Innate Host Resistance
Obesity is an epidemic, rapidly spreading across nations. Excess
Supersize Me!
bout one-third of the U.S. population is obese, with 60% considered
A overweight. This is a staggering statistic, and it has been increasing
steadily over the past SO years. Interestingly, obesity rates correlate to
diets high in saturated fats, as found in many fast food products. The fats
in foods are not the only problem, though. Increasing portion size has
added dramatically to the obesity issue. In many ways, the American diet
is supersized. These facts prompted a number of scientists to study the
impact of obesity on the immune system. Results of studies have provided
additional insight into the mechanisms by which the innate resistance
arm of the mammalian immune system functions.
Innate resistance is an elegant system of sensory and response
molecules that detect invasion by microorganisms. Capture of microbial
pieces and parts with pathogen-associated molecular patterns (PAMPs) by
toll-like and NOD-like receptors (TLRs and NLRs, respectively) triggers an
ancient gene activation response that upregulates the inflammatory
process. This response synthesizes chemical messengers (cytokines) that
alert the host to combat the alien invaders by recruiting an army of
proteins and cells. An equally elegant system has recently gained
attention whereby TLRs and NLRs detect and respond to host cell
damage. Called damage- or danger-associated molecular patterns
(DAMPs), these molecules are typically released from stressed or dying
host cells. Recognition of DAMPs stimulates cytokine expression to
facilitate cellular repair. Both systems activate the same inflammatory
process but usually with very different outcomes. In a series of revealing
papers, scientists from Tokyo to Boston studying obesity and its associ­
ated problems have pieced together the amazing story of how the
intricate system for the detection of PAMPs and DAMPs by TLRs and NLRs
is upset when we "supersize."
Originally thought to just be an energy reserve, visceral (belly) fat is a
specialized tissue composed of lipid-laden adipocytes (fat cells), preadipo­
cytes, phagocytes called macrophages, and other cells held in a web of
dietary fat, as often found in fast foods, is implicated in several
metabolic diseases. Of great interest is how fat cells produce
chemica/signals that control inflammatory processes.
extracellular matrix proteins. Normal adipocytes make pro- and anti­
inflammatory cytokines, striking a delicate balance between opposing
inflammatory functions to maintain homeostasis needed for tissue repair
and regeneration functions.
However, studies now show strong correlations between increasing
visceral adipose (obese conditions) and increased serum levels of
pro-inflammatory cytokines (adipokines). This is because saturated fatty
acids are recognized as DAMPs by visceral adipocytes and their associated
macrophages. One of the pro-inflammatory adipokines, interleukin (IL)-18,
and a macrophage marker of inflammation, (-reactive protein (CRP), are
especially increased in the obese. This has suggested that obesity is akin
to chronic inflammation. In fact, data demonstrate that pro-inflammatory
markers are increased in people with metabolic syndrome (a condition
recognized by high blood pressure, insulin resistance, and high choles­
terol leading to clogged arteries), and decreased in people with lean body
profiles and people who exercise regularly.
Adipocytes also make anti-inflammatory adipokines, including
adiponectin (an activator of glucose uptake and fatty acid oxidation in
muscle). Investigators have shown that adiponectin protects against
metabolic and cardiovascular disorders in leaner individuals.
All together, the data suggest that a low level of homeostatic
inflammation is maintained in normal adipose tissue, balancing
inflammatory mediators for tissue sustainability. However, shifting from
lean to obese conditions causes the visceral adipocytes along with
recruited macrophages and lymphocytes, to secrete pro-inflammatory
cytokines that alter the structure and function of the adipose tissue. This
promotes chronic and systemic, low-grade inflammation with severe
consequences for the cardiovascular system. Importantly, return to a
leaner mass and increasing exercise reverses the effect. Thus, under­
standing how tissue-specific inflammation is induced and regulated by
PAMPs and DAMPs offers insight into how human disease reflects
behavioral choices.
While microorganisms can certainly influence gene expression,
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
and other life forms, and provide an "appropriate" response to prevent
invasion by the foreign material. When microorganisms inhabit a
multicellular host, competition for resources at the cellular level occurs. In
this chapter, we explore the mechanisms by which mammals (principally
humans) express and use innate resistance factors to defend themselves
against invasion by foreign substances.
Readiness Check:
Based on what you have learned previously, you should be able to:
tl Explain basic eukaryotic cell biology (sections 5.1-5.7)
tl Diagram the flow of information in eukaryotes from DNA to protein
