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Microbiology, 5/e

Lansing M Prescott, Augustana College
Donald A Klein, Colorado State University
John P Harley, Eastern Kentucky University

Normal Microbiota and Nonspecific Host Resistance

Study Outline

Introduction
1. Pathogenicity-the ability to produce pathological changes (disease) as the result of a parasitic symbiosis between a microorganism and a host
2. Pathogen-any disease-producing microorganism
Gnotobiotic Animals
1. Gnotobiotic-an environment or animal in which all microbial species present are known or that is germ-free (e.g., mammalian fetuses in utero are free from microorganisms)
2. Gnotobiotic animals allow investigation of the interactions of animals with specific microorganisms that are deliberately introduced into the animal
3. Gnotobiotic colonies of mammals are established by cesarean-section delivery in a germfree isolator; germ-free bird colonies are established by sterilizing egg surfaces and then hatching the eggs in sterile isolators; gnotobiotic colonies are kept in a sterile environment, and normal mating and delivery (hatching) of gnotobiotic animals maintains the colony
4. Gnotobiotic animals are not anatomically or physiologically normal
  1. Can have poorly developed lymphoid tissue, thin intestinal walls, enlarged cecum (birds), or low antibody titers
  2. Require nutritional supplements
  3. Have reduced cardiac output and lower metabolic rates
  4. Are more susceptible to pathogens, but may be resistant to diseases caused by protozoa that use bacteria as a food source (e.g. Entamoeba histolytica) and dental caries
Normal Microbiota of the Human Body
1. Internal tissues are normally free of microorganisms; however, many other sites are colonized; normal microbiota are the microorganisms regularly found at any anatomical site
2. Reasons to acquire knowledge of normal human microbiota
  1. It provides greater insight into possible infections resulting from injury to these sites
  2. It gives perspective on the possible sources and significance of microorganisms isolated from an infection site
  3. It increases understanding of the causes and consequences of growth by microorganisms normally absent from a specific body site
  4. It aids awareness of the role these indigenous microorganisms play in stimulating the immune response
3. Distribution of the normal microbiota-can be inside body (endosymbiosis) or outside body (ectosymbiosis)
  1. Skin
    1. Resident microbiota multiply on or in the skin; transients normally die in a few hours
    2. Skin surface varies from one part of the body to another and generally is a hostile environment; skin surface undergoes periodic drying, is slightly acidic, salty, and has antibacterial substances (e.g., lysozyme)
    3. Most skin bacteria are found on superficial cells, colonizing dead cells, or closely associated with oil and sweat glands
      1. ) Staphylococcus epidermidis and corynebacteria (dry areas and sweat glands)
      2. ) Gram-negative bacteria (moist areas)
      3. ) Yeast (scalp)
      4. ) Dematophytic fungi (e.g., those causing ringworm and athletes foot)
      5. ) Propionibacterium acnes is prevalent in skin glands and is associated with acne vulgaris
  2. Nose and nasopharynx
    1. Nose-just inside the nares; Staphylococcus epidermidis and S. aureus are predominant; they are also found on skin of face
    2. Nasopharynx-above the level of the soft palate; contains nonencapsulated strains of some of the same species that may cause clinical infection (e.g., streptococci and Neisseria); other species also are found
  3. Oropharynx-between the soft palate and upper edge of the epiglottis; houses many different species, including staphylococci and streptococci
  4. Respiratory tract-no normal microbiota due to the enzyme lysozyme in mucus and the phagocytic action of alveolar macrophages
  5. Mouth-contains those organisms that survive mechanical removal by adhering to surfaces such as the gums and teeth; normal microbiota includes streptococci, lactobacilli, and actinomycetes; some contribute to the formation of dental plaque, dental caries, gingivitis, and periodontal disease
  6. Eye-aerobic commensals are found on the conjunctiva
  7. External ear-resembles microbiota of the skin; includes some fungi
  8. Stomach-most microorganisms are killed by acidic conditions unless they pass through very quickly; the number of microorganisms present increases immediately after a meal, but decreases quickly
  9. Small intestine
    1. Duodenum-few microorganisms present because of stomach acidity and inhibitory action of bile and pancreatic secretions; those that are found are gram-positive rods and cocci
    2. Jejunum-Enterococcus fecalis, diphtheroids, lactobacilli, and Candida albicans are occasionally found
    3. Ileum-microbiota resembles that of the colon (e.g., anaerobic gram-negative rods and Enterobacteriaceae)
  10. Large intestine (colon)-largest microbial population of the body
