Transmission of infectious disease role of virulence factors in bacterial invasiveness
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Transmission of Infectious Disease: Role of Virulence Factors in Bacterial Invasiveness. General Definitions. Normal Flora. Microorganisms that are associated with a host, established at a particular anatomical location and don’t harm their host Important part of innate immunity

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Normal flora
Normal Flora Factors in Bacterial Invasiveness

  • Microorganisms that are associated with a host, established at a particular anatomical location and don’t harm their host

  • Important part of innate immunity

    • Compete for space and nutrients with harm harmful organisms

  • When displaced from normal site to other areas  may cause disease

    • Example: Staphylococcus aureus in nose and throat can enter a wound and cause serious infections


  • Commensalism Factors in Bacterial Invasiveness - the microorganism (commensal) benefits, while the host is neither harmed nor helped

    • The microorganism shares the same food source with the host

    • The microorganism is not directly dependent on the metabolism of the host

    • The microorganism causes no particular harm to host


  • Example Factors in Bacterial Invasiveness

    • the common nonpathogenic strain of Escherichia coli lives in the human colon;

    • this facultative anaerobe uses oxygen creating an anaerobic environment in which obligate anaerobes (e.g. bacteroids) can grow.

    • The bacteroids benefit but the E. coli derives no obvious benefit or harm.


  • Mutualism Factors in Bacterial Invasiveness

    • There is some reciprocal benefit to both partners

    • The microorganism (mutualist) and host are metabolically dependent upon each other

    • Syntropism is a mutually beneficial relationship in which each organism provides one or more growth factors, nutrients or substrates for the other organism;

      • also referred to as cross-feeding or the satellite phenomenon

      • Example: Intestinal flora synthesizing vitamin K and B complex vitamins for host


  • Parasitism Factors in Bacterial Invasiveness - relationship in which a symbiont harms or lives at the expense of a host

  • Host - the body of the animal in which the parasite lives;

    • it provides the microenvironment that shelters and supports the growth and multiplication of the parasitic organism


  • Opportunist: Factors in Bacterial Invasiveness

    • Lack ability to cause disease during health, but may invade following illness or suppression


Nosocomial infections
Nosocomial infections Factors in Bacterial Invasiveness

  • Infections acquired during hospitalization

  • Caused by opportunists that make up our normal flora

  • Endogenous disease - a disease caused by the host’s own microbiota because the host’s resistance has dropped


Gnotobiotic animals
Gnotobiotic animals Factors in Bacterial Invasiveness

  • Germ-free animals

  • Derived from caesarian section and rearing in a strict environment

  • Make valuable models for investigating immune responses and prevention of opportunistic infections


Pathogenicity
Pathogenicity Factors in Bacterial Invasiveness

  • Ability of microbes to cause disease in the host it infects


Virulence
Virulence Factors in Bacterial Invasiveness

  • Extent of pathogenicity

  • Capacity to cause disease

    • Related to severity of disease in the host


Communicable diseases
Communicable diseases Factors in Bacterial Invasiveness

  • Contagious

  • Transmissible from one host to another


Endemic disease
Endemic disease Factors in Bacterial Invasiveness

  • Persistent disease in a defined geographical area

    • Examples:

      • Rhinoviruses

      • Malaria


  • Parasite Factors in Bacterial Invasiveness - usually the smaller of the two organisms; it is metabolically dependent on the host

  • Ectoparasite - lives on the surface of the host


  • Endoparasite Factors in Bacterial Invasiveness - lives within the host

  • Final host - the host on (or in) which the parasite either gains sexual maturity or reproduces

  • Intermediate host - a host that serves as a temporary but essential environment for parasite development


  • Transfer host Factors in Bacterial Invasiveness - a host that is not necessary for development but that serves as a vehicle for reaching the final host

  • Reservoir host - an organism (other than a human) that is infected with a parasite that can also infect humans


Infectious disease caused by parasites
Infectious Disease Caused by Parasites Factors in Bacterial Invasiveness

  • Infection - the state occurring when a parasite is growing and multiplying on or within a host


  • Infectious disease Factors in Bacterial Invasiveness - a change from a state of health as a result of an infection by a parasitic organism

    • Adverse affect on the function of part or all of the host body as a result of the presence of a parasite or its toxic products

