Chapter 15 Microbial Mechanisms of Pathogenicity

Waxy Lipid

(mycolic acid) that makes up the cell wall of Mycobacterium tuberculosis also increases virulence by resisting digestion by phagocytes, and can even multiply inside phagocytes

Cadherin

A glycoprotein called which bridges the junctions, to move from cell to cell

Cytopathic Effect (CPE)

A visible effect on a host cell, caused by a virus, that may result in host cell damage or death

Fimbriae

An appendage on a bacterial cell used for attachment

Hemolysins

An enzyme that lyses red blood cells. Membrane-disrupting toxin that destroy erythrocytes (red blood cells), also by forming protein channels

Toxoid

An inactivated toxin

Toxin

Any poisonous substance produced by a microorganism

Adherence

Attachment of a microbe or phagocyte to another's plasma membrane or other surface. The attachment between pathogen and host is accomplished by means of surface molecules on the pathogen called adhesins or ligands that bind specifically to complementary surface receptors on the cells of certain host tissues. a). Surface projections on a pathogen called adhesins (ligands) adhere to complementary receptors on the host cells. b). Adhesins can be glycoproteins or lipoproteins and are frequently associated with fimbriae. c). Mannose is the most common receptor. d). Biofilms provide attachment and resistance to antimicrobial agents.

Kinases

Bacterial enzymes that break down fibrin and thus digest clots formed by the body to isolate the infection

Coagulases

Bacterial enzymes that coagulate (clot) the fibrinogen in blood. Fibrinogen, a plasma protein produced by the liver, is converted by coagulases into fibrin, the threads that form a blood clot. The fibrin clot may protect the bacterium from phagocytosis and isolate it from other defenses of the host

A-B Toxin

Bacterial exotoxins consisting of two polypeptides. Most exotoxins are A-B toxins. The A part is the active (enzyme) component, and the B part is the binding component. 1) In the first step, the A-B toxin is released from the bacterium. 2) The B component attaches to a host cell receptor. 3) The plasma membrane of the host cell invaginates (folds inward) at the point where the A-B exotoxin and plasma receptor make contact, and the exotoxin enters the cell by receptor-mediated endocytosis. 4) The A-B exotoxin and receptor are enclosed by a pinched off portion of the membrane. 5) The A-B components of the exotoxin separate. The A component alters the function of the host cell, often by inhibiting protein synthesis. The B component is released from the host cell, and the receptor is inserted into the plasma membrane for reuse.

Antigenic Variation

Changes in surface antigens that occur in a microbial population. Some microbes vary expression of antigens, thus avoiding the host's antibodies

Which of the following statements is false?

Coaglulase destroys blood clots

Limulus Polyphemus

Contains white blood cells called amebocytes, which have large amounts of a protein (lysate) that causes clotting. In the presence of endotoxin, amebocytes in the crab hemolymph lyse and liberate their clotting protein. The resulting gel-clot (precipitate) is a positive test for the presence of endotoxin. The degree of the reaction is measured using a spectrophotometer

Noncytocidal Effect

Cytopathic effects that result in cell damage but not cell death

Cytocidal Effect

Cytopathic effects that result in cell death

Endotoxin

Endotoxins are released when gram-negative bacteria die and their cell walls undergo lysis, thus liberating the endotoxin. (Endotoxins are also released during bacterial multiplication.) Antibiotics used to treat diseases caused by gram-negative bacteria can lyse the bacterial cells; this reaction releases endotoxin and may lead to an immediate worsening of the symptoms, but the condition usually improves as the endotoxin breaks down. Endotoxins exert their effects by stimulating macrophages to release cytokines in very high concentrations. At these levels, cytokines are toxic. All endotoxins produce the same signs and symptoms, regardless of the species of microorganism, although not to the same degree. These include chills, fever, weakness, generalized aches, and, in some cases, shock and even death. Endotoxins can also induce miscarriage

IgA proteases

Enzyme that can destroy IgA antibodies of the host

Exoenzymes

Extracellular enzymes

Direct Damage

Host cells can be destroyed when pathogens metabolize and multiply inside the host cells

Membrane Ruffling

Invasins affect actin in host membrane causing "folds"

Leukocidins

Membrane-disrupting toxins that kill phagocytic leukocytes (white blood cells)

Streptolysin O (SLO)