    1. Over 300 different species have been isolated from human feces; most are anaerobes or facultative organisms growing anaerobically
    2. Normal microbiota is excreted by peristalsis, segmentation, desquamation, and movement of mucus, but is replaced rapidly because of high reproductive rate; the microbial community is self-regulating and can be disturbed by stress, altitude, starvation, diet, parasite infection, diarrhea, and use of antibiotics or probiotics
  11. Genitourinary tract
    1. Kidneys, ureter, and bladder are normally free of microorganisms; though in both males and females a few microorganisms are found in distal portions of the urethra
    2. Female genital tract hosts a complex microbiota in a state of flux due to menstrual cycle; Lactobacillus acidophilus predominates; it forms lactic acid and thereby maintains an acidic pH in the vagina and cervical os
4. The relationship between normal microbiota and the host
  1. Relationship with normal microbiota is usually mutually beneficial
  2. Normal microbiota helps repel invading pathogens by a number of mechanisms (e.g., competition, production of inhibitory chemicals)
  3. Under some conditions, normal microbiota can become pathogenic; such microorganisms are referred to as opportunistic
  4. Compromised host-host that is seriously debilitated and has lowered resistance; is often target of opportunistic microorganisms
Overview of Host Resistance
1. To establish infection pathogen must first overcome barrier defenses
2. If pathogen succeeds, immune system offers protection
  1. Immune system is composed of widely distributed cells, tissues, and organs that recognize foreign substances and microorganisms
  2. Immunity-ability of a host to resist a particular disease
  3. Immunology-the science that deals with immune responses
3. Two types of immune responses
  1. Nonspecific immune responses (also called innate or natural immunity)
    1. General resistance mechanisms inherited as part of the innate structure and function of each animal
    2. Lack immunological memory
    3. Nonspecific response occurs to same extent with each encounter
  2. Specific immune response (also called acquired or specific immunity)-discussed in chapter 32
    1. Resists a particular foreign agent
    2. Improves on repeated exposure
    3. Involves the interaction of antigens and antibodies
Cells, Tissues, and Organs of the Immune System
1. Cells of the immune system
  1. Leukocytes-white blood cells; arise from pluripotent stem cells in bone marrow and migrate to other body sites to mature and perform their functions; include all the cells described below
  2. Lymphoid cells-also called lymphocytes; major cells of specific immune system; divided into three populations: T cells, B cells and Natural killer (NK) cells
  3. Mononuclear cells-two types; are both highly phagocytic; constitute the monocyte-macrophage system
    1. Monocytes-mononuclear phagocytic cells that circulate in blood for short time and can migrate to tissues where they mature into macrophages
    2. Macrophages-larger than monocytes; have more organelles and possess receptors that allow them to discriminate self from nonself; respond to opsonization (chemical enhancement of phagocytosis)
  4. Granulocytes-also called polymorphonuclear leukocytes (PMNs)
    1. Basophils-nonphagocytic; upon stimulation, release chemicals (e.g., histamine, prostaglandins) that impact blood vessels (vasoactive); basophils play important roles in allergic responses
    2. Eosinophils-mobile cells that migrate from blood stream into tissue spaces; protect against protozoa and helminth parasites
    3. Neutrophils-highly phagocytic cells that rapidly migrate to sites of tissue damage and infection
  5. Mast cells-found in connective tissue; contain granules with histamine and other chemicals that contribute to immune response; play important role in allergies and hypersensitivities
  6. Dendritic cells-phagocytizes microorganisms and then process the microorganisms' surface molecules (antigens); subsequently, the dendritic cells migrate to blood stream or lymphatic system and present foreign antigens to T cells
2. Organs and tissues of the immune system
  1. Primary lymphoid organs and tissues
    1. Thymus-site of T cell maturation
    2. Bursa of Fabricus-site of B cell maturation in birds
    3. Bone marrow-site of B cell maturation in mammals
  2. Secondary lymphoid organs and tissue
    1. Spleen-filters blood and traps blood-borne microorganisms and antigens; contains macrophages and dendritic cells that present antigens to T cells
    2. Lymph nodes-filter lymph and trap microorganisms and antigens; contain macrophages and dendritic cells that present antigens to T cells; T cells also trap antigen and present them to B cells
Physical and Chemical Barriers in Nonspecific Resistance
1. Many factors influence host microbe relationships (e.g., nutrition, age, genetic factors, hygiene)
2. Physical and mechanical barriers
  1. Skin
    1. Provides a very effective mechanical barrier
