Section B HOST defense mechanisms

4
Innate (General or Nonspecific) Host
Defense Mechanisms
CARL W. DIEFFENBACH | EDMUND C. TRAMONT | SUSAN F. PLAEGER

Host defense mechanisms against microbial invasion are a contin- family is conserved in all species from plants to humans and performs
uum. An invading microbe first encounters the physical barrier—the similar functions for all multicellular creatures.7 The detection and
skin, mucous membranes, and nonspecific antimicrobial peptides or triggering of a response to fungal, bacterial, and viral products has
proteins. If infection progresses, the next hurdle are the pattern rec- been preserved throughout evolution and is referred to as the innate
ognition receptors (PRRs) that bind specific structural signatures immune system. The major gene family associated with innate immu-
common to bacteria, viruses, and fungi and trigger immune mediators, nity is called the TLR gene family.7,8 There are additional families of
such as cytokines and chemokines. This initial engagement between receptors that are important in innate immunity—the Nod-like recep-
the host and pathogen is termed the innate immune system. It provides tor family (NLR),9 C-type lectin-like receptor family (CLR),10,11 and
immediate defense against an infection and must be breached for an retinoic acid–inducible gene I–like receptor (RIG-I).12
infection to occur (Table 4-1).1 Even if breached, the innate immune
response has an essential role in focusing and directing the microbial-
specific long-lasting immune memory of the adaptive immune system Tissue Tropisms and
(see Chapters 6 through 9).
The general nonspecific and innate host defense mechanisms repre-
Hereditary Factors
sent an effective, broad-based surveillance program that serves as a The susceptibility, morbidity, and mortality related to almost every
transitional defense system, holding a foreign invader at bay while pathogen and to infection in general are influenced significantly by the
setting the stage for the host to develop specific adaptive immunity. host’s genetic makeup. If a child’s parent died from an infectious
These mechanisms provide crucial initial encounters against all micro- disease, such as pneumonia, the child has increased probability of
organisms. The broad nature of the nonspecific and innate host defense dying from an infection (Fig. 4-1).13 The reasons for this increased
mechanisms includes the general nonspecific effects resulting from susceptibility are multifactorial and include genetic polymorphisms
physical barriers (e.g., intact skin, mucous membranes, microbicidal and defects in innate immunity, such as a Toll receptor gene,14-18 com-
peptides, mucus, biofilm, cilia, peristalsis, resident microflora, lyso- plement,19,20 cytokine and chemokines or their receptors,21-24 degrees
zyme, complement). As a pathogen circumvents the general nonspe- of limited human leukocyte antigen (HLA) diversity,25,26 and cellular
cific defenses, the invading organism is detected or sensed by the host, receptor specificities.27,28 Other factors undoubtedly will be determined
resulting in the activation of many cell types and synthesis and release in the future.29
of a range of factors, including biochemical factors that are cidal to the The microbial ligand and the host receptor vary independently as
incoming microorganism (Table 4-2),2-4 as well as a range of cytokines to their specificity. A receptor may bind to one or many different
and chemokines, which classically have been described as the acute- ligands on microorganisms, and a ligand may bind to one or many
phase response. Newer terminology has replaced the acute-phase different receptors. Most organisms preferentially colonize certain cells
response term with the initial inflammatory response. Either way, these (tissues) and spare others. This phenomenon, referred to as cellular
terms describe a range of nonspecific antimicrobial host factors that tropism or tissue tropism, is a crucial determinant of host-microor-
promote phagocytosis, microbial killing, and immune activation, ganism relationships. For example, influenza virus and mycoplasmas
which help focus the adaptive immune response. The inflammatory preferentially adhere to respiratory epithelial cells, Escherichia coli and
response factors are produced mainly in the liver as a result of detection Vibrio cholerae to intestinal cells, and Streptococcus mutans to tooth
and triggering of the innate immune system. Although many of these enamel. Gram-positive organisms more readily attach to heart valves
inflammatory response proteins are always present, it is their rapid than gram-negative organisms. Also, urinary epithelial cells from
quantitative increase that constitutes the inflammatory reaction or persons with recurrent urinary tract infections support the attachment
response. Clinically, this results in fever and malaise that typically of urinary pathogens more readily than urinary epithelial cells obtained
accompany the early phases of infection and represents, in broad terms, from those not prone to develop these infections.30 A specific example
the events that occur during infection before the establishment or of cellular tropism is the human immunodeficiency virus 1 (HIV-1),
boosting of the specific adaptive immune response. Traditionally, the which requires the presence of certain chemokine receptors, especially
factors that have correlated with the inflammatory response include (1) CCR5 or CXCR4, in conjunction with the CD4 molecule, to infect the
trigger molecules, which constitute signal systems that invoke the adap- host cell (see Chapter 120).
tive immune system, and (2) effector molecules, which are involved in Receptors on host cells may change. Evidence suggests that a viral
inflammation, antimicrobial scavenging, and killing (see Table 4-2). illness can affect tissue tropisms of the oropharynx and tracheobron-
Insights into how the host senses an invader and what microbial chial tree to allow easier colonization by bacteria.31 For example, the
components the host detects have come from many unexpected direc- cause of most of the deaths associated with the 1918 influenza pan-
tions.5 Through many elegant experiments, investigators have shown demic appeared not to be influenza directly; rather, death was caused
that a set of genes known as the Toll gene family is involved in embry- by secondary bacterial pneumonia.32,33 Some investigators believe that
onic development and antifungal responses in fruit flies. The impor- the cause of death was acute influenza and the virally triggered “cyto-
tance of this discovery was appreciated fully with the identification of kine storm,” an overwhelming inflammatory response to the influenza
the lipopolysaccharide (LPS) receptor as a Toll-like receptor (TLR) virus.34 As the genetics and cellular characteristics of cellular and tissue
gene.6 This provided the direct evidence that the TLR genes are respon- tropisms become better elucidated, they will offer a new paradigm for
sible for sensing and triggering the initial response. The Toll gene the development of treatment modalities and vaccines.
37
38 Part I Basic Principles in the Diagnosis and Management of Infectious Diseases

