Pathogenesis (How Microbes Cause Disease)

What is pathogenesis?*

A biological mechanism or mechanisms that leads to disease

What is pathogenicity?

The ability of an organism to cause disease

What is Virulence? What are pathogenic determinants? *

• Degree of pathogenicity

• Attributes of bacteria or viruses that enable or enhance their ability to cause disease

What is an Infection?*

• The invasion of the host by disease-causing microorganisms

How does a microorganism cause disease?*

• Virulence Factors*

  • Must gain access to a host

  • Adherence to host cells

  • Penetrate/evade immune response

  • Damage host cells and tissue

    • Exotoxins

      • A-B toxins, membrane-disrupting toxins, superantigens, and genotoxins

  • Exit portals

Adherence*

• Means by which pathogens attach themselves to host tissue

• Necessary for pathogenicity

• Surface molecules on pathogens that bind to receptors on host cells are called adhesins

  • Glycoproteins or lipoproteins

  • Usually binds to sugars on host cells like mannose

• Adhesins include:

  • Pili

  • Capsules

  • Cell wall components

Penetration into Host Cell*

• Bacteria attach to host cells by using adhesins

• Produce surface proteins called invasins that promote bacteria entering into host cell

Evade Immune Responses/Defenses*

• Capsules*: Escape phagocytosis

• Cell wall components:

  • M protein* -

    • Cell wall of S. pyogenes

    • Mediates attachment and helps evade phagocytosis

    • M - mutants are unable to avoid phagocytosis and can’t survive in host

  • Opa protein* -

    • Outer membrane of N. gonorrhoeae

    • Attachment/internalization by host cells

    • Inhibit T cell proliferation and activation

  • Mycolic Acid* -

    • Mycobacterium tuberculosis, waxy cell wall allows it to avoid digestion by phagocytosis and can multiply inside phagocytes

How Bacterial Pathogens Damage Host Cells*

• Using host nutrients

  • Siderophores* - sequestering iron away from host proteins, like hemoglobin

  • Direct interaction with iron-transport protein

• Causing direct damage in the area of infection

  • Uses host cells as a source of nutrients and produces waste products

• Inducing hypersensitivity - damaging body cells, too high of a temp.

• Producing toxins

  • Exotoxins* -

    • Proteins produced inside a pathogen that is secreted into surrounding or released by lysis

    • Genes often carried on plasmids or phages

    • Work by affecting particular aspects of host cells and/or host metabolic pathway

  • Endotoxins* -

    • Lipid proteins (lipid A) of lipopolysaccharides that are part of the outer membrane of gram (-) bacteria. These are released when bacteria die, and the cells lyse

Exotoxins Continued*

• Diseases caused by bacteria that produce exotoxins are often caused by the exotoxin itself, not the bacteria

• The body produces antibodies against toxins called antitoxins

• Exotoxins inactivated by heat or chemicals called toxoids can be used to vaccinate to stimulate antitoxin production

  • Tetanus and diphtheria vaccines

• Types of Exotoxins:

  • A-B toxins -

    • Most exotoxins

    • A is the active part, B is the binding component

    • diphtheria toxin, cholera toxin

  • Membrane disrupting toxins -

    • Cause lysis of host cell by disrupting their plasma membrane

    • Aids bacteria escape from sacs within phagocytes

    • hemolysins, leukocidins

  • Superantigens -

    • Provoke a very intense immune response

    • Nonspecifically stimulates proliferation of T cells

    • Release enormous amounts of cytokines

      • Fever, nausea, vomitting, shock

      • S. aureus

  • Genotoxins -

    • Damage DNA

    • Causes mutation and may lead to cancer

Portals of Exit*

• Respiratory Tract

  • Coughing, sneezing

• Gastrointestinal tract

  • Feces, saliva

• Genitourinary tract

  • Urine, vaginal secretions

• Skin

• Blood

  • Biting arthropods, needles/syringes

Portals of Entry*

• Mucous Membranes

  • Gastrointestinal tract

  • Respiratory tract

  • Genitourinary tract

  • Conjunctiva

• Skin

  • Unbroken = Impenetrable, to most organisms

  • Some microbes can gain access through openings in the skin such as hair follicles

• Parenteral route

  • Directly deposited into the tissue beneath the skin or mucous membrane due to cuts, injections, bites, and surgery

Numbers of Invading Microbes

• Generally, if only a few microorganisms enter, not much happens

• The more that get in = better chance of causing disease

• We measure these to determine the virulence of pathogens

• Quantitatively: ID50 and LD50

ID50*

• The dose that causes disease in 50% of the population

  • Used to compare relative virulence under defined conditions

LD50*

• The dose that kills 50% of the population within a certain time

  • Usually, toxic agents

    • Botulism toxin

    • Shiga toxin

  • Defined conditions

  • Lower # = more toxic

ID50 & LD50 (Virulence)*

Enzymes/Exoenzymes

• Bacteria produce exoenzymes that aid in virulence

  • Coagulase - Clot Fibrinogen in blood, may protect bacteria from phagocytosis + other cellular defense mechanisms

  • Kinases - Breaks clots formed by the body to isolate and contain bacteria and allow it to extend infection

  • IgA Protease - Chops/cleaves up antibodies

  • Collagenases - Breaks down connective tissue of muscles and tissues, facilitating the spread of the bacteria

• Act over and over again, so small amounts are harmful

Antigenic Variation

• Pathogens can alter their surface proteins by a process called antigenic variation

• By the time the body mounts an immune response, the pathogen has already altered its antigen

  • Influenza virus

  • N. gonorrhoeae

Etiology*

• The Triad

  • Disease agent

  • Susceptible host

  • Environment that brings host and agent together

  • Out of balance = get disease

• Disease results from the interaction between the agent and susceptible host in an environment that supports transmission of the agent from a source to that host