      1. ) Thick outer layer is packed with keratinocytes; these cells produce keratins that are recalcitrant to microbial attack, and they secrete other specialized proteins that produce inflammation
      2. ) Continuous shedding removes microorganisms that adhere to skin
      3. ) Relative dryness slows microbial growth
      4. ) Mild acidity inhibits growth of many microorganisms
      5. ) Normal microbiota acts antagonistically and competes for attachment sites and nutrients
      6. ) Sebum forms a protective layer
      7. ) Normal washing continually removes microorganisms
    2. ) If pathogen penetrates tissue under skin, it encounters skin-associated lymphoid tissue (SALT)
      1. ) Langerhans cells-specialized dendritic cells that phagocytize antigens then migrate to lymph nodes and differentiate into interdigitating dendritic cells, a type of antigen-presenting cell
      2. ) Intraepidermal lymphocytes-function as T cells to destroy antigen
  2. Mucous membranes
    1. Mucus secretions form a protective covering that contains antibacterial substances, such as lysozyme, lactoferrin, and lactoperoxidase
    2. Contain mucosal-associated lymphoid tissue (MALT)
      1. ) Several types, including gut-associated (GALT) and bronchial associated (BALT)
      2. ) MALT operates by the action of M cells, which phagocytize antigen and transport it either to a pocket within the M cell containing B cells and macrophages or to lymphoid follicles containing B cells
  3. Respiratory system-aerodynamic filtration deposits organisms onto mucosal surfaces, and mucociliary blanket transports them away from the lungs; coughing, sneezing, and salivation also remove microorganisms; alveolar macrophages destroy those pathogens that get to the alveoli
  4. Gastrointestinal tract
    1. Gastric acid kills most microorganisms
    2. In intestines, pancreatic enzymes, bile, intestinal enzymes, GALT, peristalsis, normal microbiota, lysozyme, and antibacterial peptides destroy or remove microorganisms
  5. Genitourinary tract
    1. Kidneys, ureters, and urinary bladder are sterile due to multiple factors (e.g., pH and flushing action)
    2. Vagina produces glycogen, which is fermented by lactobacilli to lactic acid, thus lowering the pH
  6. The eye-flushing action, lysozyme, and other antibacterial substances
  7. Chemical barriers
    1. Gastric juices, salivary glycoproteins, lysozyme, oleic acid on the skin, urea, and other chemicals have already been discussed
    2. Bacteriocins-plasmid-encoded antibacterial substances produced by normal microbiota (usually gram-negative bacteria); are lethal to related species
    3. Beta-lysin and other polypeptides
      1. Beta-lysin lyses gram-positive bacteria
      2. Leukins, plakins, cecropins, phagocytin, and other polypeptides also exhibit antimicrobial activity
Inflammation
1. Nonspecific response to tissue injury characterized by redness, heat, pain, swelling, and altered function of the tissue
2. Inflammatory response
  1. Injured tissue cells release chemical signals that activate cells in capillaries
  2. Interaction of selectins on vascular endothelial surface and integrins on neutrophil surface promotes neutrophil extravasation
  3. Neutophils attack pathogen
  4. More neutrophils and other leukocytes are attracted to site of tissue damage to help destroy microorganisms
3. Numerous inflammatory mediators function in response
  1. Kallikrein-an enzyme that catalyzes formation of bradykinin
  2. Bradykinin
    1. Binds capillary walls; this promotes movement of fluid and leukocytes into tissue and production of prostaglandins (cause pain)
    2. Binds mast cells, causing release of histamine and other inflammation mediators
  3. Histamine-promotes movement of more fluid, leukocytes, bradykinin and killikrein into tissue
4. During acute inflammation, pathogen is neutralized and eliminated by a series of events
  1. Increase in blood flow and capillary dilation bring more antimicrobial factors and leukocytes into the area; these destroy the pathogen; dead cells also release antimicrobial factors
  2. The rise in temperature stimulates the inflammatory response and may inhibit microbial growth
  3. A fibrin clot often forms and may limit the spread of the invaders so that they remain localized
  4. Phagocytes collect in the inflamed area and phagocytize the pathogen; chemicals stimulate release of neutrophils and increase the rate of granulocyte production
5. Chronic inflammation is characterized by its longer duration, dense infiltration of lymphocytes and macrophages, and formation of granulomas (in some cases)
The Complement System
1. The complement system is a set of serum proteins that play a major role in the immune response
  1. Some lyse foreign cells
  2. Some mediated inflammation and attract and activate phagocytic cells
  3. Some amplify the effects of antibodies
2. Complement acts in a cascade fashion; the complement proteins are inactive, and the activation of one leads to the sequential activation of others
