1. Mechanisms of Pathogenicity
How do microorganisms cause disease?

2. Mechanisms of Pathogenicity
The ability to cause disease in a host is called pathogenicity.
The degree of pathogenicity is called virulence.
The virulence of a microorganism or the toxicity of a toxin it produces is often expressed as the LD50 which is the number of microorganisms (or amount of toxin) needed to kill 50% of inoculated hosts (a test population) under standard conditions. LD stands for lethal dose.
The ID50 (infectious dose) is the number of microorganisms needed to cause disease in 50% of the test population under standard conditions.

3. Mechanisms of Pathogenicity
The lower the LD50 or ID50 for an organism, the more virulent the organism.
The likelihood that a disease results from an infection will increase with:
Increasing numbers of microorganisms
Decreasing resistance of the host
Certain predisposing factors may make the body more susceptible to disease or may alter the course of a disease. These factors include:

4. Mechanisms of Pathogenicity
Gender
Nutritional status
Weather and climate
Fatigue
Age
Habits
Life style
Pre-existing illness
Emotional disturbance
Chemotherapy

5. Mechanisms of Pathogenicity
In order for a microorganism to cause disease it must:
Gain entrance to the host – the avenue by which the microbe gains entrance to the host is called the portal of entry. Portals of entry include:
Mucous membranes
Respiratory tract – this is the easiest and most frequently used portal of entry (influenza, pneumonia, TB, measles and smallpox are examples of diseases caused by organisms that gain entrance via this portal of entry)

6. Mechanisms of Pathogenicity
Gastrointestinal tract – microorganisms contracted from food, water, and dirty hands gain entry this way.
Only those organisms that can survive the HCl in the stomach and the bile and digestive enzymes in the small intestine will cause disease and the pathogens will be eliminated in the feces (examples include the organisms that cause polio, infectious hepatitis, typhoid fever, bacillary dysentery, amoebic dysentery, and cholera)
Genitourinary tract – organisms that gain entry to the host this way include Treponema pallidum (syphilis), Neisseria gonorrhoeae (gonorrhea), Trichomonas vaginalis (trichomoniasis) and Herpes simplex type II (genital herpes)

7. Mechanisms of Pathogenicity
Conjunctiva of the eye – Haemophilus aegyptius which causes pinkeye (contagious conjunctivitis) gains entrance through this portal of entry
Skin – only a few microorganisms gain entry through hair follicles and sweat ducts. Necator americanus (hookworm) and Schistosoma sp. (schistosomiasis) can actually bore through the skin.
Parenteral route – this is when microorganisms are directly deposited into the tissues when the skin or mucous membrane barriers are penetrated or injured Tetanus and subcutaneous mycoses (fungal infections) are examples of diseases caused by organisms that use this portal of entry.

8. Mechanisms of Pathogenicity
Many microorganisms have a preferred portal of entry and can only cause disease when they gain entry through that route. For example S. typhi can only cause disease when it comes in through the GI tract.
Some organisms can initiate disease from a variety of portals of entry, Examples include Yersinia pestis and Francisella tularensis.
The microorganism must also attach to or adhere to host tissues. Attachment is often via surface projections called adhesions, colonization factors, or ligands (often glyco or lipoproteins) on the pathogen which bind specifically to receptors (usually carbohydrates or lipids or proteins) on the host cell.

9. Adhesions

10. Adhesions
Bacterial adhesions may be fimbrial or afimbrial in nature

11. Adhesions
E. coli has ligands on pili which attach it to intestinal epithelial cells

12. Adhesions
Neisseria gonorrhoeae has ligands on pili that attach it to epithelial cells in the genitourinary tract.
Streptococcus mutans adheres to the surfaces of tooth enamel via an extracellular polysaccharide that it secretes.
Streptococcus pyogenes binds to fibronectin on the surface of epithelial cells via a cell wall protein called M and via lipoteichoic acids in the cell wall.