Named because it is inactivated by atmospheric oxygen. Both streptolysins can cause lysis not only of red blood cells, but also of white blood cells (whose function is to kill the streptococci) and other body cells

Streptolysin S (SLS)

Named because it is stable in an oxygen environment. Both streptolysins can cause lysis not only of red blood cells, but also of white blood cells (whose function is to kill the streptococci) and other body cells

Portals of Entry - Parenteral Route

Portal of entry for pathogens by deposition directly into tissues beneath the skin and mucous membranes

How Microorganisms Enter a Host

Portals of Entry Preferred Portal of Entry Numbers of Invading Microbes Adherence

Endotoxic Shock

Septic shock caused by gram-negative endotoxins

Virulence

The degree or extent of pathogenicity

The most frequently used portal of entry for pathogens is the

The mucus membranes of the respiratory tract

Toxemia

The presence of toxins in the blood

Plasmids, Lysogeny, and Pathogenicity

a) Plasmids may carry genes for antibiotic resistance, toxins, capsules, and fimbriae. b) Lysogenic conversion can result in bacteria with virulence factors, such as toxins or capsules.

Fever Response caused by Endotoxins

1. Gram-negative bacteria are ingested by phagocytes. 2. As the bacteria are degraded in vacuoles, the LPSs of the bacterial cell wall are released. These endotoxins cause macrophages to produce cytokines called interleukin-1 (IL-1),formerly called endogenous pyrogen,and tumor necrosis factor alpha (TNF-α) 3. The cytokines are carried via the blood to the hypothalamus, a temperature control center in the brain. 4. The cytokines induce the hypothalamus to release lipids called prostaglandins, which reset the thermostat in the hypothalamus at a higher temperature. The result is a fever.

Production of Toxins

1. Poisonous substances produced by microorganisms are called toxins; toxemia refers to the presence of toxins in the blood. The ability to produce toxins is called toxigenicity. 2. Exotoxins are produced by bacteria and released into the surrounding medium. Exotoxins, not the bacteria, produce the disease symptoms. 3. Antibodies produced against exotoxins are called antitoxins. 4. A-B toxins consist of an active component that inhibits a cellular process and a binding component that attaches the two portions to the target cell, e.g., diphtheria toxin. 5. Membrane-disrupting toxins cause cell lysis, e.g., hemolysins. 6. Superantigens cause release of cytokines, which cause fever, nausea, and other symptoms; e.g., toxic shock syndrome toxin. 7. Endotoxins are lipopolysaccharides (LPS), the lipid A component of the cell wall of gram-negative bacteria. 8. Bacterial cell death, antibiotics, and antibodies may cause the release of endotoxins. 9. Endotoxins cause fever (by inducing the release of interleukin-1) and shock (because of a TNF-induced decrease in blood pressure). 10. Endotoxins allow bacteria to cross the blood-brain barrier. 11. The Limulus amebocyte lysate (LAL) assay is used to detect endotoxins in drugs and on medical devices.

Pathogenic Properties of Fungi, Protozoa, Helminths, and Algae

1. Symptoms of fungal infections can be caused by capsules, toxins, and allergic responses. 2. Symptoms of protozoan and helminthic diseases can be caused by damage to host tissue or by the metabolic waste products of the parasite. 3. Some protozoa change their surface antigens while growing in a host, thus avoiding destruction by the host's antibodies. 4. Some algae produce neurotoxins that cause paralysis when ingested by humans.

Pathogenic Properties of Viruses

1. Viruses avoid the host's immune response by growing inside cells. 2. Viruses gain access to host cells because they have attachment sites for receptors on the host cell. 3. Visible signs of viral infections are called cytopathic effects (CPE). 4. Some viruses cause cytocidal effects (cell death), and others cause noncytocidal effects (damage but not death). 5. Cytopathic effects include stopping mitosis, lysis, formation of inclusion bodies, cell fusion, antigenic changes, chromosomal changes, and transformation

Opa

A bacterial outer membrane protein; cells with Opa form opaque colonies

Resistance (R) Factor

A bacterial plasmid carrying genes that determine resistance to antibiotics

Adhesin

A carbohydrate-specific binding protein that projects from prokaryotic cells; used for adherence, also called a Ligand

Ligand

A carbohydrate-specific binding protein that projects from prokaryotic cells; used for adherence, also called an Adhesin

Aflatoxin

A carcinogenic toxin produced by Aspergillus flavus.