and regulation of this flow (sections 15.2-15.5)
33.1 Innate Resistance Overview
After reading this section, you should be able to:
• 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
To establish an infection, an invading microorganism must
first overcome many surface barriers, such as skin, degradative
enzymes, and mucus, that have either direct antimicrobial ac­
tivity or inhibit attachment of the microorganism to the host.
Because neither the surface of the skin nor the mucus-lined
body cavities are ideal environments for the vast majority of
microorganisms, most pathogens, or disease-causing micro­
organisms, must breach these barriers and reach underlying
tissues to cause disease. However, any microorganism that
penetrates these barriers encounters two levels of host de­
fenses: other innate resistance mechanisms and an adaptive
immune response.
Animals (including humans) are continuously exposed to
microorganisms that can cause disease. Fortunately animals are
equipped with an immune system that usually protects against
adverse consequences of this exposure. The immune system is
composed of widely distributed proteins, cells, tissues, and or­
gans that recognize foreign substances, including microorgan­
isms. Together they act to neutralize or destroy them, maintaining
host integrity.
Immunity
The term immunity (Latin immunis, free of burden) refers to the
general ability of a host to resist infection or disease. Immunology
is the science focused on immune responses to foreign sub­
stances and how these responses are used to resist infection. It
includes the distinction between "self" and "nonself" and all the
biological, chemical, physiological, metabolic, and physical as­
pects of the immune response. There are two fundamentally dif-
ferent yet complementary components of the mammalian immune
response. The first component arises by virtue of being a vertebrate
animal. Vertebrates have evolved to express unique features that
inherently protect against invasion by foreign substances. Some
of these features are physical and act as barriers. Other features
are chemical in nature and directly kill or inhibit invaders. Still
other features result when specialized cells recognize generic yet
highly conserved chemical motifs (expressed on bacteria, fungi,
and viruses) and initiate processes to engulf and degrade the
foreign substance. These features are collectively called the in­
nate resistance mechanisms. The second component of the
mammalian immune response is much more sophisticated, be­
ing directed by highly specialized cells that can respond to spe­
cific invaders through receptor-mediated capture events, be
programmed to "remember" their encounters with foreign sub­
stances, and amplify individual responses, recruiting other
components of the host immune system to eliminate or reduce the
threat posed by the invader.
The innate resistance mechanisms, also known as nonspe­
cific resistance and innate, nonspecific, or natural immunity, is
the first line of defense against any foreign material, including mi­
croorganisms, encountered by the host. It includes general mecha­
nisms inherited as part of the innate structure and function of each
animal (such as skin, mucus, and constitutively produced antimi­
crobial chemicals such as lysozyme). Innate resistance mechanisms
defend against foreign invaders equally and to the same maximal
extent each time a foreign invader is encountered.
In contrast, the adaptive immune response, also known
as acquired or specific immunity, defends against a particu­
lar foreign agent. The effectiveness of adaptive immune re­
sponses increases on repeated exposure to foreign agents such
as viruses, bacteria, or toxins; that is to say, adaptive responses
have "memory." Substances recognized as foreign that pro­
voke immune responses are called immunogens (immunity
generators) or, more frequently, antigens. The presence of for­
eign antigens causes specific cells to replicate and manufac­
ture a variety of proteins that function to protect the host. One
such cell, the B cell, produces and secretes glycoproteins called
antibodies. Antibodies bind to specific antigens and inacti­
vate them or contribute to their elimination. Other immune
cells become activated to destroy host cells harboring intracel­
lular pathogens, such as viruses. Innate resistance mecha­
nisms and the adaptive immune responses work together to
eliminate pathogenic microorganisms and other foreign
materials.
The distinction between innate and adaptive systems is, to a
degree, artificial. Although innate systems predominate imme­
diately upon initial exposure to foreign substances, multiple
bridges occur between the two immune system components
(figure 33.1). Importantly, a variety of cells function in both in­
nate and adaptive immunity. These cells are known as the white
blood cells, or leukocytes. Blood cell development occurs in the
bone marrow of mammals during the process of hematopoie­
sis. Leukocytes function in the innate system, whereas others
are part of a specific immune response. Some are important
 33.2 Physical and Mechanical Barrier Defenses of Innate Resistance 725