13. Adhesions
Viral ligands may project from the surface of the virus: Sendai virus

14. Adhesions
Viral ligands may be buried in the surface of the virus: Rhinovirus

15. Mechanisms of Pathogenicity
For a microorganism to cause disease it must also resist host defenses and produce substances that allow it to disseminate
Resisting host defenses:
Capsules interfere with the ability of phagocytic cells to function in phagocytosis of the microorganism
Components of the cell wall such as the M protein of Streptococcus pyogenes may help the organism to resist phagocytosis
IgA protease produced by some microorganisms will cleave IgA which is found at mucosal surfaces and is important in preventing specific attachment

16. Mechanisms of pathogenicity
Some microorganisms will undergo antigenic variation to resist host defenses
Some microorganisms are resistant to complement mediated lysis because they sterically hinder attachment of complement components
Some microorganisms may survive inside phagocytic cells by either preventing phagosome-lysosome fusion or by being resistant to the enzymatic activity of lysosomal enzymes
Some microorganisms escape the phagosome before phagosome-lysosome fusion occurs
Some organisms downregulate MHC class I expression
HIV downregulates CD4 expression

17. Bacteria blocking phagosome-lysosome fusion

18. Bacteria escaping from phagosome before fusion with the lysosome

19. Mechanisms of pathogenicity
Some microorganisms reside in immunologically privileged sites where they are protected from host defenses
Some microorganisms shed their antigens
Some microorganisms will decrease expression of their antigens
Some microorganisms will immunosuppress the host
Some microorganisms produce siderophores that allow them to acquire iron sequestered by the host
Some microorganisms produce hypothermic factors to decrease the host’s temperature
Some microorganisms produce leukocidans that kill WBCs

20. Mechanisms of pathogenicity
Some microorganisms produce coagulase that lays down a fibrin clot to wall the organism off and protect it from host defenses
S. aureus produces protein A and S. pyogenes produces Protein G which bind the Fc portion of IgG
Some microorganisms produce substances that cause macrophages to undergo apoptosis
Some microorganisms have flagella which allow them to swim away from phagocytic cells
Some microorganisms secrete substances that act to block the uptake of the microorganism by a phagocytic cell (by depolymerizing actin).
The substances are delivered directly to the phagocytic cell via a type III secretion system (will be discussed later)

21. Action of Protein A

22. Preventing uptake of bacteria

23. Mechanisms of pathogenicity
Substances that contribute to dissemination:
Some microorganisms produce kinases that break down fibrin clots that the host produces in the inflammatory reaction to prevent the spread of a microorganism
Some microorganisms produce hemolysins that destroy RBCs as well as other types of tissue cells to allow dissemination. Many of the hemolysins act as porins to alter membrane permeability.
Some microorganisms produce hyaluronidase which dissolves hyaluronic acid which holds cells together.
Some microorganisms produce DNAses which can be used for salvaging nucleotides, but it can also help microorganisms to spread because of the breakdown of viscous nucleic acids which could hinder the microorganism’s movement

24. Mechanisms of pathogenicity
Some microorganisms produce collagenases that break down collagen which forms the framework of muscles
Some microorganisms produce lipases that break down lipids
Some microorganisms produce necrotizing factors to kill host cells to facilitate dissemination.
Some microorganisms produce substances that cause the tissue cells to undergo apoptosis.
Some microorganisms recruit actin to provide the force for intracellular movement

25. Actin polymerization

26. Mechanisms of pathogenicity
For a microorganism to cause disease it must damage host cells:
Direct damage
Attachment, penetration and multiplication may cause direct damage.
Penetration may involve outer membrane proteins and/or type III secretion systems that deliver substances that actively induce the uptake of bacteria in nonphagocytic cells. (Note that it was previously stated that type III secretion systems can also deliver substances that act to block the uptake of microorganisms by phagocytic cells).
What is a type III secretion system?
Found in Gram negative bacteria
Is similar in structure to type IV pili and type II secretion systems

27. Mechanisms of pathogenicity
Both type II and type III secretion pathways export proteins through both the inner and the outer membranes of the bacteria
The type II secretion pathway is the general secretory pathway that acts to secrete substances outside the bacteria. A similar pathway is found in Gram positive bacteria.
The type III secretory pathway acts as a molecular syringe to inject substances, including toxins, directly into target cells.

