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steadily over the past SO years. Interestingly, obesity rates correlate to visceral adipose (obese conditions) and increased serum levels of
diets high in saturated fats, as found in many fast food products. The fats pro-inflammatory cytokines (adipokines). This is because saturated fatty
in foods are not the only problem, though. Increasing portion size has acids are recognized as DAMPs by visceral adipocytes and their associated
added dramatically to the obesity issue. In many ways, the American diet macrophages. One of the pro-inflammatory adipokines, interleukin (IL)-18,
is supersized. These facts prompted a number of scientists to study the and a macrophage marker of inflammation, (-reactive protein (CRP), are
impact of obesity on the immune system. Results of studies have provided especially increased in the obese. This has suggested that obesity is akin
additional insight into the mechanisms by which the innate resistance to chronic inflammation. In fact, data demonstrate that pro-inflammatory
arm of the mammalian immune system functions. markers are increased in people with metabolic syndrome (a condition
Innate resistance is an elegant system of sensory and response recognized by high blood pressure, insulin resistance, and high choles
molecules that detect invasion by microorganisms. Capture of microbial terol leading to clogged arteries), and decreased in people with lean body
pieces and parts with pathogen-associated molecular patterns (PAMPs) by profiles and people who exercise regularly.
toll-like and NOD-like receptors (TLRs and NLRs, respectively) triggers an Adipocytes also make anti-inflammatory adipokines, including
ancient gene activation response that upregulates the inflammatory adiponectin (an activator of glucose uptake and fatty acid oxidation in
process. This response synthesizes chemical messengers (cytokines) that muscle). Investigators have shown that adiponectin protects against
alert the host to combat the alien invaders by recruiting an army of metabolic and cardiovascular disorders in leaner individuals.
proteins and cells. An equally elegant system has recently gained All together, the data suggest that a low level of homeostatic
attention whereby TLRs and NLRs detect and respond to host cell inflammation is maintained in normal adipose tissue, balancing
damage. Called damage- or danger-associated molecular patterns inflammatory mediators for tissue sustainability. However, shifting from
(DAMPs), these molecules are typically released from stressed or dying lean to obese conditions causes the visceral adipocytes along with
host cells. Recognition of DAMPs stimulates cytokine expression to recruited macrophages and lymphocytes, to secrete pro-inflammatory
facilitate cellular repair. Both systems activate the same inflammatory cytokines that alter the structure and function of the adipose tissue. This
process but usually with very different outcomes. In a series of revealing promotes chronic and systemic, low-grade inflammation with severe
papers, scientists from Tokyo to Boston studying obesity and its associ consequences for the cardiovascular system. Importantly, return to a
ated problems have pieced together the amazing story of how the leaner mass and increasing exercise reverses the effect. Thus, under
intricate system for the detection of PAMPs and DAMPs by TLRs and NLRs standing how tissue-specific inflammation is induced and regulated by
is upset when we "supersize." PAMPs and DAMPs offers insight into how human disease reflects
Originally thought to just be an energy reserve, visceral (belly) fat is a behavioral choices.
specialized tissue composed of lipid-laden adipocytes (fat cells), preadipo While microorganisms can certainly influence gene expression,
cytes, phagocytes called macrophages, and other cells held in a web of physiology, and behavior of the eukaryotic host, the integrity of any host
723
724 CHAPTER 33 I Innate Host Resistance
organism depends on its ability to recognize foreign invading substances ferent yet complementary components of the mammalian immune
and other life forms, and provide an "appropriate" response to prevent response. The first component arises by virtue of being a vertebrate
invasion by the foreign material. When microorganisms inhabit a animal. Vertebrates have evolved to express unique features that
multicellular host, competition for resources at the cellular level occurs. In inherently protect against invasion by foreign substances. Some
immune response. ture a variety of proteins that function to protect the host. One
Animals (including humans) are continuously exposed to such cell, the B cell, produces and secretes glycoproteins called
antibodies. Antibodies bind to specific antigens and inacti
microorganisms that can cause disease. Fortunately animals are
vate them or contribute to their elimination. Other immune
equipped with an immune system that usually protects against
cells become activated to destroy host cells harboring intracel
adverse consequences of this exposure. The immune system is
lular pathogens, such as viruses. Innate resistance mecha
composed of widely distributed proteins, cells, tissues, and or
nisms and the adaptive immune responses work together to
gans that recognize foreign substances, including microorgan
eliminate pathogenic microorganisms and other foreign
isms. Together they act to neutralize or destroy them, maintaining
materials.
host integrity.
