 Ques%on Why do the pathogens make the macrophages produce soluble mediators?

21 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

22 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

23 Toll-like Receptors

24 What happens next? Ques%on

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26 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

27 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

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29 Leukocyte recruitment to sites of inflammation or DC

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31 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

32 Principle 3 Pathogen location determines protective immune mechanisms CD8 + T cells CD4 + T cells

33 The source of pep=des for MHC 1 and II 33

34 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

35 An=gen Presenta=on MHC II and CD4 T cells From Janeway, Immunobiology, 5th edi%on 35

36 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

37 Structural features of antibodies FAb fragment Fc fragment 12. Effector functions

38 IgG IgM IgA IgD

39 Antibodies

40 Antibodies protect by binding and blocking

41 Antibodies provide protection by opsonization

42 Antibodies protect by activating ( fixing ) complement

43 Principle 4 Nonopportunistic pathogens subvert normal mechanisms of immunity Opportunistic pathogens exploit defects in immunity

44 Bacteria, Fungi and Protozoa

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46 QUESTION Huge eukaryotes that cannot be engulfed by macrophages? How do we kill them?

47 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"

48 Nematodes FECAL ORAL" Enterobius vermicularis" Trichuris trichuria" Ascaris lumbricoides (lung)" SKIN INFECTION" Hookworms (lung)" Strongyloides stercoralis (lung)"

49 14d. Release of histamine, heparin, glycosaminoglycans, eosinophil chemotac%c factor, etc.

50 Ques%on? how does IgE bind to mast cells

51 15.

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53 (Eosinophilia is associated with infec=on by invasive worms) 16. Eosinophil

54 Eosinophil inclusion bodies contain: major basic protein, eosinophil ca=onic protein, phospholipase B ( Charcot- Leyden crystals), etc 17c.

55 Ques%on How does IgE bind to Eosinphils?

56 Ques%on Pathogens that grow in the cytoplasm! How do we kill them?

57 Bacteria, Fungi and Protozoa

58 Six things a virus needs to do. 1. Attachment. 2. Entry/Penetration. 3. Uncoating. 4. Protein expression & Gene Replication. 5. Assembly. 6. Release Influenza virus (orthomyxovirus)

59 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

60 MHC I bound pep%de ac%vates CD8+ T cell

61 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

62 Mechanisms of CTL-mediated lysis of target cells