  • Pathogen - any parasitic organism that produces an infectious disease

  • Pathogenicity - the ability of a parasitic organism to cause a disease


Latency
Latency Factors in Bacterial Invasiveness

  • When no symptoms present themselves

  • Intermittent latency

    • Herpes simplex virus (HSV)

      • Lies dormant in neural tissue and is induced to replicate by various factors including intense sunlight and stress

  • Quiescent latency

    • Persistence over very long periods of time (many years)

      • Varicella zoster

        • Chickenpox in children

        • Shingles in the elderly


Outcome of host parasite relationships

Outcome of Host-Parasite Relationships Factors in Bacterial Invasiveness


The final outcome of host parasite relationships
The final outcome of host-parasite relationships Factors in Bacterial Invasiveness

  • Dependent on three factors:

    • The actual number of parasites in the body

    • How virulent the parasite is

    • How effective the host’s resistance is to infection



What determines virulence

What Determines Virulence? even if the host has high resistance


  • Virulence even if the host has high resistance – a measure of pathogenic intensity determined by three properties of the pathogen:

    • Invasiveness – organism’s ability to penetrate the first line of defense and spread to adjoining tissues in the host

    • Infectivity – organism’s ability to establish a primary site of infection

    • Pathogenic potential – organism’s ability to induce morbid symptoms, determined by toxigenicity


What is toxigenicity
What is toxigenicity? even if the host has high resistance

  • Refers to organisms ability to produce toxic compounds (toxins) that are harmful and cause disease

  • Toxins = specific metabolic products of pathogen

    • Exotoxins

    • Endotoxins

    • Leukocidins

    • Hemolysins


Ld 50 and id 50
LD even if the host has high resistance50 and ID50

  • LD50

    • Lethal dose 50

    • Number of pathogens required to kill 50% of subjects in a given time period

  • ID50

    • Infectious dose 50

    • Number of pathogens required to infect 50% of subjects


Components influencing infectious disease

Components Influencing Infectious Disease even if the host has high resistance


  • Transmissibility even if the host has high resistance of the pathogen - involves initial transport to the host

    • Direct contact - coughing, sneezing, body contact (shaking hands, kissing)

    • Indirect contact – deposition into an environmental medium including soil, water, food and bedding

      • Inanimate object that harbor and transmit disease = fomites

    • Vectors - living organisms that transmit a pathogen from one host to another

      • Mosquitoes (Malaria, West Nile Virus)

      • Tick (Rocky Mountain spotted fever, Lyme disease)

      • Flea (Plague)


  • Zoonoses even if the host has high resistance

    • Disease which are mainly prevalent in an animal population but can be transferred to humans

      • Rabies

      • Plaque

      • Brucellosis

      • Tularemia


  • Attachment even if the host has high resistance and colonization (multiplication) by the pathogen

    • Pathogen must be able to adhere to and colonize host cells and tissue;

      • this is mediated by special molecules or structures called adhesins

    • Examples of adhesins

      • Filamentous hemagglutinin of Bordetella pertussis (binds to cilia of RT)

      • Fimbriae, pili

      • Glycocalyx (dental plaque)

      • Lectin

      • Capsule

      • S layer

      • Slime layer

      • Teichoic and lipoteichoic acids


  • Pathogen must compete with normal microbiota for essential nutrients


  • Invasion and evasion of host defense mechanisms

    Invasion and Evasion of Host Defense Mechanisms even if the host has high resistance


    • Invasion of the pathogen even if the host has high resistance

      • Requires penetration of the host’s epithelial cells or tissues

      • Invasiveness = features that enable pathogens to escape immune detection/defenses and cause overt infection


    Portals of entry
    Portals of Entry even if the host has high resistance

    • Each infectious organism has its own portal of entry and portal of exit from the host

    • Entry:

      • Respiratory tract via nose and throat

        • M tuberculosis can survive in dried sputum for weeks

      • Gastrointestinal tract via mouth

        • S. typhi multiply only I cells of intestinal mucosa

      • Skin and mucus membranes

      • Genitourinary system (STD)

      • Blood (insects, transfusions, needles)

    • Exit: Usually the same as the portals of entry


    • Pathogen-associated mechanisms even if the host has high resistance involve the production of lytic substances that may:

      • Attack the ground substance and basement membranes of integuments and intestinal linings

      • Depolymerize carbohydrate-protein complexes between cells or on cell surfaces

      • Disrupt cell surfaces and extracellular matrix


    • Passive mechanisms even if the host has high resistance of entry involve:

      • Breaks, lesions, or ulcers in the mucous membranes

      • Wounds, abrasions, or burns on the skin surface

      • Arthropod vectors that penetrate when feeding

      • Tissue damage caused by other organisms

      • Endocytosis by host cells


    • Gaining of even if the host has high resistanceaccess to deeper tissues

    • Penetration into the circulatory system

  • Growth and multiplication of the pathogen - pathogen must find an appropriate environment

    • pH

    • Oxygen tension

    • Nutrient availabililty (including specialized growth factors)

    • Intracellular growth

      • Mycobacterium tuberculosis in alveolar macrophages

    • Extracellular growth

      • Pyogenic infections – pus formation in extracellular spaces (pyogenic streptococci – S. pyogenes)


  • Dissemination by evasion
    Dissemination by Evasion even if the host has high resistance

    • Pathogens spread throughout the host tissue and sometimes even gain entry into lymphatic capillaries and then eventually into the circulation

      • Localized infection = limited

      • Systemic dissemination = multiple organs

    • Enhanced by microbial products and enzymes (virulence factors)


    • Capsules and fimbriae – even if the host has high resistanceantiphagocytic, requires antibodies for opsonization

    • Leukocidins - extracellular enzymes that kill phagocytic leukocytes by causing degranulation of lysosomes

    • Hemolysins - extracellular enzymes that kill erythrocytes by forming a pore (iron released)

      • Streptolysin O – inactivated by oxygen, beta hemolysis when incubated anaerobically (S. pyogenes)

      • Streptolysin S – not oxygen sensitive, beta hemolysis under aerobic conditions

        • If phagocytosed, acts as a leukocidin and kills macrophages


    • Coagulase even if the host has high resistance – clots fibrinogen in plasma, protecting pathogen from phagocytosis and other host defenses

    • Collagenase – Degrades collagen in connective tissue promoting the spread of the pathogen

    • Deoxyribonuclese – reduces viscosity of exudates, improving pathogen mobility


    • Elastase even if the host has high resistance – degrades laminin in ECM

    • Exotoxin B – aka pyrogenic exotoxin b – protease

    • Hydrogen peroxide and ammonia – damage to respiratory and urogenital systems


    • Hyaluronidase even if the host has high resistance – degrades hyaluronic acid in intercellular ground substances holding cells together – increases mobility

    • IgA protease – Degrades antibody (IgA isotype) into Fab and Fc fragments

    • Lecithinase – degradation of lecithin in PM (phosphatidylcholine)


    • Protein A – even if the host has high resistancebinds IgG at Fc, prevents C’ activation

    • Streptokinase (fibrinolysin, staphylokinase)– binds plasminogen and induces production of plasmin, and digestion of fibrin clots – increasing mobility of pathogen from clotted areas


    Toxins

    TOXINS even if the host has high resistance


    • Toxigenicity even if the host has high resistance - the capacity of an organism to produce a toxin

      • Intoxications – diseases caused as a result of toxin produced inside the body

      • Toxin - a specific substance, often a metabolic product of the organism, that damages the host in some specified manner

      • Toxemia - symptoms caused by toxins if they enter the blood of the host


    Two main categories of toxins
    Two main categories of toxins even if the host has high resistance

    • Exotoxins

    • Endotoxins


    Exotoxins

    EXOTOXINS even if the host has high resistance


    Characteristics of exotoxins
    Characteristics of Exotoxins even if the host has high resistance

    • Soluble, heat-labile proteins produced by and released from an organism during growth and replication

    • May damage the host at some remote site

    • Genes that encode exotoxins are located on chromosomes, plasmids and bacteriophages


    • Make up most lethal substances yet identified even if the host has high resistance

    • Have specific disease associations and specific effects in the host

      • Often named after the disease that they cause (e.g. cholera toxin, diphtheria toxin)

    • Stimulate strong immune responses

      • Highly immunogenic

      • Induce production of neutralizing antibodies (antitoxins)

    • Inactivated by a variety of chemicals to form immunogenic toxoids (e.g. formaldehyde, iodine)

    • Do not cause fever in the host with exception of superantigens


    • Subclassification depends on how they exert their effects: even if the host has high resistance

      • Neurotoxins damage nervous tissue

      • Enterotoxins damage the small intestine

      • Cytotoxins do general tissue damage

      • cAMP-producing increae cAMP levels

      • Superantigens – trigger massive T cell stimulation and cytokine production (TNF-alpha)


