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Prescott’s Microbiology, 9th Edition
33
Innate Host Resistance
CHAPTER OVERVIEW
Humans resist parasitic relationships by employing both nonspecific and specific mechanisms. The nonspecific
resistance mechanisms are explored in this chapter. Physical barriers of innate resistance are discussed for
several tissues and organs. The details of innate immunity are presented, including complement activation,
cytokines, and acute phase proteins. There is a discussion of immunity and the cells and organs involved in
human immune responses. The mechanisms of cellular immunity are presented and inflammation detailed.
LEARNING OUTCOMES
After reading this chapter you should be able to:
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identify the major components of the mammalian host immune system
integrate the major immune components and their functions to explain in general terms how the immune
system protects the host
identify the barriers that help prevent microbial invasion of the host
explain how the physical and mechanical barriers function to prevent microbial invasion of the host
relate host anatomy and secretions to the success of innate resistance strategies
discuss host mediators that have antimicrobial actions
describe in general terms the activation of the host complement system and its three outcomes
list the three categories of cytokines and discuss their major functions
correlate host protection from microbial invasion with specific mediators
recognize the different types of leukocytes involved with innate resistance
outline the leukocyte response to microbial invasion
integrate leukocyte distribution within the host with host resistance
differentiate between primary and secondary lymphoid organs and tissues in terms of structure and
function
predict connections between innate host resistance and specific immune responses
explain the methods by which pathogens are recognized by phagocytes
describe the processes of autophagy and phagocytosis
forecast how biochemical activities within the phagocyte result in pathogen destruction
outline the sequence of innate host responses that result in inflammation
distinguish acute and chronic inflammation in terms of the host responses involved in each
construct a concept map relating host cells and processes that remove pathogens
CHAPTER OUTLINE
I.
Innate Resistance Overview
A. To establish infection, a pathogen must first overcome barrier defenses
B. If a pathogen succeeds, the immune system offers protection
1. The immune system is composed of widely distributed cells, tissues, and organs that recognize
foreign materials and microorganisms
C. Immunity—ability of a host to resist a particular disease; immunology—the science that deals with
immune responses
1. Two types of immune responses
a. 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
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Prescott’s Microbiology, 9th Edition
b.
Specific immune response (also called acquired, adaptive, or specific immunity)
1) Resists a particular foreign agent by an immune response (e.g., production of
antibodies) to specific antigens
2) Improves on repeated exposure
c. Multiple bridges occur between innate and adaptive immunity; a variety of white blood
cells function in both systems
II. Physical and Mechanical Barrier Defenses of Innate Resistance
A. Many factors influence host-microbe relationships (e.g., nutrition, age, genetic factors, hygiene)
B. Physical and mechanical barriers
1. Skin—provides a very effective mechanical barrier to microbial invasion, due to its thick,
closely packed cells, frequent shedding and by being acidic and salty
2. Mucous membranes—mucus secretions form a protective covering that contains antibacterial
substances, such as lysozyme, lactoferrin, and lactoperoxidase
3. Respiratory system
a. Aerodynamic filtration deposits organisms onto mucosal surfaces, and microbes become
entrapped in mucus (mucociliary blanket)
b. Activity of ciliated epithelial cells transports microbes away from the lungs (mucociliary
escalator); coughing, sneezing, and salivation also remove microorganisms
c. Alveolar macrophages destroy those pathogens that get to the alveoli
4. Gastrointestinal tract
a. Gastric acid kills most microorganisms
b. In intestines, pancreatic enzymes, bile, intestinal enzymes, GALT, peristalsis, normal
microbiota, lysozyme (produced by Paneth cells), and antibacterial peptides (cryptins)
destroy or remove microorganisms
5. Genitourinary tract
a. Kidneys, ureters, and urinary bladder are sterile due to multiple factors (e.g., pH and
