Immunity to Microbes. Cellular and Molecular Immunology (7 th : Chap 15)

Transcription

1 Immunity to Microbes Cellular and Molecular Immunology (7 th : Chap 15)

2 Infection Entry of the microbe Invasion and colonization of host tissues, Evasion of host immunity Tissue injury or functional impairment

3 General Features of Immune Responses to Microbes Defense : the effector mechanisms of innate and adaptive immunity Innate : early defense, microbial evolution to escape the innate system Adaptive more sustained and stronger response: more specific Distinct and specialized ways to different types of microbes : effective combat

4 General Features of Immune Responses to Microbes The survival and pathogenesis of microbes: influenced by the ability of the microbes to evade or resist the effector mechanisms of immunity Latent, or persistent, immune response controls but does not eliminate the microbe the microbe survives without propagating the infection tissue injury and disease m caused by the host response to the microbe and its products rather than by the microbe itself

5 Immunity to Extracellular Bacteria

6 Immunity to Extracellular Bacteria Replicate outside host cells circulation connective tissues in tissue spaces : lumens of the airways, gastrointestinal tract Induce inflammation tissue destruction at the site of infection Production toxins :diverse pathologic effects, cytotoxic and kill the cells Endotoxin : bacterial cell wall component LPS ) gram negative bacteria, activate MØ and DC Exotoxin: bacterial secretion

7 Innate Immunity to Extracellular Bacteria Complement activation Phagocytosis Inflammatory response Complement activation Alternative pathway of complement peptidoglycan : gram positive bacterial cell wall component LPS : gram negative bacteria cell wall component Mannose : mannnose-lectin pathway Opsonization & enhanced phagocytosis of the bacteria Membrane attack complex : lyses bacteria Complement byproducts: stimulate inflammatory response :

8 Innate Immunity to Extracellular Bacteria Activation of phagocytes and inflammation Mannose receptors, scavenger receptors : recognition of bacteria : Promote phagocytosis Fc receptors, complement receptors : recognition of opsonized bacteria : phagocytosis and activation of phagocytes TLR and cytoplasmic sensors : recognition of microbial products : microbiocidal activity

9 Innate Immunity to Extracellular Bacteria Activated DC & Phagocytes Secret cytokines Induce luekocyte infiltration into the infection site Recruited luekocytes ingest and destroy the bacteria

10 Adaptive Immunity to Extracellular Bacteria Humoral Immunity : major response : block infection to eliminate the microbe s : neutralize their toxins Directed against cell wall antigens, secreted and cell-associated toxins polysaccharides : thymus independent antigens Neutralization: high affinity IgG, IgM, IgA (mucosal lumens) Opsonization & phagocytosis : IgG Classical complement activation pathway: IgM and IgG

11 Antibody Responses to Extracellular Microbes Fig. 15-1A

12 Adaptive Immunity to Extracellular Bacteria CD4 helper T cells: Protein antigens Produce cytokines : local inflammation Enhance the phagocytic and microbicidal activity of macrophages and neutrophils Stimulate antibody production Th17 responses : recruit neutrophils and monocytes Promote local inflammation Defective Th17 : increased susceptibility to bacterial and fungal infections Formation of multiple skin abscesses STAT3 mutation : Th17 transcription factor Job s syndrome, Hyper IgE syndrome Th1 response activates microbes stimulate production of opsonizing and complment binding antibody isotypes.

13 T Cell Responses to Extracellular Microbes Fig. 15-1B

14 Inflammation & septic shock Injurious Effects of Immune Responses Neutrophil & MØ Eradicate the infection But cause tissue damage Local production of reactive oxygen species, Lysosomal enzymes Septic shock Circulatory collapse and disseminated intravascular coagulation cytokine storm TNF, IL-6, IL-1: main septic shock contributing cytokines IFN-r and IL-12 : Related to depletion or suppression of T cells unchecked microbial spread Superantigens : bind to TCRs and MHC class II molecules Activate many more T cells than do conventional peptide antigens