because they link the innate arm of Host Defenses

the immune system to the adaptive.
The leukocytes form the basis for im­
Innate and nonspecific Acquired and specific
mune responses to invading mi­
crobes and foreign substances. Many
of these cells reside in specialized
tissues and organs. Some tissues and
organs provide supportive functions
in nurturing the cells so that they
can mature and respond correctly to
antigens.
The bridges that interconnect the
innate and adaptive immune re­
sponses are numerous and present Skin Defensins
Tcells
Mucous Lysozyme
challenges for anyone studying immu­ B cells
membranes Complement
nology. However, the amazing com­
plexity of the mammalian immune
system and its capacity to prevent in-
fection from the billions of microor-
Opsonization
ganisms encountered every day drive
numerous "how" questions, whose
answers we explore in this chapter. We Resident
responders
begin our discussion with an intro-
duction to the physical and chemical
...._------------: Inflammation
barriers that microbes face upon en­
counter with a host. We then present
the various cells, tissues, and organs of Cell
innate defenses, discussing the mech- cooperation

anism by which they detect and re­

Figure 33.1 Some Major Components of the Mammalian Immune System. Double-headed arrows
spond to foreign invaders. In this
indicate potential bridging events that unite innate and acquired forms of immunity.
discussion, reference is made to pro­
cesses and chemicals that are de-
scribed in detail either later in this chapter or in chapter 34 With few exceptions, a potential microbial pathogen invading a
(adaptive defenses). Chapter 34 also explains the mechanisms by human host immediately confronts a vast array of innate defense
which the adaptive immune response functions and how it can mechanisms (figure 33.2). Although the effectiveness of an indi­
sometimes go astray. To help you navigate this information, vidual mechanism may not be great, collectively they are formida­
cross-references to the detailed discussion are provided. ble. Many direct factors (nutrition, physiology, fever, age, genetics)
and equally as many indirect factors (personal hygiene, socioeco­

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

Sebaceous continuously, removing microorganisms that manage to adhere

glands (fatty
to their surface. The skin is slightly acidic (around pH 5 to 6) due
acids)
to sebum, secretions from sweat glands, and organic acids pro­
duced by commensal staphylococci. It also contains a high con­
centration of sodium chloride and is subject to periodic drying.
Mucus----�

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

Urination reactive oxygen species that is toxic to many microorganisms.

I.,_. Peptidoglycan structure (section 3.4); Oxygen concentra­
Figure 33.2 Host Defenses. Some nonspecific host defense tion (section 7.3)
mechanisms that help prevent entry of microorganisms into the host's tissues.