In response to the presence of endotoxin, phagocytes secrete tumor necrosis factor (TNF). This causes

A fever; a decrease in blood pressure

Inclusion Body

A granule or viral particle in the cytoplasm or nucleus of some infected cells; important in the identification of viruses that cause infection

Streptolysins

A hemolytic enzyme, produced by streptococci

Biofilm

A microbial community that usually forms as a slimy layer on a surface

Saxitoxin

A neurotoxin produced by some dinoflagellates

Phalloidin

A peptide toxin produced by Amanita phalloides,affects plasma membrane function

Amanitin

A polypeptide toxin produced by Amanita spp., inhibits RNA polymerase

Antitoxin

A specific antibody produced by the body in response to a bacterial exotoxin or its toxoid

Interferon

A specific group of cytokines. Alpha- and beta-IFNs are antiviral proteins produced by certain animal cells in response to a viral infection. Gamma-IFN stimulates macrophage activity

Lysogeny

A state in which phage DNA is incorporated into the host cell without lysis

Septic Shock

A sudden drop in blood pressure induced by bacterial toxins

Invasin

A surface protein produced by Salmonella typhimurium and Escherichia coli that rearranges nearby actin filaments in the cytoskeleton of a host cell

Limulus Amebocyte Lysate (LAL) Assay

A test to detect the presence of bacterial endotoxins

Mycotoxin

A toxin produced by a fungus

Ergot

A toxin produced in sclerotia by the fungus Claviceps purpurea that causes ergotism.

Some cytopathic effects of viruses

A virus can produce one or more of the following cytopathic effects: 1. At some stage in their multiplication, cytocidal viruses cause the macromolecular synthesis within the host cell to stop. Some viruses, such as herpes simplex virus, irreversibly stop mitosis. 2. When a cytocidal virus infects a cell, it causes the cell's lysosomes to release their enzymes, resulting in destruction of intracellular contents and host cell death. 3. Inclusion bodies are granules found in the cytoplasm or nucleus of some infected cells. These granules are sometimes viral parts — nucleic acids or proteins in the process of being assembled into virions. Diagnostic inclusion bodies are also associated with measles virus, vaccinia virus, smallpox virus, herpesvirus, and adenoviruses. 4. At times, several adjacent infected cells fuse to form a very large multinucleate cell called a syncytium. Such giant cells are produced from infections by viruses that cause diseases, such as measles, mumps, and the common cold. 5. Some viral infections result in changes in the host cell's functions with no visible changes in the infected cells. For example, when measles virus attaches to its receptor called CD46, the CD46 prompts the cell to reduce production of an immune substance called IL-12, reducing the host's ability to fight the infection. 6. Some virus-infected cells produce substances called interferons. Viral infection induces cells to produce interferons, but the host cell's DNA actually codes for the interferon. This protects neighboring uninfected cells from viral infection. 7. Many viral infections induce antigenic changes on the surface of the infected cells. These antigenic changes elicit a host antibody response against the infected cell, and thus they target the cell for destruction by the host's immune system. 8. Some viruses induce chromosomal changes in the host cell. For example, some viral infections result in chromosomal damage to the host cell, most often chromosomal breakage. Frequently, oncogenes (cancer causing genes) may be contributed or activated by a virus. 9. Most normal cells cease growing in vitro when they come close to another cell, a phenomenon known as contact inhibition.Viruses capable of causing cancer transform host cells. Transformation results in an abnormal, spindle-shaped cell that does not recognize contact inhibition. The loss of contact inhibition results in unregulated cell growth

Disseminated Intravascular Coagulation (DIC)

Acquired hemorrhagic syndrome in which clotting and bleeding occur simultaneously

Cachectin

Also called Cachectin. TNF binds to many tissues in the body and alters their metabolism in a number of ways. One effect of TNF is damage to blood capillaries; their permeability is increased, and they lose large amounts of fluid. The result is a drop in blood pressure that results in shock. Low blood pressure has serious effects on the kidneys, lungs, and gastrointestinal tract. In addition, the presence of gram-negative bacteria such as Haemophilus influenzae type b in cerebrospinal fluid causes the release of IL-1 and TNF. These, in turn, cause a weakening of the blood brain barrier that normally protects the central nervous system from infection. The weakened barrier lets phagocytes in, but this also lets more bacteria enter from the bloodstream.