    Mechanism of action of exotoxins
    Mechanism of Action of Exotoxins even if the host has high resistance

    • Inhibition of protein synthesis

    • Impairment of nerve synapse function

    • Membrane transport disrupted (e.g. electrolyte imbalance resulting in a flow os water into the intestine)

    • Damage to plasma membrane

    • Increased cAMP levels (cyclic adenosine monophosphate)

    • Cytokine production induced by superantigens


    Two types of membrane disrupting exotoxins
    Two Types of Membrane Disrupting Exotoxins even if the host has high resistance

    • 1: A channel forming (pore-forming) type of exotoxin that inserts itself into the normal host cell membrane and makes an open channel (pore)

      • Exotoxin attaches to the cholesterol portion of the host cell plasma membrane

      • Examples: Leukocidins (pneumococci, streptococci, and staphylococci) and Hemolysins (streptococci)

    • (See Figure 34.6)


    • 2: A even if the host has high resistancephospholipid-hydrolyzing phospholipase exotoxin destroys membrane integrity.

      • The exotoxins removes the charged polar head groups from the phospholipid part of the host cell membrane.

      • This destabilizes the membrane and causes the host cell to lyse.

      • Example: gas gangrene caused by Clostridium perfringensa-toxin


    Exotoxin transport mechanisms
    Exotoxin Transport Mechanisms even if the host has high resistance

    • A close look at the AB Model

      • Exotoxins lack an independent cell entry function and must bind to specific receptors on host cell membranes to be transported across the membrane

      • The “A” subunit of the toxin exerts its toxic effect (the A subunit has the enzyme activity that causes damage to the host)

      • The “B” subunit binds to the host receptor (e.g. ganglioside receptors are used for different exotoxins – GM1 for cholera toxin; GT1 for tetanus toxin; GD1 for botulinum toxin)


    • Together the A and B subunits form a dimeric exotoxin that will bind to host membranes and enter using two different routes:

      • Pore

      • Receptor-mediated endocytosis (involving clathrin-coated pits)

        • Example: diphtheria toxin – protein synthesis inhibition

          • CURL = component of uncoupling of receptor ligand

          • EF2 is consumed in reaction and is not available for translation


    Properties of neurotoxins
    Properties of Neurotoxins will bind to host membranes and enter using two different routes:

    • Can be ingested as a preformed toxin or made in the body

    • Affect the nervous system directly and the small intestine indirectly

    • Examples:

      • Staphylococcal enterotoxin B (SEB)

      • Bacillus cereus emetic toxin (vomiting)


    • Botulinum toxin will bind to host membranes and enter using two different routes:

      • Flaccid paralysis caused by inhibiton of acetylcholine activity at neuromuscular junction

      • Ingestion of preformed toxin

      • Infant botulism: spores germinate in the gut (dust, honey)


    • Tetanus toxin will bind to host membranes and enter using two different routes:

      • Spores germinate in necrotic tissue

      • Spastic paralysis caused by blocking inhibitory nerve impulses that cause constant stimulation of somatic motor neurons


    Properties of enterotoxins
    Properties of Enterotoxins will bind to host membranes and enter using two different routes:

    • Directly affect intestinal mucosa

      • Vomiting, dysentery and diarrhea

    • Elicit massive fluid secretion into intestine

    • Water and electrolytes move across intestingal cells into the lumen of the gut

    • Examples:

      • Cholera toxin

      • Escherichia coli

      • Staphylococcal food poisoning

      • Shigella dysentery

      • Enterohemorrhagic and enteroinvasive E. coli


    Properties of superantigens
    Properties of Superantigens will bind to host membranes and enter using two different routes:

    • Pyrogenic (fever-inducing) toxins

    • Bind to MHC class II on macrophages and the variable region on subsets of T cell receptors of CD4+ TH1 cells (inflammataory T cells)

    • Induce macrophages to produce TNF-alpha and Interleukin-1 (IL-1 = endogenous pyrogen)


    • TNF-alpha will bind to host membranes and enter using two different routes:

      • Aka cachectin

      • Associated with chronic infection and weight loss (cachexia)

      • If TNF alpha is injected into experimental animals, it reproduces shock characteristic of Gram negative infections

      • TNF-alpha also activates nitric oxide synthase (NOS) gene transcription

        • NO regulated blood pressure (relaxes amooth muscle cells of blood vessels causing BP to decrease)

        • If BP drops too low, hypovolemic shock results (toxic shock, septic shock)

      • Pros: promotion of phagocytosis and increases wound healing

      • Cons: fever, rash (scarlet fever, toxic shock syndrome), inflammation, shock, death


    • See Figure 32.5 will bind to host membranes and enter using two different routes:

      • Superantigens stimulate T cells bearing a particular Vb element of the T-cell receptor, regardless of the nature of the Va receptor element.