15 Inflammation & septic shock Injurious Effects of Immune Responses Superantigens Bind to TCRs and MHC class II molecules Activate many T cells Large amount of cytokines systemic inflammatory syndrome. Enterotoxin Mice Humans SEB V β 7, ,17 V β 3,12,14,15,17,20 SEC 2 V β 8.2,10 V β 12,13,14,15,17,20 SEE V β 11, 15, 17 V β 5.1, 6.1-6,3, 8, 18 TSST-1 V β 15,16 V β 2

16 Activation of T cells by Bacterial Superantigen Fig. 15-2

17 Injurious Effects of Immune Responses Humoral immune response Rheumatic fever Antibodies against bacterial cell wall protein. Cross-react with myocardial proteins Deposited in the heart and cause inflammation carditis Poststreptococcal glomerulonephritis : infection of the skin or throat with β-hemolytic streptococci : deposit in kidney glomeruli and cause nephritis

18 Immune Evasion by Extracellular Bacteria Antiphagocytic mechanisms Inhibition of complement Inactivation of complement product Genetic variation of surface antigen : H. Influenza glycosidases chemical alterations in surface LPS

19 Immune Evasion by Extracellular Bacteria

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21 Immunity to Intracellular Bacteria Able to survive and replication within phagocytes Inaccessible to circulating antibodies Cell-mediated immunity to eliminate the bacteria

22 Innate Immunity to Intracellular Bacteria Phagocytes and NK cells Phagocytes: neutrophils, MØ Ingest microbe Resistant to degradation within phagocytes TLR and NLR family recognize the bacterial product phagocyte activation Express NK cell activating ligands on infected cells activate NK cells IL-12 and IL15 secretion by DC and MØ NK cell activating cytokine NK cell: early defense before the adaptive immunity SCID mice can control infection with L. monocytogenes by NK cell-derived IFN-r production Innate immunity usually fails to eradicate these infections Requires adaptive immunity to eradicate the bacteria

23 Adaptive Immunity to Intracellular Bacteria T cell-mediated immunity : major protective response : Not transferable with serum CD4 T cells : recruit and activate phagocyte & CTL kills infected cells : Th1 cells under the influence of IL-12 express CD40L and IFN-γ activate macrophages and dendritic cells Activated Macrophage : microbicidal substances reactive oxygen specific, nitric oxide, lysosomal enzymes

24 Adaptive Immunity to Intracellular Bacteria IFN-γ : stimulates the production of antibody isotypes (IgG2a) : : complement and opsonize bacteria for phagocytosis IL-12 and IFN-γ mutation susceptibel to infections with mycobacteria CD8 T cell respsonses : bacterial antigens transported from phagosomes into the cytosol : Infected cells to be killed by CTLs

25 Immunity to Intracellular Bacteria Fig. 15-3

26 T Cell Responses to Intracellular Microbes Fig. 15-4

27 Adaptive Immunity to Intracellular Bacteria Macrophage activation tissue injury Delayed type hypersensitivity (DTH) reactions Intracellular bacteria evolution to resist killing within phagocytes Persist for long periods and cause chronic antigenic stimulation T cell and macrophage activation formation of granuloma surrounding granulomatous inflammation : confinement of microbe spread but cause tissue necrosis and fibrosis

28 Adaptive Immunity to Intracellular Bacteria Tuberculosis Protective immunity and pathologic hypersensitivity coexist Infection containment by alveolar macrophages 90% of infected patients remain asymptomatic but bacteria survive in the lungs in macrophages 6-8 weeks after infection, macrophages travel to draining lymph nodes and CD4 T cell activation CD8 T cell activation IFN-γ production macrophage activation enhances ability to kill phagocytosed bacilli TNF produced by T and macrophages local inflammation and macrophage activation M. tuberculosis survive in macrophage because components of its cell wall inhibit the fusion of phagocytic vaculoes with lysosomes Continued T cell activation formation of granulomas Necrotizing granulomas and fibrosis

29 Adaptive Immunity to Intracellular Bacteria Two polar forms of leprosy Lepromatous and tuberculoid forms Due to different patterns of T cell differentiation and cytokine production in individuals.

