Pathogenicity-the ability to produce pathological changes (disease) as the result of a parasitic symbiosis between a microorganism and a host
Pathogen-any disease-producing microorganism
Gnotobiotic Animals
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)
Gnotobiotic animals allow investigation of the interactions of animals with specific microorganisms that are deliberately introduced into the animal
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
Gnotobiotic animals are not anatomically or physiologically normal
Can have poorly developed lymphoid tissue, thin intestinal walls, enlarged cecum (birds), or low antibody titers
Require nutritional supplements
Have reduced cardiac output and lower metabolic rates
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
Internal tissues are normally free of microorganisms; however, many other sites are colonized; normal microbiota are the microorganisms regularly found at any anatomical site
Reasons to acquire knowledge of normal human microbiota
It provides greater insight into possible infections resulting from injury to these sites
It gives perspective on the possible sources and significance of microorganisms isolated from an infection site
It increases understanding of the causes and consequences of growth by microorganisms normally absent from a specific body site
It aids awareness of the role these indigenous microorganisms play in stimulating the immune response
Distribution of the normal microbiota-can be inside body (endosymbiosis) or outside body (ectosymbiosis)
Skin
Resident microbiota multiply on or in the skin; transients normally die in a few hours
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)
Most skin bacteria are found on superficial cells, colonizing dead cells, or closely associated with oil and sweat glands
) Staphylococcus epidermidis and corynebacteria (dry areas and sweat
glands)
) Gram-negative bacteria (moist areas)
) Yeast (scalp)
) Dematophytic fungi (e.g., those causing ringworm and athletes foot)
) Propionibacterium acnes is prevalent in skin glands and is associated with acne vulgaris
Nose and nasopharynx
Nose-just inside the nares; Staphylococcus epidermidis and S. aureus are predominant; they are also found on skin of face
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
Oropharynx-between the soft palate and upper edge of the epiglottis; houses many different species, including staphylococci and streptococci
Respiratory tract-no normal microbiota due to the enzyme lysozyme in mucus and the phagocytic action of alveolar macrophages
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
Eye-aerobic commensals are found on the conjunctiva
External ear-resembles microbiota of the skin; includes some fungi
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
Small intestine
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
Jejunum-Enterococcus fecalis, diphtheroids, lactobacilli, and Candida albicans are occasionally found
Ileum-microbiota resembles that of the colon (e.g., anaerobic gram-negative rods and Enterobacteriaceae)
Large intestine (colon)-largest microbial population of the body
Over 300 different species have been isolated from human feces; most are anaerobes or facultative organisms growing anaerobically
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
Genitourinary tract
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
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
The relationship between normal microbiota and the host
Relationship with normal microbiota is usually mutually beneficial
Normal microbiota helps repel invading pathogens by a number of mechanisms (e.g., competition, production of inhibitory chemicals)
Under some conditions, normal microbiota can become pathogenic; such microorganisms are referred to as opportunistic
Compromised host-host that is seriously debilitated and has lowered resistance; is often target of opportunistic microorganisms
Overview of Host Resistance
To establish infection pathogen must first overcome barrier defenses
If pathogen succeeds, immune system offers protection
Immune system is composed of widely distributed cells, tissues, and organs that recognize foreign substances and microorganisms
Immunity-ability of a host to resist a particular disease
Immunology-the science that deals with immune responses
Two types of immune responses
Nonspecific immune responses (also called innate or natural immunity)
General resistance mechanisms inherited as part of the innate structure and function of each animal
Lack immunological memory
Nonspecific response occurs to same extent with each encounter
Specific immune response (also called acquired or specific immunity)-discussed in chapter 32
Resists a particular foreign agent
Improves on repeated exposure
