"SLE334 Medical Microbiology and Immunology, T2, 2017Topic 3: The War – Infection and Transmission of DiseaseImmune defenses in action(Mims’ Chapter 14)Lecture 10Thursday 3 August 2017LT13 (HC2.005), 1-2 pm(date, time and venue different for Geelong students)Dr Sharon La [email protected] Medical Microbiology and Immunology, T2, 2017This lecture will cover……•? Examples of how different types of immunitycontribute to the body's defenses against microbes- antimicrobial proteins (eg lysozyme)- early immune response (eg phagocytosis, IFN, TNF,respiratory burst)- antibody-mediated immunity - cell-mediated immunity•? Effect of Nutrition on immunity SLE334 Medical Microbiology and Immunology, T2, 2017Introduction•? Skin, mucous membranes and cilia form barriersto invading microbes •? Upon penetration, innate immune responsekicks in first (i.e. complement, phagocytic/ cytotoxic cells and cytotoxic molecules)•? Adaptive immune response (with specificity andmemory capacity) kicks in next•? Antibodies (B cells) important in combatinginfection from extracellular microbes while T-cellimmunity required for intracellular infectionsSLE334 Medical Microbiology and Immunology, T2, 2017Antimicrobial proteins (lysozyme) protects thelung against invading bacteriaTransgenic mice making greater amounts of lysozyme are more resistant to infection withPseudomonas aeruginosa. SLE334 Medical Microbiology and Immunology, T2, 2017Early immune response•? Alternative pathway of complement activation part of early defence system•? C-reactive protein (CRP) is an antibacterial agent produced by liver cells inresponse to cytokines•? Macrophages recognize bacteria (endotoxins like LPS) as foreign using Toll- like receptors (TLR)•? It is not known whether or not fever is useful for the host•? Natural killer (NK) cells are rapid in controlling viral and other intracellularinfections•? Phagocytes engulf, kill and digest parasites–? Oxidative mechanism•? Involves reactive oxygen intermediates (ROIs)•? Cytotoxic lipids prolong activity of ROIs–? Non-oxidative mechanism•? Involves use of phagocyte’s cytotoxic granules•? Nitric oxide (NO) is strongly cytotoxic•? Cytokines contribute to both infection control and pathology–? Interferons (i.e. IFNa, IFNß, IFN?) constitute major part of early response to viruses–? Tumour necrosis factor (i.e. TNFa) can be good or bad (i.e. tuberculosis)SLE334 Medical Microbiology and Immunology, T2, 2017INF? is needed to induce bacterial killingNatural killer (NK) cells:-? provide an early source of cytokines and chemokines during infection, until there is time for theactivation and expansion of antigen-specific T cells. -? provide an important source of interferon-gamma (IFN?) during the first few days of infectionSLE334 Medical Microbiology and Immunology, T2, 2017Phagocytosis of C. albicans by neutrophilFigure 14.3 (A) Electronmicrograph and (B)diagrammaticrepresentation ofneutrophil containingphagocytosed CandidaalbicansSLE334 Medical Microbiology and Immunology, T2, 2017Macrophages interactingvigorously with wormsFig 5.Colored scanning electronmicrographs demonstrate theflexibility of IgG-adsorbed worm-likeparticles and ability of macrophagesto bend worms by attachment atdifferent points. Scale bars = 2 µm.http://www.springerimages.com/Images/Biomedicine/1-10.1007_s11095-008-9626-z-4 SLE334 Medical Microbiology and Immunology, T2, 2017Oxidative killing: oxygen-dependentmicrobicidal activity during respiratory burst2 3314(NADPH Oxidase)SLE334 Medical Microbiology and Immunology, T2, 2017CYTOKINES•? family of non-antigen-specific molecules with diverse activities•? involved in cell-to-cell communication. •? play crucial roles in protection against infectious diseases.