The distinction between innate and adaptive systems is, to a
degree, artificial. Although innate systems predominate imme
Immunity diately upon initial exposure to foreign substances, multiple
The term immunity (Latin immunis, free of burden) refers to the bridges occur between the two immune system components
general ability of a host to resist infection or disease. Immunology (figure 33.1). Importantly, a variety of cells function in both in
is the science focused on immune responses to foreign sub nate and adaptive immunity. These cells are known as the white
stances and how these responses are used to resist infection. It blood cells, or leukocytes. Blood cell development occurs in the
includes the distinction between "self" and "nonself" and all the bone marrow of mammals during the process of hematopoie
biological, chemical, physiological, metabolic, and physical as sis. Leukocytes function in the innate system, whereas others
pects of the immune response. There are two fundamentally dif- are part of a specific immune response. Some are important
33.2 Physical and Mechanical Barrier Defenses of Innate Resistance 725
Retrieve, Infer, Apply nomic status, living conditions) influence all host-microbe rela
tionships. In addition to these direct and indirect factors, a
1. Define each of the following: immune system, immunity,
vertebrate host has some specific physical and mechanical barriers.
immunology, antigen, antibody.
These barriers, along with the host's secretions (flushing
2. Compare and contrast the adaptive and innate immune responses.
mechanisms), are the first line of defense against microorgan
isms. Protection of body surfaces and the mucus-membrane in
terfaces between the host and its environment is essential in
33.2 Physical and Mechanical Barrier preventing microbial access to host nutrients.
Defenses of Innate Resistance
Skin
After reading this section, you should be able to:
Intact skin contributes greatly to innate host resistance because it
• Identify the barriers that help prevent microbial invasion of the host
is a very effective mechanical barrier to microbial invasion. Its
• Explain how the physical and mechanical barriers function to
outer layer consists of thick, closely packed cells called keratino
prevent microbial invasion of the host
cytes, which produce keratins (figure 33.3). Keratins are sclera
• Relate host anatomy and secretions to the success of innate
resistance strategies proteins (i.e., insoluble proteins) that are the main components of
hair, nails, and the outer skin cells. These outer skin cells shed
726 CHAPTER 33 I Innate Host Resistance
Saliva-----;..-;¥"'?��\
(lysozyme, Mucous Membranes
lactoferrin, The mucous membranes of the eye (conjunctiva) and the respi
peroxidase)
ratory, digestive, and urogenital systems withstand microbial
invasion because the intact stratified epithelium and mucus
form a protective covering that resists penetration and traps
microorganisms. Many mucosal surfaces are bathed in specific
antimicrobial secretions. For example, cervical mucus, pros
tatic fluid, and tears are toxic to many bacteria. The conjunctiva
that lines the interior surface of each eyelid and the exposed
surface of the eyeball is a good example of how a mucous mem
brane functions to provide chemical as well as physical protec
(
tion from microorganisms. It is kept moist by the continuous
flushing action of tears from the lacrimal glands. Tears contain
large amounts of lysozyme, lactoferrin, and other antimicrobial
chemicals.
