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Anti-infectious immunity Prof. Ilona Hromadníková 3rd year of the curriculum Most frequent causes of death Most frequent infectious diseases causing mortality Role of normal flora in Host Defense Against Infectious Disease Presence of normal flora at a body site has several benefits: Major host immune defense Primes immune system Antibodies produced and cell mediated immunity stimulates the immune system Exclusion of potential pathogens Competition for space and nutrients Role of Normal Flora in Infectious Diseases – usually normal flora but can cause disease when host is compromised or normal environment disturbed Trauma (accident or surgery) – NF introduced to sterile site Immunosuppressive disease or drug – reduce or alter immune response Chronic illness in host (i.e., diabetes) Opportunists Pathogenicity and Virulence Pathogenicity – ability to produce disease True pathogens – can cause disease in healthy host; examples: B. anthracis (anthrax), N. gonorrhoeae, M. tuberculosis (TBC) Opportunists – don’t usually cause disease, but can when host compromised; examples: S. aureus, S. pneumoniae (meningitis, sepsis, pneumonia, etc.) Modern medical advances allow these organisms to cause serious infections Virulence – degree of harm produced by the organism in the host Humoral (antibody-dependent) immune response Neutralisation Opsonisation Opsonisation followed by C activation Antibody-dependent cytotoxicity (ADCC) – NK cells Neutralisation Antibodies may neutralize the activity of bacterial exotoxines (Clostridium tetani tetanus a C. botulinum -botulism, Corynebacterium diphteriae - diphteria) viruses other microorganisms Mechanisms: blockage of critical epitopes – prevention of adherence onto the cell surface or the entrance into the cell Neutralisation Opsonisation Microorganisms are coated with antibodies IgG, IgA (neutrophiles) or IgE (eosinophiles), those are recognised by phagocytes via appropriate FcR C system activation on antibody-coated microorganism, phagocytosis of complement- opsonized particules (C3b) via CR on phagocytes Opsonisation Opsonisation C system activation – classical pathway Antibody-coated microorganism, C1 binds to Fc fragment of IgM or IgG, creation of C3-convertase C3a (chemotaxis) and C3b, further C5-convertase C5a (chemotaxis) and C5b (membrane attack complex, cell lysis) Phagocytosis of opsonized microorganisms by neutophiles and eosinophiles via binding of C3b onto CR3 and CR4 (degradation can be oxygendependent - production of reactive oxygen species via NADPH-complex, or oxygen-independent) Lytic phase complement activation C5b678(9)n membrane attack complex = MAC (n = 13-18) Antibody-dependent cell-mediated cytotoxicity (ADCC) Interaction of NK cells via CD16 (FCR) with IgG opsonized cell – lysis (perforines, granzymes) or production of reactive oxygen metabolites Macrophages, eosinophiles and platelets participate in cytotoxic mechanisms, when target cell is too big for phagocytosis Immunopatologic reaction type II dependent on IgG and IgM Immune response against extracellular bacteria Toxigenic bacterial infection Exotoxines – exclusive virulent factors, immune response against them eliminate sign of infection (mainly produced by G+ bacteria, less by Gbacteria) Endotoxines – components of bacteria cell surface (LPS with toxic Lipid A) in all G-bacteria Ab amplify phagocytosis or activate C system Different antigens (polysaccharides) of various bacteria Types of bacteria Endotoxines complexes of LPS-protein (toxic Lipid A), in all G- bacteria Specific bacterial exotoxines Specific bacterial enzymes contributing to microbial invasiveness Encapsulated bacteria Streptococcus pneumoniae, Neisseria meningitides, Klebsiella pneumoniae, Haemophilus influenzae type B An outer covering, a capsule, made of polysaccharide - antigens In pathogens contributes to their virulency and invasivity Resistent to phagocytosis. Capsular polysaccharide inhibits phagocytosis (macrophages, neutrophiles) FcR mediated phagocytosis is inefficient Effective phagocytosis requires both Fc and CR (C3b a C3bi) opsonisation Electric Charge and hydrophilicity of encapsulated