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
the kidney are so hypertonic that few organisms can survive there.
In males, the anatomical length of the urethra (20 em) provides a
distance barrier that excludes microorganisms from the urinary
bladder. Conversely, the short urethra (5 em) in females is more
readily traversed by microorganisms; this explains why urinary
tract infections are 14 times more common in females than in males.
The vagina has another unique defense. Under the influence
of estrogens, the vaginal epithelium produces increased amounts
of glycogen that acid-tolerant Lactobacillus acidophilus bacteria
degrade to form lactic acid. Normal vaginal secretions contain
up to 108 of these bacteria per milliliter. Thus an acidic environ­
ment (pH 3-5) unfavorable to most other organisms is estab­
lished. Cervical mucus also has some antibacterial activity.
Retrieve, Infer, Apply
1. Why is the skin such a good first line of defense against pathogenic
microorganisms?
2. How do intact mucous membranes resist microbial invasion of the host?
3. Describe the different antimicrobial defense mechanisms that operate
within the respiratory, gastrointestinal, and genitourinary systems of
mammals. How do they protect against pathogenic microorganisms?
33.3 Chemical Mediators
in Innate Resistance
After reading this section, you should be able to:
• 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
Mammalian hosts have a chemical arsenal with which to combat
the continuous onslaught of microorganisms. Some of these
chemicals (gastric juices, salivary glycoproteins, lysozyme, oleic
acid on the skin, urea) have already been discussed with respect
to the specific body sites they protect. In addition, blood, lymph,
and other body fluids contain a potpourri of antimicrobial chem­
icals such as defensins and other polypeptides. Importantly, the
normal microbiota also assist in host resistance by contributing
their own chemicals to fend off competitors. How chemical de­
fenses protect the host is the next topic.
Antimicrobial Peptides
Antimicrobial peptides are low molecular weight proteins that
exhibit broad-spectrum antimicrobial activity toward bacteria,
viruses, and fungi. They are evolutionarily conserved and many
are positively charged, thereby electrostatically attracted to mi­
crobial cell surfaces. Antimicrobial peptides are amphipathic;
that is, they have hydrophobic and hydrophilic components so
they are soluble in both aqueous and lipid-rich environments.
Antimicrobial peptides kill target cells through diverse mecha­
nisms after interacting with their membranes. Two major types of
antimicrobial peptides are cationic peptides and bacteriocins.
Cationic Peptides
Humans produce three generic classes of cationic peptides whose
biological activity is related to their ability to damage bacterial
plasma membranes. Most form pores or transient gaps, thereby
altering membrane permeability, often leading to lysis.
The first group of cationic peptides includes linear, a-helical
peptides that lack cysteine amino acid residues. An important exam­
ple is cathelicidin. Cathelicidins are produced by a variety of cells
(e.g., neutrophils, respiratory epithelial cells, and alveolar macro­
phages), and substantial heterogeneity exists between cathelicidins
made by various cells. � Protein structure (appendix I)
A second group, the defensins, are peptides that are rich
in arginine and cysteine, and are thus disulfide linked. Two
types of defensins have been reported in humans-a and [3. a
defensins, tend to be slightly smaller than [3 defensins and are
found in the granules of neutrophils, intestinal Paneth cells
(these defensins are called cryptidins), and intestinal and re­
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
structural repeats. Histatin, one such peptide isolated from hu­
man saliva, has antifungal activity. It translocates to the fungal
cytoplasm, where it targets mitochondria.
Other natural antimicrobial products called chemokines
include fragments from (1) histone proteins, (2) lactoferrin,
and (3) immune mediators that recruit cells to specific loca­
tions. A number of antibacterial peptides are produced by bac­
teria as well. The most notable of these are the bacteriocins, as
discussed next.
Bacteriocins
Many of the normal bacterial microbiota release toxic proteins
called bacteriocins that are lethal to other strains of the same spe­
cies as well as other closely related bacteria. Bacteriocins are pep­
tides that may give their producers, which are naturally immune
to their bacteriocins, an adaptive advantage against other bacte­
ria. Ironically, they sometimes increase bacterial virulence by
damaging host cells such as mononuclear phagocytes. Bacterio­
cins are produced by Gram-negative and Gram-positive bacteria.
For example, Escherichia coli synthesizes bacteriocins called coli­
cins, which are encoded by genes on several different Col plas­
mids (see table 3.3). Some colicins bind to specific receptors on
the cell envelope of sensitive target bacteria and cause cell lysis,
attack specific intracellular sites such as ribosomes, or disrupt
energy production. Other examples include the !antibiotics pro­
duced by genera such as Streptococcus, Bacillus, Lactococcus, and
Staphylococcus. These antimicrobial peptides act as defensive ef­
fector molecules protecting the bacterial flora and its human
host. 1-+11 Normal microbiota of the human body (section 32.3)