Normal m
Lysozyme (muramidase) is an enzyme that lyses bacteria
by hydrolyzing the bond connecting N-acetylmuramic acid
and N-acetylglucosamine of the bacterial cell wall peptidogly
can-especially in Gram-positive bacteria (figure 33.4). Tears
and other mucous secretions also contain significant amounts
of the iron-binding protein lactoferrin. Lactoferrin is released
by activated phagocytic cells called macrophages and poly
morphonuclear leukocytes (PMNs). It sequesters iron from the
blood plasma, reducing the amount of iron available to invad
ing microbial pathogens thereby limiting their ability to multi
ply. Finally, mucous membranes produce lactoperoxidase, an
enzyme that catalyzes the production of superoxide radicals, a
NAG NAM
�
�(1-4) bond
CH,OH CH,OH
Connective tissue
:o\ CH
I
NH
I
c c
o-r ' o-r \
\ CH2
\
To cross bridge
Figure 33.3 Photomicrograph of Human Skin. Note the stratified Figure 33.4 Action of Lysozyme on the Cell Wall of Gram-Positive
cell layers, epidermis composed of keratinocytes, and dermis composed of Bacteria. This enzyme degrades the cell wall peptidoglycan by hydrolyzing
fibroblasts and connective tissue. The outer layers slough away, taking the [3(1�4) bonds that connect alternating N-acetylglucosamine (NAG) with
attached microorganisms with them. N-acetylmuramic acid (NAM) residues.
33.2 Physical and Mechanical Barrier Defenses of Innate Resi stance 727
Respiratory System
The average person inhales at least eight microorganisms a min
ute, or 10,000 each day. Once inhaled, a microorganism must first
survive and penetrate the air-filtration system of the upper and
lower respiratory tracts. Because the airflow in these tracts is very
turbulent, microorganisms are deposited on the moist, sticky mu
cosal surfaces. Microbes larger than 10 fJ..m usually are trapped by
hairs and cilia lining the nasal cavity. The cilia in the nasal cavity
beat toward the pharynx, so that mucus with its trapped microor
ganisms is moved toward the mouth to be expelled (figure 33.5).
Humidification of the air within the nasal cavity causes many
microorganisms to swell, and this aids phagocytosis. Microbes
smaller than 10 fJ..m (i.e., most bacterial cells) often pass through
the nasal cavity and are trapped by the mucociliary blanket that
coats the mucosal surfaces of lower portions of the respiratory
system. The trapped microbes are transported by ciliary action
the mucociliary escalator-that moves them away from the lungs
(figure 33.5). Coughing and sneezing reflexes clear the respira
tory system of microorganisms by expelling air forcefully from
the lungs through the mouth and nose, respectively. Salivation
also washes microorganisms from the mouth and nasopharyn
geal areas into the stomach. Microorganisms that succeed in
reaching the alveoli of the lungs encounter a population of spe
cialized cells called alveolar macrophages. These cells ingest and
kill most inhaled microorganisms by phagocytosis (p. 743}.
Right lung Left lung
Gastrointestinal Tract (a)
Most microorganisms that reach the stomach are killed by the acidic
gastric juice (pH 2-3}, which is a mixture of hydrochloric acid, pro
teolytic enzymes, and mucus. However, some microorganisms and
their products (e.g., protozoan cysts, Helicobacter pylori, Clostridium
spp., and staphylococcal toxins) can survive the stomach acidity.
Furthermore, organisms embedded in food particles may be pro
tected from gastric juice and reach the small intestine. There, these
microorganisms often are damaged by various pancreatic enzymes,
bile, enzymes in intestinal secretions, and the GALT system (p. 742).
Peristalsis (Greek peri, around, and stalsis, contraction) and the nor
mal shedding of columnar epithelial cells act in concert to purge in
testinal microorganisms. In addition, the normal microbiota of the
large intestine (table 32.2) is extremely important in preventing the
establishment of pathogenic organisms. For example, the metabolic
products (e.g., fatty acids) of many normal microbiota in the intesti
nal tract prevent unwanted microorganisms from becoming estab
lished. Other normal microbiota outcompete potential pathogens
Cilia Microvilli
for attachment sites and nutrients. The mucous membranes of the (b)
intestinal tract contain cells called Paneth cells (figure 33.2). These Figure 33.5 Schematic of the Respiratory Tract Showing Its Components.
cells produce lysozyme (figure 33.4) and peptides called cryptidins, The tract is lined with ciliated epithelial cells of the respiratory tract. (a) The
a type of defensin (p. 728). Cryptidins are toxic for some bacteria, as respiratory tract is lined with a mucous membrane of ciliated epithelial cells.
they form membrane channels that result in cell lysis. (b) Cilia (X 5,000) sweep particles upward toward the throat to be expectorated.
