Virulence: Allows pathogen to cause disease

• Virulence genes:

  • Chromosomal based

  • plasmid or phage based

• Virulence factors:

  • Adherence

  • Cell invasion

  • Immune response inhibitors

  • Colonizations

  • Toxins

• Primary vs. opportunistic pathogens

Staphylococcus aureus virulence factors

Streptococcus pyogenes virulence factors

Pathogen → Host: The Process of Infection & Causing Disease

• Enter Host

  • Portals of Entry

    • Mucous membrane - respiratory tract; gastro-intestinal (GI) tract; genitourinary tract

    • Skin: hair follicles, sweat glands, conjunctiva

    • Parenteral route: deposition of microbes directly under skin or mucous membrane

    • Pathogens have preferred portals of entry. Entering through a different portal may present with milder or no symptoms at all

  • Also need to consider adhesion and number of infecting microbes

• Penetrate/Evade host defenses

  • Capsule

  • Enzymes

  • Fimbriae/Pili

• Damage host

  • Toxins

  • intracellular pathogens

• Exit host

  • Portal of entry is generally the same portal for exit

Infectious dose - number of infectious agents required to cause disease symptoms

• Measure of virulence

• ID₅₀ - infectious dose needed to cause disease symptoms in 50% of experimental hosts

Lethal dose - number of pathogens required to kill host

• LD₅₀ - dose of pathogen required to kill 50% of experimental group of animal hosts

• measure of potency

Attachment of pathogens at portal of entry

• Bind via adhesins/ligands on the pathogen to host cell receptors

• Examples: glycocalyx, fimbriae, M protein of Streptococcus pyogenes

Biofile formation - microbial community contained in an exopolysaccharide matrix; adhere to surfaces

• Very resistant

• dental plaque, catheters, IV’s, heart valves

Penetration of Host Defenses

Factors that allow for bacterial invasions of host:

• Capsule - impairs phagocytosis by host cells

• Cell wall components:

  • cell wall mycolic acids of Mycobacterium tuberculosi - has thick hydrophobic envelope which can serve as a way to avoid the immune system

  • M protein: Streptococcus pneumoniae

    • aids in attachment

    • anti-phagocytic properties

    • inactive complement

  • OPA protein of Neisseria gonorrhea & other neisseria

    • aids in attachment

    • Transcytosis - transport through cell layers

    • Allows the pathogen to go into epithelial cells that make up blood vessels, monocytes that differentiate into t cells and b cells, and hitches a ride with neutrophils. When pathogens are inside cells, they’re hidden from the immune system.

Extracellular enzymes:

• Coagulase (Staphylococci) - clot blood; isolate bacteria from host

  • Process that enable fibrinogen to form into fibrin which makes clots. The formation of fibrin causes isolation from the host and its immune system like a protective cocoon.

• Kinases - destroy blood clots

  • e.g., streptokinase

  • Allows for pathogen to spread as it breaks clots and allows pathogen to go into previously clotted injuries which then allows it to gain access to the inside of our bodies.

• Hyaluronidase - hydrolyzes hyaluronic acid, polysaccharide bridging cells of connective tissue → allows microbes to spread (streptococcus)

  • breaks apart the chemical fibers that connect your connective tissues which allows the pathogen to penetrate those tissues

• Collagenase - digests collagen; in connective tissue of muscle, organs, tissues. Similar to Hyaluronidase

• Protein A (Staphylococcus) - Acts as an Fc receptor

  • Neutralizes antibodies as they’re bound on the wrong end (the Fc receptor).

• Proteases - destroys host proteins; IgA protease

Antigenic variation:

• Alteration of pathogen surface proteins; possess alternate genes

• The immune body can’t respond right away as the antigens are changed. Allows for the pathogen to go undetected.

