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现代医学导论 2012级食品安全与营养专业求是科学班 病原微生物的致病机理 及机体免疫调控机制 Infection and immunity Dr. Jing Qian Zhejiang University School of Medicine April 09, 2014 Pathogenesis of bacterial infection Terms Pathogen: A microorganism enable to cause disease. Nonpathogen: A microorganism that does not cause disease. Opportunistic pathogen: A microorganism does not cause disease in normal conditions, but is capable of causing disease in some special conditions. Pathogenicity: The ability of a microorganism to cause disease. Pathogenesis of bacterial infection Terms Virulence: The quantitative ability of a pathogen to cause disease. Virulent agents cause disease when introduced into the host. It contains invasiveness and toxigenicity. LD50: The number of pathogen required to cause lethal disease in half of the exposed hosts. ID50: The number of pathogens required to cause disease or infection in half of the exposed hosts. Pathogenesis of bacterial infection Terms • Adhesion (adherence, attachment): the process by which bacteria stick to the surfaces of host cells. Adhesion is a key initial step during infection (then invasion). • Invasion: The process whereby microoganisms enter host cells or tissues as well as spread in the body. • Toxigenicity: The ability of a microorganism to produce a toxin that contributes to the development of disease. • • Pathogenesis of bacterial infection includes: a) general process of infection b) mechanisms of microbes causing disease A bacterial infectious disease is a multi-factorial event which depends on: i. Nature (virulence) of bacterial species or strain. ii. Number of invaded bacteria. iii. Route of bacteria invading hosts. Generally, infection process caused by a bacterial pathogen involves the four steps as the following: I. Adhesion II. Penetration and spread III. Survival and propagation in the host IV. Tissue injury Any bacterial factors involved in the four steps determine the virulence of bacteria. Bacterial virulence is dependent on various virulent factors produced by bacteria. Degradative enzymes • Collagenase: to destroy collagen. There are a lot of collagens in soft tissue including connective tissue. • Hyaluronidas: to destroy hyaluronic acid. Hyaluronic acid is a major component in the matrix of connective tissue. • Coagulase: to coagulate fibrinogen in tissue fluid and plasma into fibrin. (to protect bacteria from damage by many agents) • Streptokinase/fibrinolysin: The former activates fibrinogenase to thrombin, which results in the degradation of fibrin. And the latter directly lyse fibrin. • Streptodornase: it is a DNase. • Cytolysins: 1) hemolysins (to dissolve red blood cells) 2) Leoukocisins (to kill leukocytes or tissue cells ) Bacteria cause tissue injury by many factors or some special mechanisms involving: a) Exotoxin b) Endotoxin c) Inducement of Immunopathological reaction Exotoxins Cytotoxin: e.g. diphtheria toxin Nuerotoxin: e.g. tetanospasmin Enterotoxin: e.g. cholera enterotoxin Cell surface Toxic Binding A B Endotoxins (LPS) Original and development of Bacterial Infection Source of infection Exogenous infection Infections caused by infectious agents that are come from the external environment or other hosts (patient, carrier, diseased animal or animal carrier). Definition of “carrier”: individuals infected with infectious agents but no clinical signs or symptoms. Endogenous condition Infections caused by normal flora under certain conditions (opportunistic infection) Transmission of bacteria Bacteria can be transmitted in airborne droplets to the respiratory tract, by ingestion of food or water or by sexual contact. Specific bacterial species are being transmitted by different routes to specific sites in the human body: 1. Respiratory 2. Gastroenteric 3. Genitourinary tract 4. Closely contact 5. Insect bite 6. Blood transfusion 7. Parenteral route 8. Skin and other mucosa (eye) Types of bacterial infection According to infectious state: Inapparent or subclinical infection: The infection with no manifesting characteristic clinical signs and symptoms. Latent infection: The infection is inactive but remains capable of producing clinical signs and symptoms. Apparent infection : The infection characteristic clinical signs and symptoms. with manifesting Types of bacterial infection According to infectious sites: Local infection: The infection is limited to a small area of the body. 1. 