30 Adaptive Immunity to Intracellular Bacteria Lepromatous leprosy, High specific antibody titers but weak cell-mediated response Mycobacteria proliferate within macrophages and detectable in large numbers Inadequate macrophage activation Destructive lesions in the skin and underlying tissue IL-4 suggestive Th2

31 Adaptive Immunity to Intracellular Bacteria Tubercloid leprosy Strong cell-mediated immunity Granulomas around nerves and produce peripheral sensory nerve defects Secondary traumatic skin lesions but less with tissue destruction and a paucity of bacteria in the lesions IFN-γ and IL-2 production in lesions

32 Role of T Cell Cytokines in Infections (1) Fig. 15-5A

33 Role of T Cell Cytokines in Infections (2) Fig. 15-5B

34 Immune Evasion by Intracellular Bacteria Immune evasion Various strategies to resist elimination by phagocytes Inhibiting phagolysosome fusion Escaping the cytosol

35 Immunity to Fungi Endemic caused by fungi present in the environment Opportunistic : cause mild or no disease in healthy individual but may cause severe disease in immunodeficient persons Compromised immunity Neutrophil deficiency HIV Therapy for disseminated cancer and transplant rejection Pneumonia Combination of extracellular and intracellular bacteria

36 Innate and Adaptive Immunity to Fungi Neutrophil and macrophages mediate immune response Phagocytes and DC sense fungal organisms by TLRs and dectins: lectin-like receptors ) Neutrophils liberate fungicidal substances (reactive oxygen species and lysosomal enzymes) and phagocyose fungi for intracellular killing Cryptococcus neoformans inhibit production of TNF and IL-12 by macrophage stimulate production of IL-10, inhibiting macrophage activation

37 Innate and Adaptive Immunity to Fungi Histoplasma capsulatum Intracellular parasite in macrophages CD4 and CD8 T cell cooperate to eliminate the yeast forms of C. neoformans Colonize the lungs and brains in immunodeficient hosts Extracellular fungi elicit strong Th17 responses Dectin-1 : a receptor for fungal polysaccharide Production of IL-6, Il-23 Candida : mucosal surfaces and cell-mediated immunity

38 Immunity to Viruses Obligatory intracellular microorganisms After entering host cells, viruses can cause tissue injury and disease Viral replication interferes with normal cellular protein synthesis and function Leads to injury and ultimately death of the infected cells Lytic and lysogenic Immunity to block infection and eliminate infected cells Prevention by type I IFN and neutralizing antibodies

39 Immune Responses Against Viruses (1) Fig. 15-6A

40 Immune Responses Against Viruses (2) Fig. 15-6B

41 Innate Immunity to Viruses Inhibition of infection by type I inteferons NK cell-mediated killing of infected cells Type I IFN: inhibits viral replication in both infected and uninfected cells by inducing an antiviral state NK cells recognize infected cells that virus has shut off class I MHC expression Viral RNA and DNA endosomal TLR and RIG-like receptors IRF transcription fectors inteferon gene transcription

42 Induction of Type I Interferons by Viruses Fig. 15-7

43 Adaptive Immunity to Viruses Antibody blocks virus binding and entry into host cells CTLs eliminate the infection by killing infected cells Ab: T dependent high affinity Ab in germinal center reaction effective against viruses only during the extracellular stage of the microbes early in the course of infection before entry into host cells when released from infected cells or cells are killed Binds to viral envelope or capsid antigens Functions mainly as neutralizing antibodies to prevent virus attachment and entry into host cells Prevents both initial infection and cell-to cell spread Neutralization, opsonization, complement activation

44 Adaptive Immunity to Viruses Elimination of viruses within cells is mediated by CTLs, which kill the infected cells CTL surveillance against viral infection Direct and cross-presentation Massive proliferation during viral infection Cytopathic viruses (RNA viruses) : stimulate strong innate response, does not require CD4 T cell help Non cytopathic latent infection (DNA viruses) elicit CTL responses only in the presence of CD4 help

