Microbial Pathogenesis

What is microbial pathogenesis? 

Microbial pathogrnrsis is the ways in which microorganisms (Bacteria) causes disease. Microbial Mechanisms of Pathogenicity means how Microorganisms Cause Disease.

Entry into the Host

A bacteria must access and adhere to host tissues, penetrate or evade host defenses, and damage tissue to cause disease.

Portals of Entry

The three main portals of entry are:

1. Mucous membranes
2. Skin
3. Parenteral

Microbial Mechanisms of Pathogenicity

1. Mucous Membranes

Epithelial tissue oplining the:

Respiratory tract:  Easiest and most frequently used entry site for microbes.

Gastrointestinal tract: Another common entry site.  Enter through water, food, contaminated fingers and fomites.  Must survive stomach HCl, enzymes, and bile.

Genitourinary tract: Entry site for most sexually transmitted diseases (STDs).

Conjunctiva:  Membrane covering eyes and eyelids.

2. Skin

Unbroken skin is impenetrable by most microbes.
Some microbes gain access through hair follicles and sweat glands.
Nectator americanus (hookworm) can bore through intact skin.
Certain fungi (dermatophytes) grow on skin and produce enzymes that break down keratin.

3. Parenteral Route  

Microbes are deposited directly into the tissues beneath the skin or mucous membranes.

Examples:  Injections, bites, cuts, wounds, surgery, punctures, and splitting due to swelling or drying.

Preferred Portal of Entry

Many microbes have a preferred portal of entry which is a prerequisite to cause disease.

Example:  Streptococcus pneumoniae that are inhaled can cause pneumonia; if swallowed generally don’t cause disease.

Adherence: is the atterchement of bacteria to a host.

Attachment between of microbe to host tissue requires:

Adhesins or Ligands:  Surface molecules on pathogen that bind specifically to host cell surface molecules.  May be located on glycocalyx, fimbriae, viral capsid, or other surface structure.

Receptors:  Surface molecules on host tissues to which pathogen adhesins bind.

How Bacterial Pathogens Penetrate Host Defenses

Capsules

Increase the virulence of many pathogens.
Examples:  Streptococcus pneumoniae, Klebsiella pneumoniae, Hemophilus influenzae, Bacillus anthracis,  and Yersinia pestis.
Resist host defenses by impairing phagocytosis.
Host can produce antibodies to capsule, which attach to microbe and allow phagocytosis.

Cell Wall Components

M protein: Found on cell surface and fimbriae of Streptococcus pyogenes.  Mediates attachment an dhelps resist phagocytosis.

Waxes:  In cell wall of Mycobacterium tuberculosis helps resist digestion after phagocytosis.

Enzymes

Extracellular enzymes (exoenzymes) lyse cells, form or dissolve clots, and dissolve materials in tissue.

Leukocidins:  Destroy white blood cells that are phagocytes.  Produced by staphylococci and streptococci.

Hemolysins:  Destroy red blood cells.  Produced by clostridium perfringens (gangrene) and streptococci.

Coagulases:  Produce blots in blood.  Clots may protect bacteria from host immune system, by walling off site of infection.  Produced by some staphylococci.

Bacterial Kinases:  Break down clots produced by body to isolate infection.  Made by streptococci and staphylococci.

Hyaluronidase:  Breaks down hyaluronic acid which holds cells together in connective tissue.  Made by some streptococci and gangrene causing clostridia.

Collagenase:  Breaks down collagen which forms connective tissue of muscles, skin, and other organs.  Produced by several clostridia.

Necrotizing Factors:  Kill body cells.

Hypothermic factors:  Decrease body temperature.

Lecithinase:  Destroys plasma membrane of  cells.

Proteases:  Break down proteins in tissue.

Severe gangrene caused by Clostridium perfringens.
Source:  Tropical Medicine and Parasitology, 1997

Necrotizing fasciitis with blood filled vesicles.
Source:   Perspectives in Microbiology, 1995

Penetration into Host Cells

for a bacteria to get into the host cell need to have some of these factors:

• Invasins:  Surface proteins that alter actin filaments of host cell cytoskeleton, allowing microbes to enter cells. Examples:  Salmonella typhinurium and E. coli.
• Cadherin:  A glycoprotein that bridges junctions between cells, allowing microbes to move from one cell to another.