TABLE
4-1 Nonspecific, Innate, and Adaptive Immunity

Property Nonspecific Innate Adaptive

Receptors None Fixed in genome Encoded in gene segments
Rearrangement not necessary Rearrangement required
Distribution Covers every interface with the environment Cell type or tissue specific Clonal
Recognition None, limited Conserved molecular patterns Details of molecular structure
Action time Continuous Immediate activation of effectors Delayed activation
Response Shield holds, provided no breaks in the barrier Costimulatory molecules, apoptosis pathways, cytokines, Clonal expansion or anergy
chemokines
Initial inflammatory response proteins, defensins Initial inflammatory response proteins Effector cytokines, humoral,
cell-mediated immunity
Adapted from Janeway CA, Medzhitov R. Innate immune recognition. Annu Rev Immunol. 2002;20:197-216.

Infectious diseases represent one of the strongest and most impor- Other known linkages include HLA-B27 and reactive arthropathy
tant selection pressures in human evolution (see Chapter 5). Tuber- (Reiter’s syndrome), HLA-DR4 and chronic Lyme arthritis, the pre-
culosis, measles, and smallpox had devastating effects on the native disposition of persons with blood group O to cholera, which presum-
populations of North and South America, presumably because there ably is linked to the expression of glycosphingolipids in the small bowel
was no selective pressure on the indigenous populations to evolve mucosa, DRB1*01 and DRB1*04 with symptomatic parvovirus B19
natural immunity against these pathogens before being exposed infection,53 HLA-CW*0202 with human papillomavirus–induced cer-
through contact with the more urbanized Europeans. Conversely, the vical cancer,54 and various polymorphisms with clearance and persis-
sickle cell trait has a protective effect against falciparum malaria, which tence of cervical human papillomavirus infection,55 tuberculoid
benefits inhabitants of areas where this parasite is endemic. Persons leprosy, acute glomerulonephritis, paralytic poliomyelitis, meningo-
homozygous for a mutation in the gene that codes for the CCR5 coccal disease,56 and Dengue hemorrhagic fever.57 Infections also can
chemokine receptor (Δ32CCR5) are resistant to contracting HIV-1 affect the susceptibility to allergic and autoimmune diseases. Solid
through sexual contact.35 Persons of Northern European origin are epidemiologic data have suggested that the increase in the incidence
more likely to carry this deletion than Africans and Asians, who almost of these diseases in industrialized countries is a consequence of
never carry it.35 A number of genetic changes have been correlated with decreased incidence of infectious diseases.58 In summary, the outcome
slow or nonprogression to acquired immunodeficiency syndrome of almost every microbial-host interaction is linked to host genetics.
(AIDS), including heterozygosity for Δ32CCR5 or other chemokine
polymorphisms, increased secretion of α-defensins, changes in HLA-
B*35 subtypes, and upregulation of CD91, the heat-shock protein Natural Physical Barriers to the Entry
receptor.36-41 Although resistance to HIV-1 infection also has been
linked to class II HLA-DRB3 discordance, this is more likely the result
of Microorganisms into the Body
of a chance encounter with discordant HLA antigens integrated into The morphologic integrity of body surfaces is an important and effec-
the HIV to which the recipient host is exposed.42 Severity of and sus- tive first line of defense. The epithelial coverings and linings share
ceptibility to tuberculosis have been linked to variations in the SLS11A1 many similar properties, such as production of defensins,59,60 catheli-
gene (formerly known as the NRAMP1 gene), an HLA-DQ allele, and cidins,61 and populations of γδ cells62,63 and unique defense molecules,
interleukin (IL)-12 deficiency and TLR8 polymorphisms (S, T, U).43-50 such as lysozyme.64,65 Although we have these nonspecific barriers, we
Susceptibility to pneumococcal disease has been linked to defective have also come to appreciate the vast nature of the microbe communi-
production of antibody to the pneumococcal capsule.51 The congenital ties that colonize each of us. On a per cell basis, we are more bacterial
absence of a terminal component of complement predisposes to than human.66
repeated episodes of disseminated neisserial infections, and genetic
polymorphism of the binding domain of surfactant-A2 binding
SKIN
increases the susceptibility to Neisseria meningitidis dissemination (see
Chapters 7 and 211).52 The intact skin forms an effective mechanical barrier to invasion by
microorganisms partly because it is composed of tightly associated
epithelial cells covered by a highly cross-linked keratin layer. As noted,
0.15
Probability of dying with infection

