Mechanisms of Pathogenicity Introduction 1. Pathogenicity is the ability of a pathogen to produce a disease by overcoming the defenses of the host. 2.

Virulence is the degree of pathogenicity. Presence of either a capsule, or certain cell wall components or enzymes gives microbe greater ability to produce a disease or gives it greater ability to overcome the defenses of the host. Entry of a Microorganism into the host 1. The specific route by which a particular pathogen gains access to the body is called its portal of entry. Most pathogens gain access to the host, adhere to host tissues, penetrate host defenses and damage the host tissue to cause disease. Some microbes can cause disease without penetrating body; e.g., dental caries & acne MUCOUS MEMBRANES 1. Many microorganisms can penetrate mucous membranes of the conjunctiva (delicate membrane that covers eyeball & lines eyelids) and the respiratory, gastrointestinal, and genitourinary tracts. 2. Microorganisms that are inhaled with droplets of moisture and dust particles gain access to the respiratory tract. 3. The respiratory tract is the most frequently used portal of entry. Diseases contracted via this route are common cold, pneumonia, tuberculosis, influenza, measles, smallpox 4. Microorganisms enter the gastrointestinal tract via food water, and contaminated fingers. Some microbes survive hydrochloric acid & enzymes and will cause disease. Diseases contracted are: poliomyelitis, hepatitis A, shigellosis, cholera. 5. Microbes penetrating reproductive tract are those that cause STDs (syphilis, gonorrhea, vaginitis- Candida, Trichomonas, Gardnerella; soft chanre-Haemophilus; genital herpes (HSV II & occasionally type I), genital warts, AIDS, candidiasis, trichomoniasis). 6. Microbes penetrating urinary tract cause diseases like cystitis ( E. coli, Staphy. saprophyticus), pyelonephritis (inflammation of kidneys. E. coli ) 7. Microbes penetrating conjunctiva cause diseases like conjunctivitis SKIN 1.Most microorganisms cannot penetrate intact (unbroken) skin; they enter hair follicles ( S. aureus -pimples; Pseudomonas dermatitis, acne ) and sweat ducts. 2. Some fungi infect the skin itself e.g. ringworm (Trichophyton, Microsporum, Epidermophyton), candidiasis PARENTERAL ROUTE 1. Some microorganisms can gain access to tissues by inoculation through the skin and mucous membranes in bites, injections, punctures, cuts, wounds, surgery, splitting due to swelling/dryness 2. This route of penetration is called the parenteral route. PREFERRED PORTAL OF ENTRY 1. Many microorganisms can cause infections only when they gain access through their specific portal of entry. Respiratory tract: meningococcal meningitis, pneumonia, tuberculosis, influenza, measles, chickenpox GI tract: cholera, salmonellosis, typhoid fever, hepatitis A, mumps, polio, trichinosis. GU tract: gonorrhea, syphilis Skin/Parentral: gangrene, tetanus, leptospirosis,, hepatitis B, rabies, malaria NUMBERS OF INVADING MICROBES 1. Few microbes might be overcome by hosts defenses. 2. If large nos. enter, the stage is set for disease. ADHERENCE 1. Surface projections on a pathogen called adhesins (ligands) adhere to host cells. 2. Ligands can be glycoproteins or lipoproteins and are frequently associated with fimbriae. Streptococcus mutans attach to tooth surface by glycocalyx (adhesin) E. coli have adhesins on fimbriae that alows it to stick to cells of small intestine N. gonorrhoeae has adhesins that allows it adhere to GU tract, eyes & pharynx Helicobacter pylori(stomach ulcers) attaches to stomach Bordetella pertussis produces surface antigens that help it attach to cilia of resp. tract. Pseudomonas aeruginosa (Pneumonia) attaches to resp. tract by pili. How Pathogens Penetrate Host Defenses CAPSULES contribute to virulence 1. Some pathogens have capsules that prevent them from being phagocytized. Such pathogens are virulent; e.g, S. pneumonia, Klebsiella pneumonia, H. influenzae (pneumonia & meningitis in children), B. anthracis