2. 3. 4. 5. Generalized or systemic infection: Toxemia: Exotoxins enter bloodstream but no bacteria in the blood. Endotoxemi: Endotoxins enter bloodstream but no bacteria in the blood. Bacteremia : Bacteria enter bloodstream without propagation in bloodstream (bloodstream only used as a channel tool for bacteria to spread) Septicemia: Bacteria enter bloodstream with propagation and release their virelent substances (e.g., toxins). Pyemia : Pyogenic bacteria enter bloodstream with propagation and release their virulent substances, and spread through bloodstream into the target organs to form new pyogenic foci. Pathogenesis of viruses infection Steps in virus-host interaction •Entry into the host •Primary replication •Spread •Cell and tissue tropism •Secondary replication •Cell injury and persistence •Host immune response Viral pathogenesis the seven steps from entry to disease 1 Replication at the site of entry 2 Lymph node HSV VZV 3 Primary viremia 4 Replication sites 5 Secondary viremia 6 Replication sites 7 Transmission to other hosts Cytomegalovirus Ganglion Bone marrow Sites of virus entry Transmission of viruses aerosols parental direct contacts sexual Outcomes of viral infections acute, self limiting chronic Locally restricted (z. B. Rhinitis, Enteritis) Latent, reactivation (Phases without viremia) (eg Herpesviruses) Chronic persistent (permanent Virus production) (eg Hepatitis B and C) systemic local replication => Viremia (eg. Measles) active progression (eg HIV) Patterns in acute and persistent infections raute 7/2002 Pathogenesis of fungal infection A. Superficial mycoses B. Cutaneous mycoses C. Subcutaneous mycoses D. Systemic mycoses Pathogenesis of fungal infection A. Superficial mycoses B. Cutaneous mycoses Oral thrush Host immune responses to infection The two columns of immunity immunity innnate immunity nonspecific immunity constitutional, skin: defensins aqcuired immunity specific immunity humoral constitutional, blood : complement reactive, blood: interferons cellular NK cells cellular cytotoxic Early phase of immunity Infectious agent Infektions-Erreger Epithelial barrier Epithel-Barriere uns pezifis che Innate immunity Abwehr polymorphkernige polymorphonuclear Monozyten Monocytes Granulozyten (P MN) Granulocytes (PMN) N K-Zellen NK cells ? draining drainierender Lymphknoten lymphnode Interleukin/Cytokin Interleukine/cytokine Balance balance Polarization of der the Polarisation T Zell-Antwort T-cell response Time table of innate and specific immunity complement interferon a/b NK cells CD4 lymphocytes CD8 lymphocytes antibodies days after infection Antimicrobial Defenses for Infectious Agents Intracellular Bacteria Bacteria Viruses Fungi Parasites Complement + - - - - Interferon-α/β - - ++++ - - Neutrophils ++++ - - + + Macrophages ++ +++ ++ ++ + NK cells - - +++ - - CD4 TH1, DTH - ++ +++ +* + CD8 CTL - - ++++ - - Antibody ++ + + + ++(IgE)† *CTL, By activation of macrophages. †Immunoglubulin E and mast cells are especially important for worm infections. Cytotoxic T lymphocytes; NK, natural killer. Time table of innate and specific immunity for bacteria infection Effects of innate and specific immunity on viral infectionpositive part Toll-like receptors Surveillance systems for microbes Surveillance systems for microbes pathogen associated microbial patterns (PAMP) pattern recognition receptors (PRR) Toll-like receptor pathways TLR4 has been reserved for gramnegative bacteria Interferons Prevention and treatment of viral infection human interferons IFN-a source all cells inductor viral dsRNA antiviral action localization number of subtypes Function IFN-b all cells viral dsRNA +++ chromosome 9 22 Antiviral infection activation of NK cell IFN-g T-lymphos antigen/mitogen +++ + chromosome 12 chromosome 9 1 1 anti-tumor regulation of enhancement of CMI immunity Interferon-inducing dsRNA: 30 bp interferon a and b: gene products to remember 2‘,5‘-oligo adenylate cyclase RNA dependent proteinkinase Interferon occupies receptors on vicinal cells 30 bp dsRNA induces production of a & b Interferon interferon activates > 100 genes 2‘, 5‘-oligo adenylate synthetase activation of an endonuclease degradation of viral RNA RNA dependent proteinkinase (PKR) phosphorylation & inactivation of elongationfactor EF-2 arrest of proteinsynthesis Inhibition of virus replication raute 10/2002