the skin possesses an array of antimicrobial properties that form a

protective shield consisting of a battery of broad-spectrum defensive
chemicals, principally peptides, synthesized as precursors and proc­
0.10 essed by specific proteases into mature active forms that target micro-
Parent dead bial membranes in a manner similar to disinfectants. These help keep
pathogenic organisms out and the normal flora are also checked by
these functions. The antimicrobial peptides include cathelicidins,
0.05 β-defensins, and dermicidin.3,60,61,67-70 Not only do they function
directly to kill microbes, they also act as chemokines to attract migrat-
Parents alive ing phagocytic cells. β-defensin, LL-37, cathelicidin levels, and hexa-
decenoic acid are depressed in atopic skin, a condition in which
0.00 microbial suprainfection is common.71,72
20 30 40 50 60 The relative dryness or desiccating effect of skin, its mild acidity (the
Age (years) so-called acid mantle, pH 5 to 6), and the normal skin flora act in
Figure 4-1 Probability of dying from an infection before a given concert to form an effective prohibitive environment. Inflamed skin is
age for adoptees with at least one biologic parent who died before more permeable to water and is more hospitable to colonization. It
age 50 (parent dead) of an infection versus adoptees whose bio- has been speculated that oily skin may retard evaporation of water,
logic parents were alive at that age (parents alive). resulting in increased numbers of colonizing microorganisms. The
 4 Innate (General or Nonspecific) Host Defense Mechanisms 39

TABLE
4-2 Excreted Antimicrobial Peptides (ADPs) and Proteins

ADP/Protein Cellular Source Special Characteristics

α-Defensins
HNP1-HNP4 Neutrophils, eosinophils Broad spectrum of antimicrobial activity; chemoattracts monocytes, T cells, dendritic
cells; inhibition of complement activation; activation of mast cells
HD-5–HD-6 Intestinal tract, HD-5 (female reproductive tract) Released as propeptide by Paneth cells
β-Defensins
hBD-1 Keratinocytes, airway epithelia, urogenital tract Antimicrobial activity compared with other β-defensins
hBD-2 Keratinocytes, airway epithelia, intestinal tract Mainly active against gram-negative bacteria and fungi; chemoattracts dendritic cells,
T cells, neutrophils, mast cells
hBD-3 Keratinocytes, airway epithelia Potent broad spectrum of antimicrobial activity
hBD-4 Airway epithelia, keratinocytes (mRNA) Potent activity against Pseudomonas aeruginosa, less activity against Escherichia coli
and gram-positive bacteria
hBD-6 (propeptide) Epididymis, testis, airway epithelia E. coli
hBD-18 Epididymis, testis, sperm, pancreas E. coli
hBD-28 Epididymis, testis Antimicrobial activity
Cathelicidin LL-37 Leukocytes, airway epithelia, urogenital tract, Antimicrobial activity, immunomodulatory functions
keratinocytes
Ribonucleases
Eosinophil cationic Eosinophils Antibacterial and antiviral activity
protein (ECP)
Eosinophil-derived Eosinophils Antiviral activity, chemoattracts and activates dendritic cells
neurotoxin (EDN)
Angiogenin (RNase5) Leukocytes, epithelial cells, fibroblasts Antimicrobial activity and angiogenic activity
RNase7 Keratinocytes, airway epithelia Antimicrobial activity
RNase8 Placenta Antimicrobial activity
S-100 proteins
Psoriasin (S100A7) Keratinocytes, airway epithelia, urogenital tract Potent antibacterial activity against E. coli
Calprotein (S100A8/A9) Leukocytes, skin Active at high concentrations against Candida albicans
Calcitermin (S100A12) Airway secretions Active against gram-negative bacteria
Complement Hepatocytes (Blood) Microbial lysis, chemotaxis, immunomodulatory functions, immune clearance
Mannose-binding lectin/ Liver Binds to carbohydrates on the surface of viruses, bacteria, fungi, protozoa to activate
protein (MBL/MBP) the complement system or act directly as an opsonin
Fibronectin Hepatocytes (Blood) Blocks the attachment of many microorganisms, especially P. aeruginosa
Histatins Salivary gland exocrine cells Antifungal activity
Lactoferrin/lactoferricin Neutrophils, body fluids Inhibits bacterial growth by its ability to sequester iron; toxic to several viruses
Bactericidal/permeability- Neutrophils, epithelial cells Active against gram-negative bacteria, neutralizes LPS
increasing protein (BPI)
Dermcidin (DCD-1) Sweat glands Anionic peptide, exclusively produced by human eccrine sweat glands
Antileukoprotease (ALP) Keratinocytes, airway epithelia, gut, body fluids Broad-spectrum antimicrobial activity; inhibits various proteinases (e.g., elastase,
cathepsin G, trypsin); contributes to anti-HIV effect of saliva
Cryopyrin Macrophages, neutrophils Antimicrobial activity
Lysozyme Skin, airway epithelia, body fluids, tears Broad antibacterial activity by degrading peptidoglycans
Elafin Neutrophils, epithelial cells Weak antimicrobial activity
Phospholipase A2 (PLA2) Neutrophils, macrophages, Paneth cells, tears Antimicrobial activity, especially against gram-positive bacteria
Peptidoglycan recognition Neutrophils, various epithelial cells Antimicrobial activity, especially against gram-positive bacteria
proteins
Neutrophil gelatinase- Neutrophils, various epithelial cells Antimicrobial activity through its ability to bind bacterial ferric siderophores
associated lipocalin
(NGAL)
Hepcidin Liver Mainly acts as an iron-regulatory hormone (limits iron availability to invading
microorganisms)
Surfactant proteins Mucosal surfaces Antimicrobial activity
Granulysin Cytolytic T cells, natural killer cells Antimicrobial activity
Histones Neutrophils, gut, placenta Bactericidal activity, LPS-neutralizing activity
Adrenomedullin Epithelial cells, sweat and sebaceous glands, Antimicrobial activity
body fluids
Azurocidin (CAP37) Neutrophils Mainly against gram-negative bacteria, increases vascular permeability, binds to
endotoxin, attracts monocytes
Cathepsin G Neutrophils Proteolytic-independent antibacterial activity
Proteinase 3 Neutrophils Active against bacteria and fungi
Platelet-derived AMPs Platelets Seven AMPs have been isolated from platelets
Chemokines Many cell types Many chemokines have antimicrobial activity
Human epididymis 2 Epididymal Family of sperm-binding proteins with antimicrobial activity
(HE2) family
Dermcidin Skin eccrine sweat glands Antimicrobial activities, keratinocyte activation
Tamm-Horsfall protein Kidney Binds microbes
AMP, adenosine monophosphate; LPS, lipopolysaccharide.
Adapted from Harder J, Glaser R, Schroder JM. Human antimicrobial proteins—effectors of innate immunity. J Endotox Res. 2007;13:317-338; Ganz T. Defensins: Antimicrobial
peptides of innate immunity. Nat Rev Immunol. 2003;3:710-720; Chen H, Zhiman X, Peng L, et al. Recent advances in the research and development of human defensins. Peptide.
2006;27:931-940; and Pazigier M, Hoover DM, Yang D, et al. Human β-defensins. Cell Mol Life Sci. 2006;63:1294-1313.
40 Part I Basic Principles in the Diagnosis and Management of Infectious Diseases

