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Mechanisms of Pathogenicity. How do microorganisms cause disease?. Mechanisms of Pathogenicity. The ability to cause disease in a host is called pathogenicity. The degree of pathogenicity is called virulence.
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Mechanisms of Pathogenicity How do microorganisms cause disease?
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 LD50which 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.
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:
Mechanisms of Pathogenicity • Gender • Nutritional status • Weather and climate • Fatigue • Age • Habits • Life style • Pre-existing illness • Emotional disturbance • Chemotherapy
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)
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)
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.
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 toreceptors(usually carbohydrates or lipids or proteins) on the host cell.
Adhesions • Bacterial adhesions may be fimbrial or afimbrial in nature
Adhesions • E. coli has ligands on pili which attach it to intestinal epithelial cells
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.
Adhesions • Viral ligands may project from the surface of the virus: Sendai virus
Adhesions • Viral ligands may be buried in the surface of the virus: Rhinovirus
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
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
Bacteria escaping from phagosome before fusion with the lysosome
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
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)
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
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
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
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.
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
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
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)
Exotoxins • Many have an A (toxic effect)/B (binding) structure:
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.
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.
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.
Mechanisms of pathogenicity • Indirect damage – indirect damage may also occur due to immunopathologic mechanisms • Immediate hypersensitivity reactions (due to IgE antibodies)
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.
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.