bacteria restrict their phagocytosis Identification of bacteria by cells of innate immunity Cells of innate immunity express Pattern Recognition Receptors (PPR) which recognise Pathogen Associated Molecular Patterns (PAMPs) stimulation of phagocytosis or activation of other inflammatory mechanisms G- bacteria – LPS ( contains lipid A)- potent activator of inflammatory immune response G+ bacteria – peptidoglycan, lipoteichoic acid, muramyldipeptid Mycobacteria – component of Freund´s complete adjuvans – strong stimulation of non-specific and specific immunity (peptidoglykan, lipoteichoic acid, lipoarabinomanan) Yeasts – glucanes of cell wall (mannoproteins) Interaction of PPR with PAMPs PPR– membrane and/or soluble Eradication of extracellular bacteria and parasites Opsonization by antibodies streptococcus, staphylococcus, Neisseria, Hemophilus, enteric bacteria – Salmonella, Shigella, Helicobacter, etc.) Entamoeba histolytica, Giardia lamblia Further stimulation of Th1 (cell-mediated cytotoxicity) and Th2-B lymphocytes (production of specific IgM, IgG, IgA and IgE opsonizing antibodies) Eradication of intracellular bacteria, fungi and parasites Mycobacteria, Yersinia, Listeria, Brucella Candida albicans, Aspergillus, Pneumocystis carinnii Leishmania, Plasmodium, Toxoplasma gondii, Trypanosoma by macrophages (iNOS bactericidal NO), stimulation of Th1 lympho, mutual co-operation Phagocytosis Eradication of intracellular bacteria, fungi and parasites They elude immune system via growing IC - particularly in phagocytes. T lymho immune response is fundamental. A result of incomplete eradication of pathogen is latent, persistent infection Inducement of delayed-type hypersensitivity (DTH), characterised by accumulation of senzibilised T lympho and activated macrophages (activatory role of IFN-) When escape of pathogen from phagolysosome to cytoplasm occurs (Listeria) – eradication of infected cells by Tc Mycobacteria Species Cell wall is rich of lipids M. tuberculosis (TBC), M. leprae (leprosy), M. avium (atypic mycobacteria in AIDS) Relevant pathogen in AIDS and immunocompromised patients Czech Republic - vaccination against TBC by Bacillus Calmette-Guérin (BCG) – atenuated strain of M.bovis, the effectivity is not 100 % PPD (Purified Protein Derivate) used for tuberculin skin test (induration after 48 h.), identification of infected individuals and/or the status after vaccination, pozitive reaction does not protect against M. tuberculosis, it gives only information about the presence of IV. type of immune reaction Bacteria Rezistence Mechanisms Bacteria generally escape from the destruction in phagocytes becouse they enter the other cells (epithelial cells, fibroblasts) Escape from killing and degradation in phagolysosome (opsonization after binding to CR only does not activate bactericidal mechanisms) – St. Aureus, Str. pyogenes, mycobacteria Mycobacteria – expression of C3b-like molecules, enter to macrophages without their activation Escape from phagosome to cytoplasm – Listeria, Shigella, Rikettsia, prevention of phagosome-lysosome fusion (Salmonella) Leishmania, Coxiella – able to live in low pH Legionella – converts phagosome into vacuole Mechanisms of pathogenic bacteria to inhibit phagocytosis Transmission of infection by parasites Direct invasion – transfusion of parasitic worms through skin (Schistosoma, Ankylostoma, Nematodes Strongyloides stercoralis) By food – tapeworms, ascarids, pintleworms, some protozoa (Toxoplasma, Giardia) By insect –malaria- mosquitos –trypanosomes - tse-tse fly –Trypanosoma cruzi – reduviid bug (Triatoma, Rhodnius) - Leishmania – transmission of Phlebotoma Prevalence and distribution of common parasitosis Types of helminths Numbers infected (million) Intestinal helminthes Ascaris 1221 lumbricoides Hookworm spp.