acidity of the skin results from the breakdown of lipids into fatty acids. an extended period. Their effectiveness is decreased by air pollutants
Sebum contains few esterified fatty acids, but the normal skin flora (such as cigarette smoke), mechanical respirators, tracheostomy, con-
partially hydrolyzes the triglycerides, liberating fatty acids. The con- comitant infection, allergenic agents, and, in some cases genetic defects
tinual desquamation of skin scales also aids in the elimination of (e.g., cystic fibrosis) and inhibitory factors of some pathogens.88
microorganisms. Because few organisms have the ability to penetrate
the skin, they usually gain access by some physical means, such as an
INTESTINAL TRACT
arthropod vector, trauma, surgical incision, or IV catheter.
The acid pH of the stomach and the antibacterial effect of the various
pancreatic enzymes, bile, and intestinal secretions are effective, non-
MUCOUS MEMBRANES
specific, antimicrobial defense factors. Paneth cells of the small intes-
Because of the inherent moisture with which they are associated, tine, located in the crypts of Lieberkühn, secrete antimicrobial
mucous membranes support a broader spectrum and larger number substances, such as β-defensins, lysozyme, and type II phospholipase
of microorganisms than does skin. Most epithelial cells possess the A.3,89 As with other mucosal surfaces, the intestinal tract expresses
same peptide shield as skin3,73,74 (see Table 4-2), however, body microbial pattern recognition receptors on a number of cell types.90
secretions, including saliva, cervical mucus, prostatic fluid, Understanding how these components work to exclude pathogens
and tears, are endowed with unique antimicrobial properties. Two while maintaining commensal species is important for maintaining the
of the more potent antimicrobial substances are lysozyme and N- health of the gut. Microbial colonization in germ-free mice triggers the
acetylmuramyl-l-alanine amidase (NAMLAA). Both substances are expression of a secreted C-type lectin with known antibacterial proper-
particularly effective against gram-positive bacteria because they ties. The protein in humans, HIP/PAP,91 represents a form of innate
hydrolyze the amino acid backbone of peptidoglycan.64 response to help maintain a symbiotic relationship.92 Peristalsis and
Local secretions also contain immunoglobulins, principally IgG and the normal loss of epithelial cells also act to purge the intestinal tract
secretory IgA, which act primarily to agglutinate microorganisms, of harmful microorganisms. Alteration of these parameters can lead to
block the attachment of organisms to receptors on host cells competi- increased susceptibility of the host to infection. For example, Salmo-
tively, or both. The body produces more secretory IgA than total IgG. nella and Mycobacterium tuberculosis (Mtb) infections are more
The IgA immunoglobulin is made relatively resistant to proteolysis by common in achlorhydric patients, and slowing peristalsis with bella-
complexing with a unique polypeptide known as secretory piece and donna or opium alkaloids prolongs symptomatic disease caused by
protein, Fv.75 There is also evidence that mucosal IgA can bind intra- gastrointestinal pathogens such as Shigella species. A number of disease
cellular pathogens or products as they are transported through the states have been shown to be accompanied by the movement, or trans-
cell.76 location, of gram-negative bacterial products across the epithelial
Mucosal secretions also contain significant amounts of iron-binding barrier and into the circulation.93 This is often accompanied by a loss
proteins. Iron is a critical element for most microorganisms and fluids of tight junctions between enterocytes or the loss of enterocytes all
that potentially are exposed to microbes are enriched with iron- together. This may be tied to loss or impairment of a subset of T cells,
binding proteins that act to keep this important factor from the Th17 cells, which secrete the enterocyte growth factor cytokine Th17.94
microorganisms. In contrast, microorganisms that routinely colonize The normal bowel microbial flora compete for nutrients (1012