Genitourinary Tract usually present in the distal portion of the urethra (table 32.2). The
Under normal circumstances, the kidneys, ureters, and urinary factors responsible for this sterility are complex. In addition to re
bladder of mammals are sterile. Urine within the urinary bladder moving microbes by flushing action, urine kills some bacteria due
also is sterile. However, in both males and females, a few bacteria are to its low pH and the presence of urea and other metabolic end
728 CHAPTER 33 I innate Host Resistance
products (e.g., uric acid, fatty acids, mucin, enzymes). Portions of Antimicrobial peptides kill target cells through diverse mecha
the kidney are so hypertonic that few organisms can survive there. nisms after interacting with their membranes. Two major types of
In males, the anatomical length of the urethra (20 em) provides a antimicrobial peptides are cationic peptides and bacteriocins.
distance barrier that excludes microorganisms from the urinary
bladder. Conversely, the short urethra (5 em) in females is more Cationic Peptides
readily traversed by microorganisms; this explains why urinary
Humans produce three generic classes of cationic peptides whose
tract infections are 14 times more common in females than in males.
biological activity is related to their ability to damage bacterial
The vagina has another unique defense. Under the influence
plasma membranes. Most form pores or transient gaps, thereby
of estrogens, the vaginal epithelium produces increased amounts
altering membrane permeability, often leading to lysis.
of glycogen that acid-tolerant Lactobacillus acidophilus bacteria
The first group of cationic peptides includes linear, a-helical
degrade to form lactic acid. Normal vaginal secretions contain
peptides that lack cysteine amino acid residues. An important exam
up to 108 of these bacteria per milliliter. Thus an acidic environ
ple is cathelicidin. Cathelicidins are produced by a variety of cells
ment (pH 3-5) unfavorable to most other organisms is estab
(e.g., neutrophils, respiratory epithelial cells, and alveolar macro
lished. Cervical mucus also has some antibacterial activity.
phages), and substantial heterogeneity exists between cathelicidins
made by various cells. � Protein structure (appendix I)
Retrieve, Infer, Apply A second group, the defensins, are peptides that are rich
1. Why is the skin such a good first line of defense against pathogenic in arginine and cysteine, and are thus disulfide linked. Two
microorganisms? types of defensins have been reported in humans-a and [3. a
2. How do intact mucous membranes resist microbial invasion of the host? defensins, tend to be slightly smaller than [3 defensins and are
3. Describe the different antimicrobial defense mechanisms that operate found in the granules of neutrophils, intestinal Paneth cells
within the respiratory, gastrointestinal, and genitourinary systems of (these defensins are called cryptidins), and intestinal and re
mammals. How do they protect against pathogenic microorganisms? spiratory epithelial cells, where they assist in bacterial degra
dation. [3 defensins are typically found in epithelial cells and
are known to stimulate mast cell degranulation (p. 737).
A third group contains larger peptides that exhibit regular
33.3 Chemical Mediators
structural repeats. Histatin, one such peptide isolated from hu
in Innate Resistance man saliva, has antifungal activity. It translocates to the fungal
cytoplasm, where it targets mitochondria.
After reading this section, you should be able to:
Other natural antimicrobial products called chemokines
• Discuss host mediators that have antimicrobial actions include fragments from (1) histone proteins, (2) lactoferrin,
• Describe in general terms the activation of the host complement and (3) immune mediators that recruit cells to specific loca
system and its three outcomes tions. A number of antibacterial peptides are produced by bac
• List the three categories of cytokines and discuss their major functions teria as well. The most notable of these are the bacteriocins, as
• Correlate host protection from microbial invasion with specific mediators discussed next.