Some important definitions

• Virulence is the relative capacity of a pathogen to invade and harm host cells.
• Pathogen Is the microorganism which cause disease. 
• Pathogenicity is the ability to cause disease.

How Bacterial Cells Damage Host Cells

Bacteria causes damenge to the host cells by three mechanisms:

1. Direct Damage
2. Toxins*
3. Hypersensitivity Reactions

Most bacterial damage is carried out by toxins.

Direct Damage

Some bacteria can induce cells to engulf them (E. coli, Shigella, Salmonella, and Neisseria gonorrhoeae).

Microbial metabolism and multiplication kills host cells.

Other microbes enter the cell by excreting enzymes or through their own motility.

Toxin Production

Toxins:  Poisonous substances produced by microbes. Frequently toxins are the main pathogenic factor.

Toxigenicity: Ability of a microbe to produce toxins.

Toxemia:  Presence of toxins in the blood.

Toxin effects: May include fever, cardiovascular problems, diarrhea, shock, destruction of red blood cells and blood vessels, and nervous system disruptions.

Of 220 known bacterial toxins, 40% damage eucaryotic cell membranes.

Two types of toxins:  

A. Exotoxins
B. Endotoxins

A.  Exotoxins

• Proteins:  Enzymes that carry out specific reactions.  
• Soluble in body fluids, rapidly transported throughout body in blood or lymph.
• Produced mainly by gram-positive bacteria.
• Most genes for toxins are carried on plasmids or phages.
• Produced inside bacteria and released into host tissue.
• Responsible for disease symptoms and/or death.

Cytotoxins:  Kill or damage host cells.

Neurotoxins:  Interfere with nerve impulses.

Enterotoxins:  Affect lining of gastrointestinal tract.

Antibodies called antitoxins provide immunity.

Toxoids:  Toxins that have been altered by heat or chemicals.  Used as vaccines for diphtheria and tetanus.

Medically Important Exotoxins

Diphtheria Toxin:  Corynebacterium diphtheriae when infected by a phage carrying tox gene.  Cytotoxin inhibits protein synthesis in eucaryotic cells.  Two polypeptides: A (active) and B (binding).

Erythrogenic Toxins:  Streptococcus pyogenes produces three cytotoxins which damage blood capillaries, causing a red rash.

Botulinum Toxins:  Produced by Clostridium botulinum.  Neurotoxin that inhibits release of neurotransmitter acetylcholine and prevents transmission of nerve impulses to muscles, causing flaccid paralysis.  Extremely potent toxins.

Tetanus Toxin:  Produced by Clostridium tetani.  A neurotoxin that blocks relaxation of skeletal muscles, causing uncontrollable muscle spasms (lockjaw) and convulsions.

Vibrio Enterotoxin:  Produced by Vibrio cholerae.  Two polypeptides: A (active) and B (binding).  The A subunit of enterotoxin causes epithelial cells to discharge large amounts of fluids and electrolytes. 

Staphylococcal Enterotoxin:  Staphylococcus aureus produces an enterotoxin similar to cholera toxin.  Other enterotoxins cause toxic shock syndrome.

Rash of Scarlet Fever Caused by Erythrogenic Toxins of Streptococcus pyogenes 

Neonatal Tetanus (Wrinkled brow and risus sardonicus)

Source:  Color Guide to Infectious Diseases, 1992

Scalded Skin Syndrome                                                  Toxic Shock Syndrome

B. Endotoxins

• Part of outer membrane surrounding gram-negative bacteria.
• Endotoxin is lipid portion of lipopolysaccharides (LPS), called lipid A.
• Effect exerted when gram-negative cells die and cell walls undergo lysis, liberating endotoxin.
• All produce the same signs and symptoms: Chills, fever, weakness, general aches, blood clotting and tissue death, shock, and even death.  Can also induce miscarriage.

Fever:  Pyrogenic response is caused by endotoxins.

Endotoxins do not promote the formation of effective antibodies.
Organisms that produce endotoxins include:

• Salmonella typhi
• Proteus spp.
• Pseudomonas spp.
• Neisseria spp.

Exotoxins versus Endotoxins

Medical equipment that has been sterilized may still contain endotoxins.  

Limulus amoebocyte assay (LAL) is a test used to detect tiny amounts of endotoxin.