skin and mucosal surfaces have evolved mechanisms to acquire iron, organisms/g of feces), and this plays a crucial protective role. Altering
despite these proteins.77,78 this symbiotic normal intestinal microflora, such as with broad-spec-
trum antibiotics, can lead to overgrowth of inherently pathogenic
organisms (e.g., Salmonella typhimurium) or suprainfection with ordi-
RESPIRATORY TRACT
narily commensal organisms (e.g., Candida albicans). As always, the
The respiratory tract has a formidable array of antimicrobial defense interfering competitive capacity of the normal flora can be overcome
mechanisms.79,80 The inhaled particles must survive and penetrate the by the introduction of large numbers of pathogenic organisms. The
aerodynamic filtration system of the upper airway and tracheobron- probability of development of salmonellosis is related directly to the
chial tree. The airflow in these areas is turbulent, causing large particles number of Salmonella organisms ingested. The exception to this is
to come in contact with the mucosal surfaces and face the full array of Shigella, which requires very few organisms to establish infection.
those defense mechanisms. Humidification also causes hygroscopic
organisms to increase in size, aiding trapping.
GENITOURINARY TRACT
When a particle is deposited, the mucociliary blanket transports the
invading offender away from the lung. Coughing aids this expulsion. Urine is normally sterile. The factors that contribute to the ability of
This system is amazingly efficient; 90% of deposited material is cleared the urinary tract to resist infection are complex. Urine is bactericidal
in less than 1 hour. In addition, the bronchial secretions contain for some strains of bacteria, mostly because of its pH, although factors
various antimicrobial substances, such as lysozyme, NAMLAA, and such as hypertonicity, urea, and other solutes play a role. Tamm-
β-defensins such as HBD-1 and HBD-2,81,82 RNase 7 and pulmonary Horsfall protein is a glycoprotein produced by the kidneys and excreted
lectins,83,84 and surfactant collectins.74,84,85 The airway epithelium also in large amounts in urine (approximately 50 mg/L). Because many
contributes to the resistance to infection. Upon exposure to pathogens, bacteria are avidly bound to it, the protein acts as a sponge and is a
lung epithelial cells express S100a, antileukoprotease,3 and large natural host defense mechanism against tissue colonization and sub-
amounts of major vault protein (MVP). In cells infected with Pseudo- sequent infection by preventing these bacteria from gaining a foothold
monas aeruginosa, MVP I localizes in lipid raft sections of cell mem- on the cellular lining of the urinary tract.95
branes and helps mediate bacterial clearance.86 The lower urinary tract is rinsed with urine four to eight times each
After a particle reaches the alveoli, physical expulsion becomes day, eliminating potential pathogenic organisms, unless they are
much less effective, and the alveolar macrophages and tissue histio- capable of firmly attaching to epithelial cells of the urinary tract (e.g.,
cytes play a more prominent role in protecting the host. These phago- Neisseria gonorrhoeae, certain strains of E. coli). Urinary retention or
cytic cells are assisted in their defense by the collectin surfactants SP-A lack of complete bladder emptying impedes this flushing process.
and SP-D, which bind to and opsonize diverse organisms, including The length of the male urethra (20 cm in an adult) also provides
gram-negative bacteria, fungi, and Pneumocystis jirovecii (formerly passive protection, and bacteria seldom gain access to the bladder in
known as P. carinii).87 men unless introduced by instrumentation. The female urethra is
Like all defense mechanisms, these nonspecific mechanisms can be much shorter (5 cm in an adult) and is traversed more readily by
overcome by the introduction of large numbers of invading organisms microorganisms, which is one reason why urinary tract infections are
(e.g., a contaminated respirator), particularly if the host is exposed for 14 times more common in women than in men.
 4 Innate (General or Nonspecific) Host Defense Mechanisms 41

