Mechanism of Pathogenicity

Pathogens & Disease Pathogens are defined as microbes

capable of causing host damage. When host damage reaches a certain

threshold, it can manifest itself as a disease. The evolution of an infectious disease in an

individual involves complex interactions between the pathogen and the host.

PATHOGENICITY & VIRULENCE

Pathogenicity – the ability to cause disease by overcoming the defenses of the host

Virulence – the degree or extent of pathogenicity

Virulence factors – the various traits or features that allow or enhance the microorganism’s ability to cause disease. These take may forms and include: adhesion organelles, toxin production,

evasion of the host’s immune response, resistance to antibiotics, ability to invade host tissues

MECHANISMS OF PATHOGENICITY

Portal of Entry

Adherence

Penetration/invasion of host defense

Damage to host cell

PORTALS OF ENTRY

To cause disease, most pathogenic bacteria must gain access to the host

including skin and mucus membranes

cuts, surgical procedures, catheters, etc may allow bacteria entrance into the host

Normal skin flora, including Staphylococcus aureus and Staphylococcus epidermidis, can enter through these barriers and establish an infection

PORTALS OF ENTRY

Many pathogens have preferred portals of entry that are necessary for disease production

If they gain entrance via another portal, disease may not occur Salmonella typhi produces disease when swallowed but

not if rubbed on the skin Streptococci that are inhaled can cause pneumonia but, if

swallowed, generally do not produce disease Bacillus anthracis can initiate disease from more than one

portal of entry (skin inoculation, GI, respiratory)

ADHERENCE. Means attachment A necessary step in pathogenicity Attachment between pathogen and host

is accomplished by means of adhesins or ligands.

Most adhesins of microbes are glycoproteins or lipoproteins

ADHERENCE

The term pili (pilus) is also used to bind the host cells

Gram positive organisms use other structures for adhesins (lipoproteins, etc). Streptococcus pyogenes uses lipoteichoic acid to bind to epithelial cells

Once attached to target cells, many bacteria can then invade the cell

ADHESINS ARE VERY DIVERSE. S. mutans plays a key role in tooth decay

attaches to the surface of teeth by its glycocalyx

E. coli have adhesins on fimbriae that adhere only to specific kinds of cells

INVASION

Not all bacteria are invasive. Invasive organisms attach and enter host cells by a number of mechanisms: Production of surface proteins called invasins Production of enzymes:

collagenase which breaks down collagen in connective tissue

hyaluronidase which breaks down hyaluronic acid that holds cells together (particularly connective tissue cells)

Coagulase which converts fibrinogen to fibrin producing a clot (may be protective against phagocytes)

Kinases which can break down clots decreasing the isolation of bacteria in clots (spreading effect)

HOW BACTERIA DAMAGE HOST CELLS.

Direct damage

The production of Toxins Types of toxins: Exotoxins and Endotoxins.

Bacterial Toxins Many different types of toxins

Exotoxins Endotoxins

Toxins are are not required for growth Genes for toxins are usually on plasmids

EXO and ENDOTOXINS.

EXOTOXINS. Produced inside some bacteria as part of their

growth and metabolism and released into the surrounding medium

Are proteins, and many are enzymes

Most bacteria that produce exotoxins are gram-positive

The genes for most exotoxins are carried on bacterial plasmids or phages.

Neurotoxin. Target the nervous system, and can

interfere with normal nerve impulse transmission, e.g. C. tetani, C. botulinum.

ENTEROTOXINS. Affect cells lining the gastrointestinal tract. E.g. V. cholerae, C. difficile.

ACTION OF AN EXOTOXIN.

Exotoxins Initial location outside

cells Transported into host

cells Alter host cell

physiology and metabolism

Typical A – B toxins AB toxin enters cells via:1) Receptor mediated endocytosis2) Fusion of vesicle with lysosome3) Acid environment of lysosome reduces disulfide bonds and releases A into cell4) A has various cellular activities

Bacterial Exotoxins

Corynebacterium diphtheriae Corynebacterium diptheriae

Produces AB exotoxin Gram positive rod Significant cause of mortality until 1950s Common location upper respiratory tract

Clostridium botulium Clostridium botulinum

Produces AB exotoxin Produces irreversible muscle relaxation Flaccid paralysis Symptoms result entirely from toxin Anaerobic gram + rod Usually ingested in contaminated food Does not involve fever or sepsis Patients die of paralysis and respiratory failure

Normal Neuronal Signaling

Mechanism of Action of botulinum toxin

NOTABLE EXOTOXINS. Diphtheria toxin. Erythrogenic toxins. Botulinum toxin. Tetanus toxin Vibrio Enterotoxin. Staphylococcal Enterotoxin.

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Bacterial Endotoxins Endotoxins

Toxin is not internalized Toxin is located on outside of microorganisms (Part of

the outer portion of the cell wall of bacteria) LPS of gram – bacteria Lipoteichoic acid or gram + bacteria

Only toxic at high levels Liposaccharide

Exert their effects when the gram negative bacteria dies and their cell wall undergo lysis, thus liberating the endotoxin(e.g use of antibiotics)

All endotoxins produce the same signs and symptoms

Endotoxins can also induce miscarriage.

Mechanism of Action of Endotoxins Endotoxins bind to

Receptors on Macrophages Neutrophils Lymphocytes

Proteins of complement Complement is a group of proteins which circulate at

constant levels in the blood When activated complement is a powerful tool

against invading pathogens Increased inflammation

Bacterial Endotoxins Endotoxins

Host cell receptors (TLR) bind to components of pathogen

Pathogen associated molecular patterns PAMPS

LPS – gram - cell walls Flagella Lipoteichoic acid – gram + cell

walls Signal transduction pathways

begin to make a cellular response Production of cytokines

Bacterial Exoenzymes Enzymes secreted by bacterial cells into

the extra cellular matrix of host Membrane Damaging Toxins

Enzyme destruction of host cell membranes Lyse red blood cells Membrane pore forming complex

Enzymes which act in the extra cellular matrix Spreading factors Breaks down connective tissue Attacks blood clots

Enzymes which subvert drug therapy in patients

Penicillinase

Some Common Exoenzymes α toxin

Pore forming toxin Common in

Staphylococcus aureus Hemolysins

Destroy red blood cells Streptolysins – group of

hemolysins excreted by Streptococcus

Streptokinase Attacks fibrin clots From Streptococcus

pyogenes

Hyaluronidase Breaks down hyaluronic

acids in connective tissue

Similar function for Collagenase Elastases

DNase DNA is viscous Thins pus (DNA &

debris) released from WBC

Clostridium perfringens Clostridium perfringens

Ananerobic gram + spore forming rod Widely distributed in nature Entry of spores by traumatic injury Not highly invasive so it requires exoenzymes for a

supportive growth environment

Exoenzymes Lecithinase lipase c – major toxin

Lyses mammalian cells indiscriminately Substrate is phophatidylcholine

Collagenase & hyaluronidase DNAase