•? important in infectious disease for two contrasting reasons:- can contribute to the control of infection- can contribute to the development of pathology•? Interferons- best-established antimicrobial cytokines are the interferons (IFNs) - IFNa and IFNß – production stimulated by viral infection - IFN? – production follows activation with immune and inflammatory stimulirather than viral infection (eg. IL-12, IL-18).•? TNFa - can be good or badSLE334 Medical Microbiology and Immunology, T2, 2017Molecularbasis of IFNaction•? IFNs interact with specificreceptors on most cells,following which they inducean antiviral state via thegeneration of at least twotypes of enzyme: a proteinkinase and a 2',5'- oligoadenylate synthetase.•? Both enzymes result in theinhibition of viral RNAtranslation and therefore ofprotein synthesisSLE334 Medical Microbiology and Immunology, T2, 2017Multiple activities of IFNs in viral immunity •? IFNa and IFNß areproduced rapidly within 24 hof infection, and constitute amajor part of the earlyresponse to viruses. •? IFN? is mainly a T-cellproduct and is thereforeproduced later, although, anearly IFN? response may bemounted by NK cells.SLE334 Medical Microbiology and Immunology, T2, 2017Blocking of TNFa causes tuberculosisLung tissue from patients with tuberculosis:(A) who did not receive antibody to TNFa- well-formed granuloma with little necrosis(B) who did receive antibody to TNFa-?minimal granuloma formation but muchfibrosis and inflammation Normal lung tissueSLE334 Medical Microbiology and Immunology, T2, 2017Antibody-mediated immunity•? Involves binding of host Ab to Ag onforeign microbe•? Effectiveness of Ab-Ag interactiondepends on:•? Speed, amount and duration•? Affinity•? Ab classes and subclasses (isotypes)•? Blocking and neutralizing effects of Ab•? Immobilization and agglutination•? Lysis•? Opsonization SLE334 Medical Microbiology and Immunology, T2, 2017EM of IgM molecule Figure 14.8 Electronmicrograph of an IgMmolecule. The crab-likeconfiguration is due tocross-linkage with a singleflagellum.SLE334 Medical Microbiology and Immunology, T2, 2017TEM of IgG molecule Immunoglobulin G antibodymolecules, coloured transmissionelectron micrograph (TEM).These antibodies have beennegatively stained. (Magnification: x1,775,000 whenprinted at 10 centimetres tall.)http://www.sciencephoto.com/media/305698/enlarge SLE334 Medical Microbiology and Immunology, T2, 2017Bacterial agglutination Latex•? Agglutination of group A streptococcus with latex particles coated with anti-group Aantibodies.•? The multivalent design of the antibody molecules enables it to link together two ormore organisms, SLE334 Medical Microbiology and Immunology, T2, 2017Phagocytosis enhanced by 1000-foldwith Ab & complement Antibody and complement accelerate the clearance of pneumococci fromthe blood of mice. SLE334 Medical Microbiology and Immunology, T2, 2017Cell-mediated immunity•? T-cell immunity correlates with control of bacterial growthin leprosy- leprosy patients' skin lesions were injected with IFN?. - resulted in an influx of T cells and macrophages into the skin lesions, and areduction in the number of bacteria.- T cells were stimulated by IFN? which activated macrophages and led to bacterialkilling.•? Evidence for protective effects of IFN? (macrophageactivation & antimicrobial molecule production)•? Cytokine signatures•? Is positive ‘delayed type hypersensitivity’ (DTH) skin testan indicator of immunity?•? Cytotoxic T-cells kill by inducing ‘leaks’ in target cellSLE334 Medical Microbiology and Immunology, T2, 2017Susceptibility to mycobacterial infectionsdue to genetic mutations in IFN? •? Three Maltese families had children who were susceptible to atypical mycobacterial infection(solid symbols), two of whom died (slashed symbols). Individuals with carrier status are shownwith half-filled symbols. •? All affected children were homozygous for the disease locus a on chromosome 6q22-q23, witha point mutation in the gene for the IFN? receptor. •? This mutation introduces a stop codon resulting in a non-functional truncated protein. "