flushing action)
b. Vagina produces glycogen, which is fermented by lactobacilli to lactic acid, thus
lowering the pH and inhibiting other organisms
III. Chemical Mediators in Innate Resistance
A. Gastric juices, salivary glycoproteins, lysozyme, oleic acid on the skin, urea, and other chemicals
have already been discussed
B. Antimicrobial peptides
1. Cationic peptides damage bacterial plasma membranes through electrostatic interactions
a. Cathelicidin—one of a group of linear alpha-helical peptides (12 to 80 amino acids)
produced by a variety of cells (e.g., neutrophils, respiratory epithelia)
b. Defensins—a diverse group of disulfide-linked, open-ended peptides (29 to 42 amino
acids) found in a variety of cells (e.g., neutrophils, Paneth cells)
c. Histatins—larger peptides with regular structural repeats
2. Bacteriocins—plasmid-encoded antibacterial peptides produced by normal bacterial flora; are
lethal to related species through a variety of mechanisms
C. Complement
1. The complement system is a set of serum proteins that play a major role in the immune
response; complement has three major physiological activities: defending against bacterial
infections, bridging innate and adaptive immunity, and disposing of wastes
2. During opsonization, the microorganism is coated with antibodies, mannan-binding protein,
and/or complement proteins (together known as opsonins); this promotes recognition and
phagocytosis
3. Complement acts in a cascade fashion; the complement proteins are produced in an inactive
form, and the activation of one (by cleavage of the protein) leads to the sequential activation of
others
4. There are three pathways of complement activation
a. Alternative complement pathway—occurs in response to intravascular invasion by
bacteria and some fungi; involves interaction of complement with the surface of the
pathogen forming the membrane attack complex
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Prescott’s Microbiology, 9th Edition
b.
Lectin complement pathway (also called the mannan-binding lectin pathway)—occurs
when macrophages stimulate liver cells to release acute phase proteins such as mannosebinding protein (a lectin), which then can activate complement via the alternative
pathway or the classical pathway
c. Classical pathway—results from antigen-antibody interactions that occur during specific
immune responses
5. Complement action
a. Membrane attack complexes can create a pore in the microbial cell membrane which
uncouples gradients and leaves cells susceptible.
b. Inflammatory action- complement fragments stimulate factors which allow inflammation
which leads to vessel permeability and attraction of neutrophils
D. Cytokines
1. Cytokines are soluble proteins or glycoproteins that are released by one cell population and act
as intercellular mediators
a. Monokines—released from mononuclear phagocytes
b. Lymphokines—released from T lymphocytes
c. Interleukins—released from a leukocyte and act on another leukocyte
d. Colony-stimulating factors (CSFs)—stimulate growth and differentiation of immature
leukocytes in the bone marrow
2. Cytokines can affect various cell populations
a. Autocrine function—affect the same cell responsible for its production
b. Paracrine function—affect nearby cells
c. 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:
a. Stimulation of cell division
b. Stimulation of cell differentiation
c. Inhibition of cell division
d. Apoptosis—programmed cell death
e. Stimulation of chemotaxis and chemokinesis
4. Interferons (INFs)—Regulatory cytokines produced by certain eukaryotic cells in response to
viral infection; in addition to protecting against viral infections, interferons also help regulate
the immune response
5. Fever—results from disturbances in hypothalamic regulatory control, leading to increase of
thermal “set point”
a. 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
b. Fever augments host’s defenses three ways
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
6. Acute phase proteins—produced by liver in response to cytokines; act as opsonins and activate
complement; collectins act as molecular scavengers that bind cellular debris
IV. Cells, Tissues, and Organs of the Immune System
A. 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
a. Respond to pathogen-associated molecular patterns (PAMPS) to recognize microbes
b. Receptors to PAMPS are known as pattern recognition receptors (PRRs)
2. 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
3. Granulocytes—also called polymorphonuclear neutrophils (PMNs)
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Prescott’s Microbiology, 9th Edition
a.