COMPONENTS OF THE CELL WALL contribute to virulence 1. Proteins in the cell wall can facilitate adherence or prevent a pathogen from being phagocytized. Proteins (M protein)on cell surface/fimbriae of Streptococcus pyogenes (sore throat) allow adherence to epithelial cells of respiratory tract. 2. Some microbes can reproduce inside phagocytes; e.g, Mycobacterium tuberculosis contains waxes and mycolic acids in its cell wall that resist phagocytosis ENZYMES contribute to virulence 1. Leukocidins destroy neutrophils and macrophages (phagocytes); e.g., staphylococci & streptococci. This decrease host resistance. 2. Hemolysins lyse red blood cells; e.g. Clostridium perfringens (gangrene) 3. Local infections can be protected in a fibrin clot caused by the bacterial enzyme coagulase (converts fibrinogen to fibrin). Protects bact. from phagocytosis; e.g. Staphylococcus 4. Bacteria can spread from a focal infection by means of kinases (which destroy blood clots. Streptokinase/fibrinolysin; staphylococcus aureus), hyaluronidase (which destroys a mucopolysaccharide that holds cells together; Clostridium), and collagenase (which hydrolyzes connective tissue collagen; facilitates spread of gangrene). Damage to Host Cells DIRECT DAMAGE When pathogen is attached to host cells, it pass through them to invade other tissues. 1. Host cells can be destroyed when pathogens metabolize and multiply inside the host cells. TOXINS 1. Poisonous substances produced by microorganisms are called toxins; toxemia refers to symptoms caused by toxins in the blood. 2. The ability to produce toxins is called toxigenicity. Some toxins produce fever, diarrhea, & shock. They also stop protein synthesis, destroy blood vessels & disrupt the nervous system by causing spasms. Exotoxins (proteins) 1. Exotoxins are produced by bacteria and released into the surrounding medium. 2. Exotoxins, not the bacteria, produce the disease symptoms. 3. Antibodies produced against exotoxins are called anti-toxins. 4. Cytotoxins include diphtherotoxin (which inhibits protein synthesis in eucaryotic cells) and erythrogenic toxins (which damage capillaries under skin & produce a red skin rash. Strep. pyogenes- scarlet rash). 5. Neurotoxins include botulinum toxin (which prevent nerve transmission from motor neuron to muscle. Acts at NMJ. Inhibits release of ACh. Result is paralysis in which muscle tone is lacking) and tetanus toxin (which prevents nerve transmission that permits relaxation of one muscle while the opposing muscle is contracting. The result is spasmodic contractions. Lockjaw). 6. Vibrio choleragen and staphylococcal enterotoxins, which induce fluid and electrolyte loss from epithelial host cells. Normal muscular contractions are disturbed leading to severe diarrhea that may accompanied vomiting. Endotoxins 1. Endotoxins are lipopolysaccharides (component of the gram-negative bacteria cell wall) . 2. Bacterial cell death, antibiotics, and antibodies may cause release of endotoxins. 3. Endotoxins cause fever (macrophage ingests bacterium. Bacterium is destroyed releasing LPS which stimulates release of IL-1 by the macrophage. IL-1 causes hypothalamus to produce a substance that resets the thermostat to a higher temp.. Can cause shock (phagocytosis of bacteria causes phagocytes to release TNF which damage blood capillaries. Fluid is loss leading to drop in BP, hence shock). Proteus cause urinary tract infections. Neisseria meningitidis cause meningitis B. pertussis produces toxins (endo- & exotoxins) that destroy ciliated cells. This allows mucus to accumulate.

Plasmids, Lysogeny, and Pathogenicity 1. Plasmids may carry genes for antibiotic resistance, toxins, capsules, and fimbriae. 2. Lysogeny can result in bacteria with virulence factors, such as toxins or capsules. Lysogeny is the process when a phage incorporate DNA into a bacterial chromosome and does not cause lysis of the bacterium. Pathogenic Properties of Nonbacterial Microorganisms VIRUSES 1. Signs of viral infections are called cytopathic effects (CPE); i.e, observable changes such as cell death etc.. 2. Some viruses cause cytocidal effects (cell death; e.g., HIV attacks T 4 cells), and others cause noncytocidal effects. 3. Cytopathic effects include the stopping of mitosis (Herpes), lysis, formation of inclusion bodies (granules such as NA or proteins found in cytoplasm/nucleus of some infected cells), cell fusion (host cells fuse to become giant cells; e.g, measles), antigenic changes, chromosomal changes (mutations; oncogenes are activated by viruses), and transformation (cells are transformed & grow without regulation; e.g., cancer). FUNGI, PROTOZOANS, HELMINTHS, AND ALGAE 1. Symptoms of fungal infections can be caused by capsules, toxins, and allergic responses. 2. Symptoms of protozoan and helminthic diseases can be caused by damage to host tissue or by the metabolic waste products of the parasite.