Involves the interaction of antigens and antibodies
Cells, Tissues, and Organs of the Immune System
Cells of the immune system
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
Lymphoid cells-also called lymphocytes; major cells of specific immune system; divided into three populations: T cells, B cells and Natural killer (NK) cells
Mononuclear cells-two types; are both highly phagocytic; constitute the monocyte-macrophage system
Monocytes-mononuclear phagocytic cells that circulate in blood for short time and can migrate to tissues where they mature into macrophages
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)
Granulocytes-also called polymorphonuclear leukocytes (PMNs)
Basophils-nonphagocytic; upon stimulation, release chemicals (e.g., histamine, prostaglandins) that impact blood vessels (vasoactive); basophils play important roles in allergic responses
Eosinophils-mobile cells that migrate from blood stream into tissue spaces; protect against protozoa and helminth parasites
Neutrophils-highly phagocytic cells that rapidly migrate to sites of tissue damage and infection
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
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
Organs and tissues of the immune system
Primary lymphoid organs and tissues
Thymus-site of T cell maturation
Bursa of Fabricus-site of B cell maturation in birds
Bone marrow-site of B cell maturation in mammals
Secondary lymphoid organs and tissue
Spleen-filters blood and traps blood-borne microorganisms and antigens; contains macrophages and dendritic cells that present antigens to T cells
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
) 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
) Continuous shedding removes microorganisms that adhere to skin
) Relative dryness slows microbial growth
) Mild acidity inhibits growth of many microorganisms
) Normal microbiota acts antagonistically and competes for attachment sites and nutrients
) Sebum forms a protective layer
) Normal washing continually removes microorganisms
) If pathogen penetrates tissue under skin, it encounters skin-associated lymphoid tissue (SALT)
) 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
) Intraepidermal lymphocytes-function as T cells to destroy antigen
Mucous membranes
Mucus secretions form a protective covering that contains antibacterial substances, such as lysozyme, lactoferrin, and lactoperoxidase
Contain mucosal-associated lymphoid tissue (MALT)
) Several types, including gut-associated (GALT) and bronchial associated (BALT)
) 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
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
Gastrointestinal tract
Gastric acid kills most microorganisms
In intestines, pancreatic enzymes, bile, intestinal enzymes, GALT, peristalsis, normal microbiota, lysozyme, and antibacterial peptides destroy or remove microorganisms
Genitourinary tract
Kidneys, ureters, and urinary bladder are sterile due to multiple factors (e.g., pH and flushing action)
Vagina produces glycogen, which is fermented by lactobacilli to lactic acid, thus lowering the pH
The eye-flushing action, lysozyme, and other antibacterial substances
Chemical barriers
Gastric juices, salivary glycoproteins, lysozyme, oleic acid on the skin, urea, and other chemicals have already been discussed
Bacteriocins-plasmid-encoded antibacterial substances produced by normal microbiota (usually gram-negative bacteria); are lethal to related species
Beta-lysin and other polypeptides
Beta-lysin lyses gram-positive bacteria
Leukins, plakins, cecropins, phagocytin, and other polypeptides also exhibit antimicrobial activity
Inflammation
Nonspecific response to tissue injury characterized by redness, heat, pain, swelling, and altered function of the tissue
Inflammatory response
Injured tissue cells release chemical signals that activate cells in capillaries
Interaction of selectins on vascular endothelial surface and integrins on neutrophil surface promotes neutrophil extravasation
Neutophils attack pathogen
More neutrophils and other leukocytes are attracted to site of tissue damage to help destroy microorganisms
Numerous inflammatory mediators function in response
Kallikrein-an enzyme that catalyzes formation of bradykinin
Bradykinin
Binds capillary walls; this promotes movement of fluid and leukocytes into tissue and production of prostaglandins (cause pain)
Binds mast cells, causing release of histamine and other inflammation mediators
Histamine-promotes movement of more fluid, leukocytes, bradykinin and killikrein into tissue
During acute inflammation, pathogen is neutralized and eliminated by a series of events
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
The rise in temperature stimulates the inflammatory response and may inhibit microbial growth