The hypotonic state of the kidney medulla presents an unfavorable Mononuclear phagocytes in blood, lymph nodes, spleen, liver, bone
milieu for most microorganisms. This can be decreased by increased marrow, and lung constitute the reticuloendothelial system. These
glucose urine levels secondary to hyperglycemia. This is a factor which cells recognize microbes, particulate matter, and damaged or senescent
accounts for the increased incidence of pyelonephritis in diabetic host cells by PRRs on the macrophage surface. The scavenger receptor
patients. family (SRAI and SRAII, MACRO, CD36, CD68, and CLA-1)102 and
The vagina has an additional unique mechanism of protection. the mannose receptor103 detect phospholipid-containing and man-
Under hormonal influence, especially estrogen, the vaginal epithelium nose-containing structures. These structures frequently are present on
contains increased amounts of glycogen that Döderlein’s bacilli and microbes but not on normal host cells. Integrins, notably CD11b/
other commensals metabolize into lactic acid. Döderlein’s bacilli is an CD18, CD11c/CD18, αV/β1, and αV/β3, indirectly recognize particulate
all-encompassing term used to describe acidogenic gram-positive rods, targets by binding soluble host constituents, including activated com-
especially lactobacilli, residing in the vagina. Normal vaginal secretions plement components, vitronectin, and fibronectin. These soluble
contain 108/mL of these bacteria. They establish an acid environment molecules interact with fragments of damaged cells, collagen debris,
that is unfavorable to most pathogenic microorganisms. The vaginal altered platelets, and microbes to enhance their clearance by
secretions of women with nonspecific vaginitis or vaginosis, a pertur- macrophages.104,105
bation of the normally protective vaginal ecosystem, and patients with Recognition of collectins (mannose-binding protein, complement
other sexually transmitted diseases are characterized by an elevated component C1q, and the surfactant SP-A) by macrophage receptor
pH.96 As with other mucosal surfaces, the genital tract also has a C1qRp also enhances phagocytosis of microorganisms coated with
number of antimicrobial factors that form a protective biochemical these ligands.105 In addition, CD14 recognizes lipid A from gram-
barrier to infection97,98 (see Table 4-2). negative bacteria and lipoteichoic acid from gram-positive bacteria.
Binding of lipid A to CD14 is facilitated by its attachment to LPS-
binding protein. When these receptors are engaged, macrophages
EYE
become programmed to remove the recognized complexed particles
Constant bathing of the eye by tears is an effective means of protection. from circulation.
Foreign substances continually are diluted and washed away via the Under resting or steady-state conditions, macrophages and mono-
tear ducts into the nasal cavity. Tears also contain large amounts of cytes kill ingested microorganisms by the generation of toxic oxygen
lysozyme and other antimicrobial substances. and nitrogen metabolites, such as hydrogen peroxide, superoxide, and
nitrous oxide (oxidative killing); nonoxidative killing occurs by
defensins, acidification of phagosomal vacuoles, deposition of acid
PHAGOCYTOSIS AND AUTOPHAGY
hydrolases and other lysosomal enzymes into phagolysosomes, and
Phagocytosis is the mechanism whereby microorganisms that enter the production of various granule-associated antimicrobial molecules,
body are engulfed and killed by various phagocytic cells, such as den- including neutrophil peptides 1 through 4, lysozyme, elastase, antileu-
dritic cells, polymorphonuclear neutrophils (PMNs), and macro- koproteases, azurocidin, cathepsin G, and bactericidal permeability–
phages (see Chapters 8 and 9). Macrophages are found in all body increasing protein.106-108 These molecules also are released into the
tissues, whereas PMNs and monocytes circulate in blood and lymph plasma and other body fluids during inflammation.109 Their microbi-
channels. There is the customary crosstalk among all these sentinel cidal capability is relatively limited, however, compared with that of
cells and, when a microorganism is sensed or detected, they secrete PMNs and activated macrophages stimulated initially by the initial
various chemotactic agents, such as chemokines, which ultimately inflammatory response and later by an adaptive immune response.
leads to cellular migration through the tissues resulting in various Those whose spleens have been surgically removed or functionally
degrees of inflammation. impaired dramatically show the importance of the reticuloendothelial
When a microbe is internalized into a phagosome, it usually is killed system: When encapsulated bacteria, such as pneumococci, are filtered
by various microbicidal factors, which include reactive oxygen and poorly from the blood, they can overwhelm the asplenic host
nitrogen intermediates and toxic peptides. The dead microorganisms more easily by relatively unfettered replication in the blood (see
are digested, the microbial peptides bind to major histocompatibility Chapter 315).
complex (MHC) molecules, and the complex migrates to the cell surface
for presentation to its cognate T-cell receptor. This process, termed
antigen presentation, results in specific T-cell clonal expansion and is a Innate Immunity and the Initial
crucial interface between the innate and the adaptive immune systems.
Opsonin-independent phagocytosis by PMNs is related to the
Inflammatory Response
contact angle between the microorganism and the surface on which it The human host is armed with a diverse array of sensors to detect an
rests. As a consequence of this physical relationship, phagocytosis invading pathogen. There are a number of cellular receptor families
is most efficient when organisms are trapped in small tissue spaces that recognize pathogen-associated molecular patterns (PAMPs).
(e.g., alveoli) than when they reside on smooth open surfaces (e.g., These PRR families include nucleotide binding and oligomerization
synovium) or float free in the blood.99 domain-like receptors (Nod-like receptors, NLR),9,110-112 C-type lectin-
Additionally, most cell types can use autophagy as an innate mecha- like receptors (CLR),114 and intracellular receptors to detect double-
nism to clear intracellular pathogens. An invading pathogen such as stranded RNA–double-stranded RNA helicase-like receptors.113 The
Mtb or Toxoplasma gondii finds safe haven in vesicular structures in best-studied PRR gene family, TLRs, is structurally conserved in all
the cytoplasm. Autophagy is where cells kill these organisms via the eukaryotes and derives its name from the Toll mutants in Drosophila.7,8
fusion of lysosomes with the pathogen-containing vesicle. In the Currently, there are 13 known mammalian TLRs (Table 4-3). The TLR
case of Mtb, the immunity-related guanosine triphosphatase (IRGM) gene family functions by detecting a range of molecular signatures,
gene triggers autophagy and generates large autolysosomal PAMPs, that are unique to pathogens or damaged host tissues. This
organelles.100 concept of pathogen-specific molecular patterns forms the basis for
The link among autophagy, infection, and chronic human diseases the current view of how the host senses invasion.7,114-119 Specific ligands
is growing. CARD15 and the IL23R gene, along with ATG16L1, have have been shown to trigger the 10 TLRs for which ligands have been
been linked in genome-wide association studies with susceptibility for identified (ligands for TLRs 10, 12, and 13 are as yet unknown120) and
Crohn’s disease. ATG16L1 should play a role in autophagy of Salmo- include microbial and host cell debris (see Table 4-3).
nella typhimurium, suggesting that incomplete clearance of intracel- Through various signaling cascades, activated TLRs lead to the acti-
lular microbes may result in the triggering of the chronic immune vation of the nuclear transcription factor nuclear factor kappa B (NF-
activation state seen in Crohn’s disease.101 κB), discussed in more detail in the next section. This in turn leads to
42 Part I Basic Principles in the Diagnosis and Management of Infectious Diseases