Non-Specific Defenses of the Host Introduction 1. 2. 3. 4. The ability to ward off disease through body defenses is called resistance. Lack of resistance is called susceptibility/vulnerability Nonspecific resistance refers to all body defenses that protect the body from any kind of pathogen. Specific resistance refers to production of proteins (antibodies) against specific microorganisms. Defenses against specific microbes

Skin and Mucous Membranes MECHANICAL FACTORS 1. The structure of intact skin ( epidermis) and the waterproof protein keratin provide resistance to microbial invasion. 2. Some pathogens, if present in large numbers, can penetrate mucous membranes (T. Pallidum, M. tuberculosis, S. pneumoniae. Mucous membranes inhibit entrance of many microbes. 3. The lacrimal apparatus protects the eyes from irritating substances and microrganisms. Dilute & wash away. 4. Saliva washes microorganisms from teeth and gums. 5. Mucus traps many microorganisms that enter the respiratory and gastrointestinal tracts; in the lower respiratory tract, the ciliary escalator moves mucus up and out. Coughing & sneezing speeds up escalator. Cigarette smoke stops it. 6. The flow of urine moves microorganisms out of the urinary tract, and vaginal secretions move microorganisms out of the vagina. 7. Defecation & vomiting expel microbes from body 8. Hairs filter microbes & dust in nose CHEMICAL FACTORS 1. Sebum contains unsaturated fatty acids, which inhibit the growth of pathogenic bacteria. Low pH discourages growth. Some bacteria commonly found on the skin can metabolize sebum and cause the inflammatory response associated with acne. 2. Perspiration washes microorganisms off the skin. 3. Lysozyme (enzyme that breaks down gram+ve & gram-ve cell walls )is found in tears, saliva, nasal secretions, and perspiration. 4. The high acidity (pH 1.2 to 3.0) of gastric juice prevents microbial growth & destroys toxins in the stomach. Exceptions: C. botulinum, Staph. aureus, Helicobacter pylori (neutralizes stomach acid & cause ulcers. 5. Normal flora prevent the growth of many pathogens. Phagocytosis 1. Phagocytosis is the ingestion of microorganisms or particulate matter by a cell. 2. Phagocytosis is performed by phagocytes, certain types of white blood cells (neutrophils, Eosinophils, Macrophages) FORMED ELEMENTS IN BLOOD 1. Blood consists of plasma (fluid) and formed elements (cells and cell fragments). 2. Leukocytes (white blood cells) are divided into three categories - granulocytes (neutrophils, basophils, and eosinophils), and agranulocytes (lymphocytes, and monocytes, macrophages). 3. During many infections, the number of leukocytes increases (leukocytosis); e.g., salmonellosis, viral infections. Some infections are characterized by leukopenia (decrease in leukocytes). E.g. meningitis, appendicitis, pneumonia, gonorrhea. ACTIONS OF PHAGOCYTIC CELLS 1. Among the granulocytes, neutrophils are the most important phagocytes.

2. Enlarged monocytes become wandering and fixed macrophages. 3. Fixed macrophages are located in selected tissues ( liver, lungs, NS, spleen, lymph nodes, bone marrow) and are part of the mononuclear phagocytic system. 4. Granulocytes predominate during the early stages of infection, whereas monocytes predominate as the infection subsides. MECHANISM OF PHAGOCYTOSIS 1. Chemotaxis is the process by which phagocytes are attracted to microorganisms. 2. The phagocyte then adheres to the microbial cells; adherence may be facilitated by coating the microbe with plasma proteins (opsonization). 3. Pseudopods of phagocytes engulf the microorganism and enclose it in a phagosome to complete ingestion. The pm engulfs microbe,; pseudopods meet & fuse. Fusion of the phagosome with a lysosome to form a phagolysosome 5. Digestion of ingested microbes by enzymes. Many phagocytized microorganisms are killed by lysosomal enzymes (lysozyme, lipases, nucleases,,proteases) and oxidizing agents (hydrogen peroxide). Formation of residual body containing indigestible material. Discharge of waste materials.