Tumor Necrosis Factor (TNF)

Also called Cachectin. TNF binds to many tissues in the body and alters their metabolism in a number of ways. One effect of TNF is damage to blood capillaries; their permeability is increased, and they lose large amounts of fluid. The result is a drop in blood pressure that results in shock. Low blood pressure has serious effects on the kidneys, lungs, and gastrointestinal tract. In addition, the presence of gram-negative bacteria such as Haemophilus influenzae type b in cerebrospinal fluid causes the release of IL-1 and TNF. These, in turn, cause a weakening of the blood brain barrier that normally protects the central nervous system from infection. The weakened barrier lets phagocytes in, but this also lets more bacteria enter from the bloodstream.

Superantigen

An antigen that activates many different T cells, thereby eliciting a large immune response. They are bacterial proteins. Through a series of interactions with various cells of the immune system, superantigens nonspecifically stimulate the proliferation of immune cells called T cells. These cells are types of white blood cells (lymphocytes) that act against foreign organisms and tissues (transplants) and regulate the activation and proliferation of other cells of the immune system. In response to superantigens, T cells are stimulated to release enormous amounts of chemicals called cytokines. The excessively high levels of cytokines released by T cells enter the bloodstream and give rise to a number of symptoms, including fever, nausea, vomiting, diarrhea, and sometimes shock and even death. Bacterial superantigens include the staphylococcal toxins that cause food poisoning and toxic shock syndrome

Siderophores

Bacterial iron-binding proteins. When a pathogen needs iron, siderophores are released into the medium, where they take the iron away from iron transport proteins by binding the iron even more tightly. Once the iron-siderophore complex is formed, it is taken up by siderophore receptors on the bacterial surface. Then the iron is brought into the bacterium. In some cases, the iron is released from the complex to enter the bacterium; in other cases, the iron enters as part of the complex

Botulinum toxin

Botulinum toxin is produced by Clostridium botulinum. Although toxin production is associated with the germination of endospores and the growth of vegetative cells, little of the toxin appears in the medium until it is released by lysis late in growth. Botulinum toxin is an A-B neurotoxin; it acts at the neuromuscular junction (the junction between nerve cells and muscle cells) and prevents the transmission of impulses from the nerve cell to the muscle. The toxin accomplishes this by binding to nerve cells and inhibiting the release of a neurotransmitter called acetylcholine. As a result, botulinum toxin causes paralysis in which muscle tone is lacking (flaccid paralysis). C. botulinum produces several different types of botulinum toxin, and each possesses a different potency

How Bacterial Pathogens Penetrate Host Defenses

Capsules Cell Wall Components Enzymes Antigenic Variation Penetration into the Host Cell Cytoskeleton

Membrane-Disrupting Toxin

Cause lysis of host cells by disrupting their plasma membranes. Some do this by forming protein channels in the plasma membrane; others disrupt the phospholipid portion of the membrane. The cell-lysing exotoxin of Staphylococcus aureus is an example of an exotoxin that forms protein channels, whereas that of Clostridium perfringens is an example of an exotoxin that disrupts the phospholipids. Membrane-disrupting toxins contribute to virulence by killing host cells, especially phagocytes, and by aiding the escape of bacteria from sacs within phagocytes (phagosomes) into the host cell's cytoplasm

Syncytium

Cytopathic Effect (CPE) can produce several adjacent infected cells fuse to form a very large multinucleate cell. Such giant cells are produced from infections by viruses that cause diseases, such as measles, mumps, and the common cold

Hemolytic

Destruction of the red blood cells inside of your body, usually by a toxin

Tetanus toxin

Diphtheria and tetanus can be prevented by toxoid vaccination Clostridium tetani produces tetanus neurotoxin, also known as tetanospasmin. This A-B toxin reaches the central nervous system and binds to nerve cells that control the contraction of various skeletal muscles. These nerve cells normally send inhibiting impulses that prevent random contractions and terminate completed contractions. The binding of tetanospasmin blocks this relaxation pathway. The result is uncontrollable muscle contractions, producing the convulsive symptoms (spasmodic contractions) of tetanus, or "lockjaw."