TABLE
cules involved in antigen presentation in monocytes, MHC class II,
4-3 Toll-like Receptors and Their Ligands* CD40, CD54, CD58, CD83, and CD86; drives monocyte differentia-
TLR Member Ligands (Origin)
tion toward a dendritic cell–like morphology; and induces secretion
of IL-4, a cytokine with potent antibody production–enhancing
TLR1 Triacyl lipopeptides (bacteria, mycobacteria)
properties.121
Soluble factors (Neisseria species)
TLR2 Lipoprotein, lipopeptides (a variety of pathogens)
Peptidoglycan (gram-positive bacteria) TOLL-LIKE RECEPTORS AND THE
Lipoteichoic acid (gram-positive bacteria) CYTOKINE CASCADE
Lipoarabinomannan (mycobacteria)
The signaling pathways for some of the TLRs have been defined and
Phenol-soluble modulin (Staphylococcus species)
are involved in cytokine production.68 For example, TLR-4, triggered
Glycoinositolphospholipids (Trypanosoma cruzi)
by either LPS or the host protein hsp70, activates many signaling
Glycolipids (Treponema maltophilum) pathways through the cytoplasmic tail. The end result is the activation
Porins (Neisseria spp.) of the transcription factors NF-κB, p38, JNK, IRF-3, and IRF-7. The
Zymosan (fungi) NLR pathway activates caspase-1, which is essential in the conversion
Atypical LPS (Leptospira interrogans, Porphyromonas gingivalis) of pro–IL-1β to the active form.111 The NF-κB pathway is the central
HSP70 (host) regulator of cellular transcription in innate and adaptive immunity,
TLR3 Double-stranded RNA (virus) and induction of NF-κB is essential for T-cell activation and expan-
TLR4 LPS (gram-negative bacteria) sion. The response represents one of the many portals transitioning
Taxol (plant) from innate to adaptive immunity. TLR-4 also triggers many costimu-
Fusion protein (RSV) latory molecules, such as CD80/CD86, that aid in the development of
Envelope proteins (MMTV) antibody-mediated and cell-mediated responses to the pathogen. The
HSP60 (Chlamydia pneumoniae) IRF-3 pathway activates the interferon response program and is
F-protein (cytomegalovirus)
HSP60 (host)
HSP70 (host)
Type III repeat extra domain A of fibronectin (host)
Oligosaccharides of hyaluronic acid (host) TABLE
Polysaccharide fragments of heparin sulfate (host) 4-4 Cytokines Induced as Part of the Innate Response
Fibrinogen (host) Cytokine Response
TLR5 Flagellin (bacteria)
IL-1 Inflammatory responses; edema and prostaglandin production;
TLR6 Diacyl lipopeptides (Mycoplasma species) production of IL-2; growth of lymphocytes
TLR7 Imidazoquinoline (synthetic compounds) IL-2 Promotes growth and differentiation of activated Th and Treg and
Loxoribine (synthetic compounds) B cells; suppresses Th17 T-cell development; activates cells of
Bropirimine (synthetic compounds) the monocyte-macrophage lineage; induces interferon-γ and
TNF-α
Guanine nucleoside analogues (synthetic compounds)
IL-4 Promotes B-cell growth and differentiation and Th2-driving
TLR8 R848/resiquimod single-stranded RNA cytokine; strong inducer of MHC class II
TLR9 CpG DNA (bacteria) IL-6 Proinflammatory; inducer of initial inflammatory response
Chromatin:IgG complexes (host) proteins in hepatocytes; activates PBMCs; B-cell differentiation
TLR10, 12, 13 ? IL-8 Enhances inflammation produced by macrophage and endothelial
TLR11 Profilin (bacteria) cells; induces T-cell chemotaxis
*This table shows ligands for mammalian Toll-like receptors (TLRs): pathogen-derived IL-10 Attenuator; antagonist to IL-12—downregulates IFN-γ, IL-1, IL-6,