B.
Basophils—nonphagocytic; upon stimulation, release chemicals (e.g., histamine,
prostaglandins) that impact blood vessels (vasoactive); basophils play important roles in
allergic responses
b. Eosinophils—mobile cells that migrate from bloodstream into tissue spaces; protect
against protozoa and helminth parasites; also may have role in allergic responses
c. Neutrophils—highly phagocytic cells that rapidly migrate to sites of tissue damage and
infection
4. Monocytes, macrophages and dendritic cells—highly phagocytic cells
a. Monocytes—mononuclear phagocytic cells that circulate in blood for short time and can
migrate to tissues where they mature into macrophages
b. Macrophages—larger than monocytes; have more organelles and possess receptors that
allow them to discriminate self from nonself; surface molecules recognize common
components of pathogens (pathogen-associated molecular patterns) and enable pattern
recognition receptors; respond to opsonization (chemical enhancement of phagocytosis)
c.
Dendritic cells—phagocytose microorganisms and kill viruses by secreting interferon-α;
mature dendritic cells migrate to blood stream or lymphatic system where they interact
with B cells and natural killer cells and present foreign antigens to T cells
5. Lymphocytes
a. Major cells of specific immune system; when activated can differentiate to stimulate the
immune response, produce antibodies, or produce memory cells
b. Divided into three populations: T cells, B cells, and natural killer cells (NK cells)
c. B lymphocytes (or B cells) mature in bone marrow and disperse throughout lymphoid
tissue; when activated, differentiate into plasma cells and produce antibodies
d. T lymphocytes (or T cells) mature in thymus gland and circulate in blood or lymphoid
tissue; when activated, T cells do not produce antibodies, but stimulate the immune
response by producing cytokine proteins
e. Natural killer cells are large, nonphagocytic, granular lymphocytes that destroy malignant
cells and cells infected with microorganisms
f.
NK cell 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) If NK cells bind class I major histocompatibility (MHC) molecule (a self antigen)
on a cell's surface, 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 through
pore-forming proteins and cytotoxic enzymes (granzymes)
Organs and tissues of the immune system
1. Primary lymphoid organs and tissues
a. Thymus—site of T cell maturation
b. Bone marrow—site of B-cell maturation in mammals
c. Bursa of Fabricius—site of B-cell maturation in birds (origin of term B cell)
2. Secondary lymphoid organs and tissue
a. Spleen—filters blood and traps blood-borne microorganisms and antigens; contains
macrophages and dendritic cells that present antigens to T cells
b. Lymph nodes—filter lymph and trap microorganisms and antigens; contain macrophages
and dendritic cells that present antigens to T cells; T cells release cytokines that stimulate
differentiation and proliferation of B cells in antibody-producing plasma cells and
memory cells
c. Some lymphoid tissue is closely associated with certain tissues
d. SALT—skin-associated lymphoid tissue
1) Langerhans cells—specialized dendritic cells that phagocytose antigens, then
migrate to lymph nodes and differentiate into interdigitating dendritic cells, a type
of antigen-presenting cell; activate T cells, which interact with activated B cells to
induce a humoral response
2) Intraepidermal lymphocytes—function as T cells to destroy antigen
e. MALT—mucosal-associated lymphoid tissue
1) Several types, including gut-associated (GALT) and bronchial-associated (BALT)
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Prescott’s Microbiology, 9th Edition
2)
MALT operates by the action of M cells in the mucous membrane; M cells
phagocytose antigen and transport it either to a pocket within the M cell containing
B cells and macrophages or to lymphoid follicles containing B cells
V.