Diphtheria toxin

Diphtheria and tetanus can be prevented by toxoid vaccination Corynebacterium diphtheriae produces the diphtheria toxin only when it is infected by a lysogenic phage carrying the toxgene. This cytotoxin inhibits protein synthesis in eukaryotic cells. It does this using an A-B toxin mechanism

Which of the following organisms is most infectious?

E. coli - ID 50 = 20

Lipid A

Endotoxin. Lipid portion of the membrane's lipopolysaccharide

Hyaluronidase

Enzyme secreted by certain bacteria, such as streptococci. It hydrolyzes hyaluronic acid, a type of polysaccharide that holds together certain cells of the body, particularly cells in connective tissue. This digesting action is thought to be involved in the tissue blackening of infected wounds and to help the microorganism spread from its initial site of infection. Hyaluronidase is also produced by some clostridia that cause gas gangrene

Types of Exotoxins

Exotoxins are divided into three principal types on the basis of their structure and function: (1) A-B toxins (2) membrane-disrupting toxins (3) superantigens

Naming Exotoxins

Exotoxins are named on the basis of several characteristics. One is the type of host cell that is attacked. For example, neurotoxins attack nerve cells, cardiotoxins attack heart cells, hepatotoxins attack liver cells, leukotoxins attack leukocytes, enterotoxins attack the lining of the gastrointestinal tract, and cytotoxins attack a wide variety of cells. Some exotoxins are named for the diseases with which they are associated. Examples include diphtheria toxin(cause of diphtheria) and tetanus toxin(cause of tetanus). Other exotoxins are named for the specific bacterium that produces them, for example, botulinum toxin (Clostridium botulinum) and Vibrio enterotoxin (Vibrio cholerae)

Trichothecenes

Fungal toxins that inhibit protein synthesis in eukaryotic cells. Ingestion of these toxins causes headaches, chills, severe nausea, vomiting, and visual disturbances. These toxins are produced by Fusarium and Stachybotrys growing on grains and wallboard in homes

Cell Wall Components

M Protein Fimbriae Opa Waxy Lipid Proteins in the cell wall can facilitate adherence or prevent a pathogen from being phagocytized

Penetration into the Host Cell Cytoskeleton

Major component of the cytoskeleton is a protein called actin, which is used by some microbes to penetrate host cells and by others to move through and between host cells. Bacteria may produce proteins that alter the actin of the host cell's cytoskeleton allowing bacteria into the cell

Portals of Entry - Mucous Membranes

Many bacteria and viruses gain access to the body by penetrating mucous membranes lining the respiratory tract, gastrointestinal tract, genitourinary tract, and conjunctiva, a delicate membrane that covers the eyeballs and lines the eyelids. Most pathogens enter through the mucous membranes of the gastrointestinal and respiratory tracts

Preferred Portal of Entry

Many microorganisms can cause infections only when they gain access through their specific portal of entry

A needlestick is an example of which portal of entry?

Parenteral route

Endotoxins are

Part of the gram-negative cell wall

Differentiate between the terms pathogenicity and virulence

Pathogenicity is the capacity for a pathogen to cause disease; virulence is the degree of pathogenicity. For a pathogen to have high pathogenicity, it must be able to cause disease -have a portal of entry, adhere to the host, remain in the host for a long enough period of time to cause damage to the host (and while not a pure requirement for pathogenicity, have a portal of exit). If a pathogen can cause disease, then virulence would be the level; something quantitative like the quantity of microbes required expressed as ID50

Collagenase

Produced by several species of Clostridium, facilitates the spread of gas gangrene. Collagenase breaks down the protein collagen, which forms the connective tissue of muscles and other body organs and tissues

Exotoxin

Produced inside some bacteria as part of their growth and metabolism and are secreted by the bacterium into the surrounding medium or released following lysis. Exotoxins are proteins, and many are enzymes that catalyze only certain biochemical reactions. Because of the enzymatic nature of most exotoxins, even small amounts are quite harmful because they can act over and over again. Bacteria that produce exotoxins may be gram-positive or gram-negative. The genes for most (perhaps all) exotoxins are carried on bacterial plasmids or phages. Because exotoxins are soluble in body fluids, they can easily diffuse into the blood and are rapidly transported throughout the body. Exotoxins work by destroying particular parts of the host's cells or by inhibiting certain metabolic functions. They are highly specific in their effects on body tissues. Exotoxins are among the most lethal substances known. It is the exotoxins that produce the specific signs and symptoms of the disease. Thus, exotoxins are disease specific.