3. There are three pathways of complement activation
  1. Classical pathway-results form antigen-antibody interactions that occur during specific immune responses (discussed in chapter 32)
  2. Alternative complement pathway-occurs in response to intravascular invasion by bacteria and some fungi; involves interaction of complement with the surface of the pathogen
  3. Lectin complement pathway-occurs when macrophages release mannose-binding protein (a lectin), which then can activate complement via the alternative pathway or the classical pathway
4. Overview of complement activation and immune responses
  1. Gram-negative bacteria at local tissue site interact with components of alternative pathway
  2. If bacteria persist or invade a second time, antibody responses activate the classical pathway
  3. Generation of C3a and C5a complement fragments leads to:
    1. Activation of mast cells, which release their contents, casing hyperemia
    2. Release of neutrophils from bone marrow into circulation, and their chemotaxis to injury site
  4. Ultimately neutrophils and phagocytes ingest and destroy the bacteria
Phagocytosis
1. Phagocytic cells (monocytes, macrophages, and neutrophils) phagocytize infecting organisms
2. Recognition of microorganisms occurs by two mechanisms
  1. Opsonin-dependent recognition-during opsonization, microorganism is coated with antibodies or complement; this promotes recognition and phagocytosis
  2. Opsonin-independent recognition-uses nonspecific and specific receptors on the phagocytic cells to recognize and bind structures on the microorganism
3. Phagocytized microorganism is enclosed in phagosome, which then fuses with lysosome; digestion occurs in phagolysosome
  1. Lysosomal enzymes (e.g., lysozyme, phospholipase, proteases) hydrolyze microbial structural molecules
  2. Lysosomes of macrophages and neutrophils have enzymes that make toxic reactive oxygen intermediates (e.g., superoxide radical) during the respiratory burst that accompanies phagocytosis
  3. Macrophages, neutrophils, and mast cells form reactive nitrogen intermediates (e.g., nitric oxide) that are potent cytotoxic agents
  4. Neutophil granules contain microbiocidal substances (e.g. defensins), which are delivered to the phagolysosome
Cytokines
1. Cytokines are soluble proteins or glycoproteins that are released by one cell population and act as intercellular mediators
  1. Monokines-released from mononuclear phagocytes
  2. Lymphokines-released from T lymphocytes
  3. Interleukins-released from a leukocyte and act on another leukocyte
  4. Colony stimulating factors (CSFs)-effect is to stimulate growth and differentiation of immature leukocytes in the bone marrow
  5. Cytokines have recently been grouped into families; examples are shown in table 31.3 of the text
2. Cytokines can affect various cell populations
  1. Autocrine function-affect the same cell responsible for its production
  2. Paracrine function-affect nearby cells
  3. Endocrine function-distributed by circulatory system to target cells
3. Exert their effects by binding to cell-surface receptors called cell-association differentiation antigens (CDs); possible effects include
  1. Stimulation of cell division
  2. Stimulation of cell differentiation
  3. Inhibition of cell division
  4. Apoptosis-programmed cell death
  5. Stimulation of chemotaxis and chemokinesis
4. Interferons
  1. Regulatory cytokines produced in response to numerous inducers, including viral infection, endotoxin, and presence of intracellular bacterial pathogens
  2. There are five major classes: IFN-a, IFN-b, IFN-g, IFN-w, and IFN-t
5. Fever-results from disturbances in hypothalamic regulatory control, leading to increase of thermal set point
  1. Most common cause of fever is viral or bacterial infection, usually due to action of an endogenous pyrogen (e.g., interleukin-1, interleukin-6, tissue necrosis factor), which induces secretion of prostaglandins; these reset the hypothalamic thermostat
  2. Fever augments hosts defenses by three pathways
    1. Stimulates leukocytes so that they can destroy the microorganism
    2. Enhances specific activity of the immune system
    3. Enhances microbiostasis (growth inhibition) by decreasing available iron to the microorganisms
Natural Killer Cells
1. Natural killer (NK) cells are large nonphagocytic granular lymphocytes that destroy malignant cells and cells infected with microorganisms
2. Recognize and target in two ways:
  1. Antibody-dependent cell-mediated cytotoxicity (ADCC)-receptors on NK cells link them to antibody-coated target cells
  2. Killer-activation receptors and killer-inhibitory receptors-binding of these two receptors determines response; if NK cell's killer-inhibitory receptor binds class I major histocompatibility (MHC) molecule (a self antigen), killing is inhibited; if there is no class I MHC on the target cell (i.e., because cell is infected with virus or is malignant), then killing occurs

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