Phagocytosis
A. Phagocytic cells (monocytes, tissue macrophages, dendritic cells, and neutrophils) phagocytose
infecting organisms; phagocytosis is the process by which invaders are recognized, ingested, and
killed. Autophagy can occur to combat intracellular parasites
B. Recognition of foreignness of the pathogen can be opsonin-dependent or opsonin-independent
1. Opsonin-independent recognition (nonopsonic)—uses nonspecific and specific receptors
(pattern recognition receptors, PRRs) on the phagocytic cells to recognize and bind structures
on the microorganism, or to signal the induction of host defense pathways
a. Multilectin protein found on dendritic cells and macrophages uses recognition based on
the interaction of surface lectins on one cell and surface carbohydrates on the pathogen
b. Recognition based on the detection of conserved molecular structures that occur in
patterns and are essential products of normal microbial physiology (pathogen-associated
molecular patterns – PAMPs; e.g., LPS)
2. NOD-like receptors (NLRs) — cytoplasmic soluble PRR that recognizes nucleotide binding
and oligomerization domains. Interacts with inflammasome
3. Toll-like receptors (TLRs) —PRRs act exclusively as signaling receptors that bind PAMPs
and communicate with the cell nucleus to elicit the appropriate response to different classes of
pathogens
C. Intracellular digestion—ingested 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 species (e.g., nitric oxide,
nitrite and nitrate) that are potent cytotoxic agents
4. Neutrophil granules contain microbiocidal substances (e.g., defensins), which are delivered to
the phagolysosome
D. Exocytosis—the antigenic remains of invaders can be expelled from the cell (as neutrophils do) or
further processed for antigen presentation on the lymphocyte cell surface (as macrophages and
dendritic cells do)
VI. Inflammation
A. Nonspecific response to tissue injury characterized by redness, heat, pain, swelling, and altered
function of the tissue
B. Inflammatory response
1. Injured tissue cells release chemical signals (chemokines) that activate cells in capillaries
2. Interaction of selectins on vascular endothelial surface and integrins on neutrophil surface
promotes neutrophil extravasation
3. Neutrophils attack pathogen
4. More neutrophils and other leukocytes are attracted to site of tissue damage to help destroy
microorganisms
C. Numerous inflammatory mediators function in response
1. Kallikrein—an enzyme that catalyzes formation of bradykinin
2. Bradykinin
a. Binds capillary walls, causing movement of fluid and leukocytes into tissue and
production of prostaglandins (cause pain)
b. Binds mast cells, causing release of histamine and other inflammation mediators
3. Histamine—promotes movement of more fluid, leukocytes, bradykinin, and kallikrein into
tissue
D. 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
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Prescott’s Microbiology, 9th Edition
2.
3.
4.
E.
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 phagocytose 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)
CRITICAL THINKING
1.
The skin is constantly being exposed to pathogenic organisms. However, it is a very effective barrier
against infection—it is not easily colonized and it is not readily penetrated. Discuss the various properties
of the skin that make it such an effective barrier against colonization and penetration.
2.
Inflammation is an important nonspecific defense in response to tissue injury. Describe the steps involved
in the inflammation response. Contrast acute and chronic inflammation.
3.
The lumen of the gastrointestinal tract is effectively exposed to the outside world and in many places along
the way the tract is separated by only a single layer of epithelial tissue. What mechanisms are in place to
protect this portal of entry from potential pathogens?
4.
The evolution of the immune system is a tale of co-evolution between host and pathogen. Some infectious
microbes have evolved the ability to evade complement or become complement resistant. What
modifications to microbes have developed to confer complement resistance?
CONCEPT MAPPING CHALLENGE
Use the following words to construct a concept map by providing your own linking words
Phagocytosis Opsonin Mucous membrane
Defensins Cytokines Bone marrow Physical barriers
MAC Neutrophils Lymphocyte Leukocytes Macrophages Dendritic cells Cytokines
Lymphoid tissue Complement system Opsonization Skin Endogenous pyrogen SALT
Interferons GALT MALT T cells B cells Thymus Basophils Histamine
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in any manner. This document may not be copied, scanned, duplicated, forwarded, distributed, or posted on a website, in whole or part.
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