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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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

Transmission of Infectious Disease: Role of Virulence Factors in Bacterial Invasiveness


Transmission of infectious disease role of virulence factors in bacterial invasiveness

  • General Definitions


Normal flora

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

    • 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


Transmission of infectious disease role of virulence factors in bacterial invasiveness

  • Commensalism - 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


Transmission of infectious disease role of virulence factors in bacterial invasiveness

  • Example

    • 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.


Transmission of infectious disease role of virulence factors in bacterial invasiveness

  • Mutualism

    • 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


Transmission of infectious disease role of virulence factors in bacterial invasiveness

  • Parasitism - 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


Transmission of infectious disease role of virulence factors in bacterial invasiveness

  • Opportunist:

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


Nosocomial infections

Nosocomial infections

  • 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

  • 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

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


Virulence

Virulence

  • Extent of pathogenicity

  • Capacity to cause disease

    • Related to severity of disease in the host


Communicable diseases

Communicable diseases

  • Contagious

  • Transmissible from one host to another


Endemic disease

Endemic disease

  • Persistent disease in a defined geographical area

    • Examples:

      • Rhinoviruses

      • Malaria


Transmission of infectious disease role of virulence factors in bacterial invasiveness

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

  • Ectoparasite - lives on the surface of the host


Transmission of infectious disease role of virulence factors in bacterial invasiveness

  • Endoparasite - 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


Transmission of infectious disease role of virulence factors in bacterial invasiveness

  • Transfer host - 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

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


Transmission of infectious disease role of virulence factors in bacterial invasiveness

  • Infectious disease - 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

  • 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


The final outcome of host parasite relationships

The final outcome of host-parasite relationships

  • 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


Transmission of infectious disease role of virulence factors in bacterial invasiveness

  • Disease often incurred if parasite is particularly virulent, even if the host has high resistance

  • Disease also incurred if virulence isn’t particularly intense, but the host’s resistance is weakened

    • Age

    • Illness

    • Immunosuppressive drugs


What determines virulence

What Determines Virulence?


Transmission of infectious disease role of virulence factors in bacterial invasiveness

  • Virulence – 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?

  • 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

LD50 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


Transmission of infectious disease role of virulence factors in bacterial invasiveness

  • Transmissibility 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)


Transmission of infectious disease role of virulence factors in bacterial invasiveness

  • Zoonoses

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

      • Rabies

      • Plaque

      • Brucellosis

      • Tularemia


Transmission of infectious disease role of virulence factors in bacterial invasiveness

  • Attachment 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


Transmission of infectious disease role of virulence factors in bacterial invasiveness

  • Adhesins bind to host cell receptors

    • Examples: fibronectin, laminin, vitronectin, sialoproteins (found in host’s extracellular matrix)

  • Pathogen must compete with normal microbiota for essential nutrients


  • Invasion and evasion of host defense mechanisms

    Invasion and Evasion of Host Defense Mechanisms


    Transmission of infectious disease role of virulence factors in bacterial invasiveness

    • Invasion of the pathogen

      • 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

    • 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


    Transmission of infectious disease role of virulence factors in bacterial invasiveness

    • Pathogen-associated mechanisms 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


    Transmission of infectious disease role of virulence factors in bacterial invasiveness

    • Passive mechanisms 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


    Transmission of infectious disease role of virulence factors in bacterial invasiveness

    • Gaining of access 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

    • 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)


    Transmission of infectious disease role of virulence factors in bacterial invasiveness

    • Capsules and fimbriae – antiphagocytic, 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


    Transmission of infectious disease role of virulence factors in bacterial invasiveness

    • Coagulase – 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


    Transmission of infectious disease role of virulence factors in bacterial invasiveness

    • Elastase – degrades laminin in ECM

    • Exotoxin B – aka pyrogenic exotoxin b – protease

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


    Transmission of infectious disease role of virulence factors in bacterial invasiveness

    • Hyaluronidase – 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)


    Transmission of infectious disease role of virulence factors in bacterial invasiveness

    • Protein A – binds 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


    Transmission of infectious disease role of virulence factors in bacterial invasiveness

    • Toxigenicity - 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

    • Exotoxins

    • Endotoxins


    Exotoxins

    EXOTOXINS


    Characteristics of exotoxins

    Characteristics of Exotoxins

    • 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


    Transmission of infectious disease role of virulence factors in bacterial invasiveness

    • Make up most lethal substances yet identified

    • 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


    Transmission of infectious disease role of virulence factors in bacterial invasiveness

    • Subclassification depends on how they exert their effects:

      • 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

    • 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

    • 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)


    Transmission of infectious disease role of virulence factors in bacterial invasiveness

    • 2: A phospholipid-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

    • 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)


    Transmission of infectious disease role of virulence factors in bacterial invasiveness

    • 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

    • 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)


    Transmission of infectious disease role of virulence factors in bacterial invasiveness

    • Botulinum toxin

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

      • Ingestion of preformed toxin

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


    Transmission of infectious disease role of virulence factors in bacterial invasiveness

    • Tetanus toxin

      • 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

    • 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

    • 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)


    Transmission of infectious disease role of virulence factors in bacterial invasiveness

    • TNF-alpha

      • 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


    Transmission of infectious disease role of virulence factors in bacterial invasiveness

    • See Figure 32.5

      • 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!!!!!!!


    Transmission of infectious disease role of virulence factors in bacterial invasiveness

    • Examples of superantigens:

      • 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


    Characteristics of endotoxins

    Characteristics of Endotoxins

    • 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


    Transmission of infectious disease role of virulence factors in bacterial invasiveness

    • Can cause systemic effects:

      • 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)


    Transmission of infectious disease role of virulence factors in bacterial invasiveness

    • Stimulates fever directly by acting as an exogenous pyrogen;

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


    Transmission of infectious disease role of virulence factors in bacterial invasiveness

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

    • Activation of Hageman Factor


    Hageman factor initiates four humoral systems

    Hageman Factor Initiates Four Humoral Systems

    • Four general categories of humoral effects activated:

      • Coagulation

      • Complement activation

      • Fibrinolysis

      • Activation of the Kininogen system


    Transmission of infectious disease role of virulence factors in bacterial invasiveness

    • Coagulation

      • Blood clotting cascade is initiated

      • Coagulation, thrombosis (blood clots n vessels)

      • Accute disseminated intravascular coagulation

      • Depletion of platelet and clotting factors – internal hemorrhaging


    Transmission of infectious disease role of virulence factors in bacterial invasiveness

    • Complement Activation

      • Alternative and classical pathways of complement activated

        • Membrane attack complexes (MAC) form

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


    Transmission of infectious disease role of virulence factors in bacterial invasiveness

    • Fibrinolysis

      • Plasminogen activation

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

      • Plasmin can also activate the complement cascade


    Transmission of infectious disease role of virulence factors in bacterial invasiveness

    • Kininogen System Activated

      • 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


    Transmission of infectious disease role of virulence factors in bacterial invasiveness

    • Teichoic acid of Gram positive cell walls can trigger similar resposes as LPS of Gram negative cells


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