A fibrin clot often forms and may limit the spread of the invaders so that they remain localized
Phagocytes collect in the inflamed area and phagocytize the pathogen; chemicals stimulate release of neutrophils and increase the rate of granulocyte production
Chronic inflammation is characterized by its longer duration, dense infiltration of lymphocytes and macrophages, and formation of granulomas (in some cases)
The Complement System
The complement system is a set of serum proteins that play a major role in the immune response
Some lyse foreign cells
Some mediated inflammation and attract and activate phagocytic cells
Some amplify the effects of antibodies
Complement acts in a cascade fashion; the complement proteins are inactive, and the activation of one leads to the sequential activation of others
There are three pathways of complement activation
Classical pathway-results form antigen-antibody interactions that occur during specific immune responses (discussed in chapter 32)
Alternative complement pathway-occurs in response to intravascular invasion by bacteria and some fungi; involves interaction of complement with the surface of the pathogen
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
Overview of complement activation and immune responses
Gram-negative bacteria at local tissue site interact with components of alternative pathway
If bacteria persist or invade a second time, antibody responses activate the classical pathway
Generation of C3a and C5a complement fragments leads to:
Activation of mast cells, which release their contents, causing hyperemia
Release of neutrophils from bone marrow into circulation, and their chemotaxis to injury site
Ultimately neutrophils and phagocytes ingest and destroy the bacteria
Phagocytosis
Phagocytic cells (monocytes, macrophages, and neutrophils) phagocytize infecting organisms
Recognition of microorganisms occurs by two mechanisms
Opsonin-dependent recognition-during opsonization, microorganism is coated with antibodies or complement; this promotes recognition and phagocytosis
Opsonin-independent recognition-uses nonspecific and specific receptors on the phagocytic cells to recognize and bind structures on the microorganism
Phagocytized microorganism is enclosed in phagosome, which then fuses with lysosome; digestion occurs in phagolysosome
Lysosomes of macrophages and neutrophils have enzymes that make toxic reactive oxygen intermediates (e.g., superoxide radical) during the respiratory burst that accompanies phagocytosis
Macrophages, neutrophils, and mast cells form reactive nitrogen intermediates (e.g., nitric oxide) that are potent cytotoxic agents
Neutophil granules contain microbiocidal substances (e.g. defensins), which are delivered to the phagolysosome
Cytokines
Cytokines are soluble proteins or glycoproteins that are released by one cell population and act as intercellular mediators
Monokines-released from mononuclear phagocytes
Lymphokines-released from T lymphocytes
Interleukins-released from a leukocyte and act on another leukocyte
Colony stimulating factors (CSFs)-effect is to stimulate growth and differentiation of immature leukocytes in the bone marrow
Cytokines have recently been grouped into families; examples are shown in table 31.3 of the text
Cytokines can affect various cell populations
Autocrine function-affect the same cell responsible for its production
Paracrine function-affect nearby cells
Endocrine function-distributed by circulatory system to target cells
Exert their effects by binding to cell-surface receptors called cell-association differentiation antigens (CDs); possible effects include
Stimulation of cell division
Stimulation of cell differentiation
Inhibition of cell division
Apoptosis-programmed cell death
Stimulation of chemotaxis and chemokinesis
Interferons
Regulatory cytokines produced in response to numerous inducers, including viral infection, endotoxin, and presence of intracellular bacterial pathogens
There are five major classes: IFN-a, IFN-b, IFN-g, IFN-w, and IFN-t
Fever-results from disturbances in hypothalamic regulatory control, leading to increase of thermal set point
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
Fever augments hosts defenses by three pathways
Stimulates leukocytes so that they can destroy the microorganism
Enhances specific activity of the immune system
Enhances microbiostasis (growth inhibition) by decreasing available iron to the microorganisms
Natural Killer Cells
Natural killer (NK) cells are large nonphagocytic granular lymphocytes that destroy malignant cells and cells infected with microorganisms
Recognize and target in two ways:
Antibody-dependent cell-mediated cytotoxicity (ADCC)-receptors on NK cells link them to antibody-coated target cells
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