45 Adaptive Immunity to Viruses Latent infections Viral DNA persists in host cells but the virus does not replication or kill infected cells Latency : balance between infection and the immune response Virus persist and deficiency in the host immune response can result in reactivation of the latent infection EBV, Herpesvirus family

46 Adaptive Immunity to Viruses Tissue injury may be cause by CTLs LCMV Induces inflammation of the spinal cord meninges Infects mengeal cells, noncytopathic Virus specific CTLS kill infected meningeal cells during the viral eradication Meningitis develops in normal mice with but not in T cell deficient mice

47 Adaptive Immunity to Viruses Tissue injury may be cause by CTLs Hepititis B virus Immunodeficient persons do not develop the disease but become carriers Transmit the infection to otherwise healthy persons The livers of patients with acute and chronic active hepatitis contain large numbers of CD8 T cells Consequence of persistent infection : HBV, formation of circulating immune complexes Deposit in blood vessel and lead to systemic vasculitis Molecular mimicry

48 Immune Evasion by Viruses Alter their antigens No longer targets of immune response RNA viruses, influenza pandemics.. Influenza Viral hemagglutinin (viral spike protein) Neuramidase Variations in these genes antigenic drift Recombine in host cells Reassorted viruses differ from prevalent strains antigenic shift 1918, 1957, 1968, 2009 (H1NI pandemic)

49 Genetic Recombination in Influenza Virus Fig. 15-8

50 Immune Evasion by Viruses Inhibition of antigen presentation

51 Immune Evasion by Viruses Production of molecules inhibiting immune responses Poxvirues: encode molecules binding to cytokines: IFN-r, TNF, IL-1, IL-18, chemokines Failure of CTL response exhaustion LCMV : PD-1 mediated exhaustion Virus kill or inactivate immunocompetent cells HIV : infect CD4 T cells

52 Immune Evasion by Viruses

53 Immunity to Parasites Infection with protozoa, helminth, ectoparasites Innate immunity Phagocytosis involvement, but parasites are resistant to phagocytic killing

54 Adaptive Immunity to Parasites Adaptive immunity Leishmenia major Survives within the eondosomes of macrophages Th1 responses: resistant to infection: IFN-r production and Macrophage activation Th2 responses: increased parasite survival and exacerbation of lesions Marlaria infection : CTL response is important IgE response IgE Ab binds to helminth surface, activate mast cells IgG and IgA brings eosinophils to the helminths Mast cells and eosinophils leads to destruction of the parasites Th2 response for IL-4 production IgE stimulation / IL5 eosinophil activation

55 Immunity to Parasites

56 Immune Evasion by Parasites

57 Strategies for Vaccine Development Vaccination success : eradicating infectious Disease Not latent No antigenic variation No interference with host immune system Limited to human hosts In use today : humoral immunity

58 Strategies for Vaccine Development Attenuated and inactivated bacterial and viral vaccines Induces all the innate and adaptive immune responses Attenuated bacterial vaccines: effective only for short periods Attenuated viral vaccines: Repeated passage in cell culture temperature-sensitive and deletion mutants more effective (polio, meals, yellow fever), often induce long-lasting immunity Purified antigen (subunit) vaccines Purified antigen or inactivated toxins Administered with an adjuvant Bacterial toxins : Diphtheria and tetanus toxins Conjugate vaccines: polysaccharides (T-independent Ag) coupling to proteins

59 Strategies for Vaccine Development Synthetic antigen vaccine Recombinant protein synthesis technology Live viral vaccines involving recombinant viruses Encoding antigens into a noncytopathic virus (vaccinia virus) and infect with the recombinant vaccinia virus Can activate full immune responses : humoral and cell-mediated immunity Safety concern

60 Strategies for Vaccine Development DNA vaccines Plasmid : encoding a protein antigen Eliciting strong CTL responses, provides CpG nucleotides (TLR9 ligand) Adjuvants and immunomodulators Adjuvants elicit innate immune responses, and cytokines (IL-12) Heat killed bacteria Aluminum hydroxide gels and lipid formulations IL-12 incorporated in vaccines Passive immunization Transfer of specific antibodies Short-lived, does not induce memory

61 Strategies for Vaccine Development