[a] 740 Strongyloides 75 stercoralis Trichuris 795 trichiura Schistosomes Schistosoma 67 mansoni Schistosoma 1 japonicum Schistosoma 119 haematobium Filarial parasites Onchocerca 37 volvulus Wuchereria 120 bancrofti Brugia malayi 10 Loa loa 13 Animal parasites[b] Distribution Worldwide Worldwide Worldwide Worldwide South America, Africa Eastern Asia Africa Africa, Central and South America Worldwide Asia Africa Basic mechanisms of parasitic pathogen escape Eradication of Helminths Complex eucaryotic organisms keeping long-time infection in human hosts lasting even decades Immune response is mediated by Th2 lymphocytes, IgE mastocytes, basophiles and eosinophiles Anti-viral immune response Course of viral infection Overcoming of barriers Entry to the cells (via appropriate receptor) and virus replication Inducement of non-specific immune mechanisms Inducement of specific immune mechanisms Memory T and B cells Eventually virus perzistence Paths of virus entry to the human body Specific receptors for viruses Virus tropism to certain cells or host CD4 (T lympho and macrophages), coreceptors = receptors for chemokines CCR-5, interaction of T lympho and macrophages with gp120 HIV EBV – infects B lymphocytes, its receptor is CD21 HBV – entry via CD71 (receptor for transferrin) Anti-viral immune response First line – non-specific immunity - interferons (INF, inhibition of virus replication) and NK cells Antibodies Th2 – B lympho co-operation mucous IgA – blockage of adherence onto epithelium (Respiratory viruses, enteroviruses) in circulation – neutralisating Ab – IgG and IgM, C system activation, virus lysis Tc – eradication of virus- infected cells Some aggressive viruses may overcome immune responses and cause severe morbidity and mortality Immunocompromised individuals (adaptive and native immunity) suffer from more severe viral infection Anti-viral immunity Lifetime perzistence (especially herpetic viruses in nerve ganglia) re-activation during weakening of IS EBV – malignancies of haematopoetic system (Hodgkin lymphoma) CMV, VzV, HHV-6, HHV-7 – recurrent aphthae HSV-1 (herpes labialis) - stomatitis herpetica, gingivostomatis herpetica virus varicela-zoster– herpes zoster, gingivitis papilomaviruses – cervix carcinoma, skin tumors Priones Discovery - S.B. Prusiner – Nobel prize Rare, transmissible, fatal, spongiform neurodegenerative diseases Protein infectious particule able to reproduce, absence of nucleic acids – PrP Organismus codes gene for normal protein PrPc, present in normal brain tissue (CNS), heart and skeletal muscles and other organs, unknown function, obviously regulation of ciarcadian rhythm, neuro-muscular synapsis, ion transport via membrane Abnormal infectious protein - PrPSC found in brains of animals with scrapie (lamb and goats) Priones PrPc and PrPSC differ in primary structure just by 1 aminoacid, however significant difference in secondary and tertiary structures, resistent to proteolytic degradation, creates insoluble aggregates similarly like amyloid deposits, damage of nervous tissue via acumulation of abnormal PrPSC and/or by lack of normal PrPc Priones and human diseases Creutzfeldt-Jakob disease (CJD) Variant CJD (vCJD) Gerstmann-Sträussler-Scheinker disease similar to CJD,but amyloid deposits in cerebelum Fatal Familial Insomnia – in families with CJD, neurone loss Kuru – tribesmen New Guinea – cannibalism– Nobel price Dr. Gajdusek Creutzfeldt-Jakob disease Most frequent between diseases caused by priones Sporadic form – 87 % - unknown reason, clinical symptoms after the age of 60 – dementia, ataxia, myoclonus Inborn (familial) form – 8 % - mutation in gene coding PrPc Transmission by iatrogennic way – 5 % aplication of GF from hypophysis, Tx of cornea, brain operation, etc. Neurone loss, astrocyte and microglia hyperplasia, amyloid deposits Variant CJD Breeding of cattle in UK – BSE – Bovinne Spongiforme Encephalopathie – mad cow disease – transmission from cattle to man by food, since 1986 sicken 180 thousands of animals, the brain looks like spondge, loss of muscle control, dezorientation, death. Infection – feeding mixture – meat and bone meal – transmission of scrapie agens (goats) to cattle, now EC legislation prohibition of nutrition of livestock and fish, obligation to test cattle for meat for the presence of BSE Human form of this disease, so-called variant CreutzfeldtJakob disease (vCJD), in UK death of 90 people Slower progression of the disease, deterioration of psyche, parastesia, ataxia, myoclonus, dementia CNS (basal ganglia), tonzila, spleen, nodules – plaque and detection of PrPSC