28. Secretion systems

29. Induced uptake

30. Mechanisms of pathogenicity
Toxins can also cause direct damage. What is a toxin?
These are poisonous substances produced by certain microorganisms.
A toxin produced by a microorganism may be entirely responsible for the pathogenicity of the microbe.
The capacity to produce toxins is called toxigenicity
Toxemia refers to symptoms caused by toxins in the blood.
There are two basic types of toxins; exotoxins and endotoxins

31. Exotoxins Most, but not all, are produced by Gram positive bacteria
Are produced and secreted via the type II secretion system
Are soluble in body fluids and are transported rapidly throughout the body
Are proteins whose genes are carried on plasmids or encoded in lysogenic bacteriophages

32. Exotoxins
Are among the most lethal toxins known to man. For example, 1 mg. of the botulinum toxin can kill 1 million guinea pigs.
Are disease specific and are frequently the cause of the disease
The host can produce anti-toxins (antibodies) which can provide immunity against the effects of the toxin.
Can be inactivated by heat, formaldehyde, iodine or other substances to produce toxoids which when injected into the body can no longer cause disease, but can still stimulate the body to produce protective anti-toxin antibodies (vaccinations)

33. Exotoxins
Many have an A (toxic effect)/B (binding) structure:

34. Exotoxins Examples of exotoxins:
Botulinum toxin – produced by Clostridium botulinum.
This toxin is unique in that it is not released until the death of the microorganism.
It acts at the neuromuscular junction to prevent the transmission of nerve impulses leading to flaccid paralysis and death from respiratory failure.
Tetanus toxin – produced by Clostridium tetani.
This toxin causes excitation of the CNS leading to spasmodic contractions and death from respiratory failure.
The disease it produces is also called “lockjaw”.
Diphtheria toxin – produced by Corynebacterium diphtheriae.
This toxin inhibits protein synthesis in eukaryotic cells and can cause death.

35. Botulinum Toxin Flaccid Paralysis

36. Tetnus toxin spastic paralysis

37. Exotoxins: Diphtheria toxin

38. Exotoxins
Staphylococcal enterotoxin – produced by Staphylococcus aureus.
This toxin induces vomiting and diarrhea by preventing the absorption of water in the intestine.
Vibrio enterotoxin – produced by Vibrio cholera.
This toxin alters the water and electrolyte balance in the intestine leading to a very severe, life threatening, watery diarrhea.

39. Vibrio enterotoxin

40. Endotoxins
Are part of the outer membrane of most Gram negative bacteria.
Are the lipid A part of the LPS.
Exert their effects when Gram negative bacteria die and the LPS is released.
All produce the same signs and symptoms, i.e., they are not disease specific.
These symptoms include fever (pyrogenic response), weakness, generalized aches and pains and sometimes shock.
Antibodies produced against them do not protect the host from their effects
Only large doses are lethal.

41. Entotoxin and the pyrogenic response

42. Endotoxin versus exotoxin

43. Endotoxin versus exotoxin

44. Mechanisms of pathogenicity
Indirect damage – indirect damage may also occur due to immunopathologic mechanisms
Immediate hypersensitivity reactions (due to IgE antibodies)

45. Mechanisms of pathogenicity
Cross-reacting or auto antibodies may form. When these bind to the host tissues, they can activate complement resulting in damage to the tissue.
Immune complex reactions can trigger severe inflammatory reactions resulting in damage to host tissues.
Immune complexes are antigen-antibody complexes that form in the bloodstream.
They may get trapped in capillaries and trigger the complement cascade with resulting tissue damage.

46. Immune complex reactions

47. Mechanisms of pathogenicity
Organisms need to have a portal of entry and they also need to have a portal of exit.
The portal of exit is usually related to the part of the body that has been infected.
The most common portals of exit are the respiratory tract and the gastrointestinal tract.
Organisms may also exit through the genital tract, urine, skin, biting insects, or contaminated needles.

48. Summary of mechanisms of pathogenicity