Cytoskeleton:

• Some pathogens enter cells of the host using filaments of the cytoskeleton; actin filaments are common means of entry

• Exploits the host cytoskeleton

• Invasins (Salmonella) - pathogen surface proteins that rearrange actin filaments → induces membrane ruffling (create more membrane folds); pathogen will be engulfed into cell

• While in a cell, particularly those that are non-motile, will take actin monomers and binds to the cell and polymerizes, propelling the bacterium through cell cytoplasm and into other cells

  • This can cause damage to the cells

If a pathogen breaches the host defenses, it can damage the host by:

• Using the host’s nutrients

  • pathogen acquire host’s iron via siderophores

    • Iron (Fe) chelators - bind iron

• Causing direct damage in the vicinity of infection

  • Intracellular pathogens, e.g., viral infection

• Production of toxins: transported by blood, lymph

  • inhibit protein synthesis

  • disruption of membrane

• Introduction of hypersensitivity reactions: overproduction of cytokines

Exotoxins - secreted to the surrounding environment

• Toxins produced by the pathogen and secreted outside and defuses into blood, tissue, etc

• Water soluble proteins (many are enzymes); most are plasmid-based or in phages (lysogenic conversion)

• Action: destroy specific host cell structures or inhibit metabolic functions; can be very lethal

• Types: A-B toxins, Membrane-disrupting toxins, Superantigens

• Antitoxins: toxoid - forms provide immunity

A-B toxins - consists of an active enzyme component (A) and a cell binding component (B)

• These toxins have specificity for certain cell types and will bind to those cells and cause damage to them

• Types:

  • Diphtheria toxin (Corynebacterium diphtheriae): inhibits protein synthesis; phage carries tox gene

  • Botulism toxin (Clostridium botulinum): neurotoxin; prevents nerve impulses to muscles; causes flaccid paralysis

  • Tetanus toxin (Clostridium tetani): neurotoxin tetanospasmin; blocks inhibitory nerve impulses to muscles; causes spasmodic contractions

• Vibrio enterotoxin (Vibrio cholerae): cholera toxin; causes cellular secretion of fluids & electrolytes → severe diarrhea & dehydration

Membrane-Disrupting Toxins - cause lysis of host cells by disrupting plasma membrane by forming protein channels in membrane or by disrupting phospholipids

• Leukocidins: kill phagocytic white blood cells

• Hemolysins: kill red blood cells

Superantigens - Stimulate intense immune response of T cells

• Produces a hypersensitive effect on the immune system

• T cells stimulated to produce cytokines; regulates immune response

• Excessive cytokine levels enter blood streams and induce symptoms; can lead to shock & death

• Erythrogenic toxins (Streptococcus pyogenes): damage blood capillaries under skin → rash; scarlet fever

• Staphylococcal enterotoxin (S. aureus)

Endotoxins - lipid portion (lipid A) of the LPS (lipopolysaccharide) layer of gram-negative bacteria → released when cells die and lyse

• Not secreted but simply a part of the lipid A portion of the LPS of a gram-negative bacteria

• Exert effect by stimulating by stimulating macrophages to release toxic levels of cytokines

• Can also activate blood clotting proteins and induce fever

• Endotoxic shock → drastic drop in blood pressure

Pathogenic Properties of Viruses

• Evading hosts → grow inside host cells

• Cytopathic effect: visible effects of viral infection

  • Cytocidal effect: results in cell death

    • Cytocidal viruses stop host cell biosynthesis & induce cell’s lysosomes to release contents

    • Inclusion bodies/granules in some infected cells

      • Are usually viral parts (nucleic acids, proteins) to be assembled, can be diagnostic

      • EX: Rabies

    • Infected cells may fuse to form multinucleate syncytium (a giant cell)

      • When an enveloped virus enters a cell through membrane fusion, it may leave behind its viral envelope w/ proteins on the cell membrane. Other cells may fuse with the infected cells through the viral envelope left behind on the cell membrane, forming a giant cell.

    • Oncogenic viruses transforms cells into cancerous cells

    • Some virus-infected cells form interferons, protects non-infected cells

    • Viral infection reduces antigenic changes on the cell surface - rid body of infected cells