      • They bind directly to the outer surface of the MHC class II molecule without requiring processing by the antigen presenting cells.

      • Net effect: Stimulation of between 2-20% of total T cell repertoire!!!!!!!


    • Examples of superantigens: will bind to host membranes and enter using two different routes:

      • Staphylococcal enterotoxins (SEA, SEB, SEC)

      • Exfoliatin toxin (Staphylococcus, scalded skin syndrome)

      • Pyrogenic toxisn of staph and strep

      • Toxic shock syndrome toxin (TSST-1) - Staphylococcus


    Endotoxins

    ENDOTOXINS will bind to host membranes and enter using two different routes:


    Characteristics of endotoxins
    Characteristics of Endotoxins will bind to host membranes and enter using two different routes:

    • Lipopolysaccharide (LPS) in Gram negative outer membranes of cell wall

    • When microbe lyses (dies) or replicates, endotoxin is released

    • Lipid A = lipid portion that is toxic

    • Heat stable (even after autoclaving!)

    • Weakly immunogenic (does not stimulate a strong adaptive immune response)

    • Strongly mitogenic for B lymphocytes (B cells proliferate non-specifically)

    • Share same structure/composition generally


    • Can cause systemic effects: will bind to host membranes and enter using two different routes:

      • Fever – pyrogenic

      • Septic shock (hypovolemic shock)

      • Disseminated intravascular coagulation (DIC) – blood coagulation/clotting

      • Diarrhea

      • Inflammation

      • Weakness

      • Intestinal hemorrhage

      • Lysis of fibrin = fibrinolysis (difficulty with clotting – internal hemorrhaging)

      • Circulatory changes (oxygen deprivation to organs)

      • Organ failure/respiratory distress/mental delirium

      • Activation of Hageman Factor (blood clotting factor XII)


    • Stimulates fever directly by acting as an will bind to host membranes and enter using two different routes:exogenous pyrogen;

      • also may stimulate fever indirectly by causing macrophages to release interleukin-1, an endogenous pyrogen



    Hageman factor initiates four humoral systems
    Hageman Factor Initiates Four Humoral Systems LPS-binding proteins in the plasma that, in turn, bind to receptors on the macrophages and monocytes triggering cytokine release that produces endotoxin effects

    • Four general categories of humoral effects activated:

      • Coagulation

      • Complement activation

      • Fibrinolysis

      • Activation of the Kininogen system


    • Coagulation LPS-binding proteins in the plasma that, in turn, bind to receptors on the macrophages and monocytes triggering cytokine release that produces endotoxin effects

      • Blood clotting cascade is initiated

      • Coagulation, thrombosis (blood clots n vessels)

      • Accute disseminated intravascular coagulation

      • Depletion of platelet and clotting factors – internal hemorrhaging


    • Complement Activation LPS-binding proteins in the plasma that, in turn, bind to receptors on the macrophages and monocytes triggering cytokine release that produces endotoxin effects

      • Alternative and classical pathways of complement activated

        • Membrane attack complexes (MAC) form

        • Inflammatory mediators produces (histamine), inducing chemotaxis and acivation of neutrophils


    • Fibrinolysis LPS-binding proteins in the plasma that, in turn, bind to receptors on the macrophages and monocytes triggering cytokine release that produces endotoxin effects

      • Plasminogen activation

        • Generates plasmin from plasminogen  degradation of fibrin  internal hemorrging

      • Plasmin can also activate the complement cascade


    • Kininogen System Activated LPS-binding proteins in the plasma that, in turn, bind to receptors on the macrophages and monocytes triggering cytokine release that produces endotoxin effects

      • Series of enzyme reactions result in the release of bradykinins and other vasoactive peptides

      • Results:

        • Vasodilation

        • Pain

        • Increased vascular permeability (fluid portion of blood leaks into interstitial spaces)

        • Hypovolemic/circulatory shock

        • Death



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