Complement
Complement refers to a collection of over 30 heat-labile proteins
found in human blood plasma. The proteins act in a cascading
fashion to lyse cell membranes, augment phagocytosis, and pro­
duce inflammatory peptides. These activities were said to "com­
plement" the other antibacterial activities of the host; hence the
name complement. The complement system is complex and has
a somewhat confusing nomenclature. However, we will examine
each process before considering the complete mechanisms of ac­
tion. Complement activation can be initiated by three different
signals, but all three lead to a common final pathway that
(1) defends against bacterial infections by facilitating and
enhancing phagocytosis, chemotaxis, activation of leukocytes,
and lysis of bacteria; (2) bridges innate and specific immune
functions by enhancing antibody responses and immunologic
memory; and (3) disposes of wastes such as dead host cells and
immune complexes, the products of inflammatory injury.
Opsonization (Greek opson, to prepare victims for) is a pro­
cess in which microorganisms or inanimate particles are coated
by serum components, thereby preparing them for recognition
and ingestion by phagocytic cells. Complement proteins func­
tion as opsonins and act as a connector between the microor­
ganism and the phagocyte. They connect the surface of the
microorganism to specific receptors on the phagocyte surface at
the other end (figure 33.6).
Degree of
Phagocytic cell Opsonin
binding
+
Antibody
(a}
++ Complement
C3b
(b)
Antibody and
++++
complement
C3b
(c)
Figure 33.6 Opsonization. (a) The intrinsic ability of a phagocyte to
bind to a microorganism is enhanced if the microorganism elicits the formation
of antibodies (Ab) that act as a bridge to attach the microorganism to the Fe
antibody receptor on the phagocytic cell. (b) If the activated complement
(C3b) is bound to the microbe, the degree of binding is further increased by
the C3b receptor. (c) If both antibody and C3b opsonize, binding is maximal.
33.3 Chemical Mediators in Innate Resistance 729
In addition to functioning in opsonization, some complement
proteins are strong chemotactic signals that recruit phagocytes to
the site of their activation. Still other complement proteins punc­
ture cell membranes to cause lysis. Interestingly, one of the several
triggers that can activate the complement process is the recognition
of specific antibody on a target cell. All together, the complement
activities unite the innate and adaptive arms of the immune system
to assist in the killing and removal of invading pathogens.
Complement Activation
Complement proteins are produced in an inactive form; they be­
come active following enzymatic cleavage. There are three path­
ways of complement activation: the alternative, lectin, and classical
pathways (figure 33.7). Although each pathway employs similar
mechanisms, specific proteins are unique to the first part of each
pathway (table 33.1). Each complement pathway is activated in a
cascade fashion: the activation of one component results in the ac­
tivation of the next. Thus complement proteins are poised for im­
mediate activity when the host is challenged by an infectious agent.
The alternative complement pathway (figure 33.7) is
thought to have evolved first; its activation is triggered by a
diverse group of molecules. The alternative pathway is initiated
in response to bacterial and some fungal molecules with re­
petitive structures, such as the lipopolysaccharide (LPS) from
Gram-negative bacteria. LPS activates complement (C) protein
3 (C3), causing it to cleave into fragments C3a and C3b. C3b
becomes stable when it binds to LPS, and once bound, C3b acts
as an opsonin and assists in bacterial capture by phagocytes
that have receptors for C3b (figure 33.6). Next a protein in
blood termed Factor B adsorbs to bound C3b and is cleaved
into two fragments by another protein, Factor D, leading to the
formation of active enzyme C3bBb (the bar indicates an acti­
vated enzyme complex). This complex is called the C3 conver­
tase of the alternative pathway because it cleaves more C3 to
C3a and C3b, thereby increasing the rate at which C3 is con­
verted and the amount of C3b coating the microbial structure.
The lectin complement pathway (also called the mannose­
binding lectin pathway) also begins with the activation of C3 con­
vertase. However, in this case, a lectin-a protein that binds to
specific carbohydrates-initiates the proteolytic cascade. A lectin
of major importance is mannose-binding protein (MBP). This
protein is produced when macrophages ingest viruses, bacteria,
or other foreign material. MBP, as its name implies, binds man­
nose, a sugar that is a major component of bacterial cell walls,
some virus envelopes, and antigen-antibody complexes. MBP en­
hances phagocytosis and is therefore an opsonin. MBP forms a
complex with another blood protein known as mannose-binding
lectin-associated serine protease (MASP). When the MBP com­
ponent of the complex binds to mannose on pathogens, the
MASP is activated. MASP cleaves the C4 and C2 complement
proteins, also circulating in the blood, to produce a C3 conver­
tase. The C3 convertase is the same as that used in the classical
complement pathway, discussed next.
Activation of the classical complement pathway is more lim­
ited; it can occur in response to a few microbial products (e.g., lipid A,