Shock

Refers to any life-threatening decrease in blood pressure. Shock caused by bacteria is called septic shock. Gram-negative bacteria cause endotoxic shock

Gram-negative Sepsis

Septic shock caused by gram-negative endotoxins

Gram-positive Sepsis

Septic shock caused by gram-positive bacteria

A life-threatening decrease in blood pressure is

Shock

M Protein

The M protein mediates attachment of the bacterium to epithelial cells of the host and helps the bacterium resist phagocytosis by white blood cells. The protein thereby increases the virulence of the microorganism

Pathogenicity

The ability to cause disease by overcoming the defenses of a host

Lysogenic Conversion

The acquisition of new properties by a host cell infected by a lysogenic phage

Portals of Entry

The avenue by which a pathogen gains access to the body. The portals of entry for pathogens are mucous membranes, skin, and direct deposition beneath the skin or membranes (the parenteral route). a) Many microorganisms can penetrate mucous membranes of the conjunctiva and the respiratory, gastrointestinal, and genitourinary tracts. b) Most microorganisms cannot penetrate intact skin; they enter hair follicles and sweat ducts. c) Some microorganisms can gain access to tissues by inoculation through the skin and mucous membranes in bites, injections, and other wounds. This route of penetration is called the parenteral route

Toxigenicity

The capacity of a microorganism to produce a toxin

Capsules

The capsule resists the host's defenses by impairing phagocytosis, the process by which certain cells of the body engulf and destroy microbes. The chemical nature of the capsule appears to prevent the phagocytic cell from adhering to the bacterium. However, the human body can produce antibodies against the capsule, and when these antibodies are present on the capsule surface, the encapsulated bacteria are easily destroyed by phagocytosis

Contact Inhibition

The cessation of animal cell movement and division as a result of contact with other cells.

Sclerotia

The compact mass of hardened mycelia of the fungus Claviceps purpurea that fills infected rye flowers; produces the toxin ergot

LD50

The lethal dose for 50% of the inoculated hosts within a given period

How Bacterial Pathogens Damage Host Cells

The microorganism can damage host cells in four basic ways: (1) by using the host's nutrients; (2) by causing direct damage in the immediate vicinity of the invasion; (3) by producing toxins, transported by blood and lymph, that damage sites far removed from the original site of invasion; and (4) by inducing hypersensitivity reactions

ID50

The number of microorganisms required to produce a demonstrable infection in 50% of the test host population

Septicemia

The proliferation of pathogens in the blood, accompanied by fever; sometimes causes organ damage

Portals of Exit

The route by which a pathogen leaves the body. 1. Pathogens have definite portals of exit. 2. Three common portals of exit are the respiratory tract via coughing or sneezing, the gastrointestinal tract via saliva or feces, and the genitourinary tract via secretions from the vagina or penis. 3. Arthropods and syringes provide a portal of exit for microbes in blood.

Portals of Entry - Skin

The skin is the largest organ of the body in terms of surface area and weight and is an important defense against disease. Unbroken skin is impenetrable by most microorganisms. Some microbes gain access to the body through openings in the skin, such as hair follicles and sweat gland ducts. Larvae of the hookworm actually bore through intact skin, and some fungi grow on the keratin in skin or infect the skin itself

Enzymes

The virulence of some bacteria is thought to be aided by the production of extracellular enzymes (exoenzymes) and related substances. These chemicals can digest materials between cells and form or digest blood clots, among other functions. a) Local infections can be protected in a fibrin clot caused by the bacterial enzyme coagulase b) Bacteria can spread from a focal infection by means of kinases (which destroy blood clots), hyaluronidase (which destroys a mucopolysaccharide that holds cells together), and collagenase (which hydrolyzes connective tissue collagen). c) IgA proteases destroy IgA antibodies

Poisonous substances produced by certain microbes are called

Toxins

Cytopathic effects are changes in host cells due to

Viral infections

Numbers of Invading Microbes

Virulence can be expressed as LD50 (lethal dose for 50% of the inoculated hosts) or ID50 (infectious dose for 50% of the inoculated hosts)