Inflammation 1. Inflammation is a bodily response to cell damage; it is characterized by redness (erythema), pain, heat, swelling (edema), and sometimes loss of function. 2. It confines & destroys microbes & repairs tissues. VASODILATION AND INCREASED PERMEABILITY OF BLOOD VESSELS 1. The release of histamine (found in many cells, especially basophils, mast cells, platelets), kinins (polypeptides in the blood), and prostaglandins (release by damage cells) causes vasodilation and increased permeabilitv of blood vessels. 2. Blood clots can form around an abscess to prevent dissemination of the infection. PHAGOCYTE MIGRATION 1. Phagocytes have the ability to stick to the lining of the blood vessels (margination). 2. They also have the ability to squeeze through blood vessels (diapedesis/emigration). 3. Pus is the accumulation of damaged tissue and dead microbes, granulocytes, and macrophages. If pus cannot drain out of inflammed region, an abscess develops. Tissue Repair is the final stage of inflammation. It involves the production of new cells. Steps in the process of inflammation & subsequent healing

Cut allows bacteria to get beneath surface of skin./ Damaged cells release histamine, kinins etc.. Capillaries dilate (vasodilation), bringing more blood to the tissue. Skin becomes reddened and warmer. Capillaries become more permeable, allowing fluids to accumulate & cause swelling (edema). Blood clotting occurs and scab forms. Bacteria multiply in cut. Phagocytes enter tissue by moving through the walls of blood vessels (diapedesis). Phagocytic cells are attracted to bacteria and tissue debris (chemotaxis) and engulf them. As dead cells and debris are removed, epithelial cells proliferate & begin to grow under scab. Scar tissue (connective tissue) replaces cells that cannot replace themselves. Fever Hypothalamus controls temperature. Setting can be altered by ingestion of gram-ve bacteria by phagocytes. Bacteria is degraded releasing LPS (endotoxins) cell wall. This cause the macrophage to release interleukin -1 (pyrogen). Il-1 acts on the hypothalamus which then produce a substance (prostaglandin) which resets the body temperature to a higher temperature. Note: fever inhibits microbial growth. A chill is a sign of rising temperarture. A crisis refers to a very rapid fall in temperature

ANTIMICROBIAL SUBSTANCES Complement System Complement consists of more than 20 plasma proteins that play a key role in host defense. They are produced by the liver & circulate in an inactive form. There are 2 pathways: classical pathway & alternative pathway. The classical pathway begins when Abs bind to antigens such as microbes and involves complement proteins C1, C4 and C2 (C stands for complement). The alternative pathway is activated by contact between complement proteins and polysaccharides at the pathogen surface. Complement proteins called factor B, factor D and factor P (properdin) replace C1, C4 and C2 in the initial steps. However, the components of both pathways activate reactions involving C3 through C9. Some complement proteins act as protease enzymes, cleaving and activating the next protein in the sequence. Classical pathway C1 has 3 subcomponents: C1q, C1r and C1s. Fragments resulting from cleavage by other components act as enzymes are assigned lowercase letters a, b, c, d or e; e.g., C3a and C3b. Ag-Ab complex binds to C1q, leading to activation of C1r, which then cleaves C1s generating an activated C1s. C1s then cleaves C4 & C2 and exposes their active forms, C4b & C2b which then fuse. C4bC2b complex (or C3 convertase) acts as an enzyme whose substrate is C3 etc. C1s activates C1q C1q activates C1r C1r activates C1s C1s (enzyme) cleaves C4 to produce C4a & C4b. C1s (enzyme) cleaves C2 to produce C2a & C2b. C4b & C2b fuse to form C4b2b which then acts as an enzyme. C4b2b (C3 convertase) cleaves C3 to form C3a & C3b. C3b then adds on to the C4b2b to form C4b2b3b which then acts as an enzyme. C4b2b3b (C5 convertase) cleaves C5 to form C5a & C5b. C5b then adds on to C4b2b3b to form C4b2b3b5b. C6, C7, C8 & C9 adds on without cleavage. Order: C1qrs42356789. NB: each protein component of complement has been assigned a number in the order of its discovery and that number is preceded by the capital letter C for complemnt