and host cell–derived ligands (in bold). and TNF-α; Th2 biasing also activates B cells
LPS, lipopolysaccharide; MMTV, mouse mammary tumor virus; RSV, respiratory IL-12 Antagonist to IL-10; induces IFN-γ, Th1 biasing
syncytial virus.
IL-13 B-cell growth factor; promotes growth and differentiation of
Adapted from Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol.
allergic effector cells
2003;21:335-376; Ozato K, Tsujimura H, Tamura T. Toll-like receptors signaling and
regulation of cytokine gene expression in the immune system. BioTechniques. IL-15 Promotes growth and differentiation of T cells and B cells;
2002;33:S66-S75; Beg AA. Endogenous ligands of Toll-like receptors: Implications for activates cells of the monocyte-macrophage lineage; induces
regulating inflammatory and immune responses. Trends Immunol. 2002;23:509-512; IFN-γ and TNF-α, promotes NK cell cytotoxicity
Lee J, Chuang T-H, Redecke V, et al. Molecular basis for immunostimulatory activity of IL-17 Proinflammatory; secreted by Th17 CD4 cells; promotes
guanine nucleoside analogs: Activation of Toll-like receptor 7. Proc Natl Acad Sci U S A. neutrophil homeostasis and intestinal epithelial integrity
2003;100:6646-6651; and Heil F, Hemm H, Hochrein H, et al. Species-specific IL-18 INF-γ inducing (in the presence of IL-12); member of the IL-1
recognition of single-stranded RNA via toll-like receptors 7 and 8. Science. family
2004;303:1526-1529.
IL-23 IL-12 family member promotes differentiation of Th17 cells
IL-25 Proinflammatory member of Th17 family; secretion by epithelial
cells induced by allergens and helminth parasites → Th2
response
the regulation of many host cytokine and cytokine receptor genes,
IL-27 Induces IL-10 → anti-inflammatory; initiates Th1-type immune
including those for IL-1, IL-1R, tumor necrosis factor-α (TNF-α), responses; suppresses Th17 and Th2 cell differentiation
IL-6, IL-8, IL-10, and IL-12, which have redundant multifactorial IL-33 IL-1 family member, promotes Th2 response; secretion by
effects (Table 4-4). Depending on the TLRs activated, cytokine pro- epithelial cells induced by helminth parasites
duction can result in the full clinical presentation of the acute-phase IFN-α, Antiviral proteins; induce upregulation of MHC class I
response, including fever (see later). Whether the acute inflammation IFN-β
results from infection or trauma, it is triggered along the same pathway. IFN-γ Activates macrophage; upregulates MHC class I and II; sustains
TLR signaling also activates the adaptive immune response.119 Adju- activated T cells; promotes antigen-presenting cell
differentiation, Th1 biasing
vants for all current vaccines function through the activation of the
TNF-α Major proinflammatory cytokine; inducer of acute-phase response
TLR pathways. The most potent adjuvant, Freund’s complete adju- along with IL-1 and IL-6; activates adhesion processes and
vant, is a water-in-oil emulsion containing mycobacterial cell wall chemoattraction
components that activate TLR-1, TLR-2, and TLR-4 (see Table 4-3). IFN, interferon; IL, interleukin; MHC, major histocompatibility complex; NK, natural
The simplest adjuvant, alum (aluminum hydroxide), induces mole- killer; PBMCs, peripheral blood mononuclear cells; TNF, tumor necrosis factor.
 4 Innate (General or Nonspecific) Host Defense Mechanisms 43

responsible for a profound antiviral state that is effective against all CD80/CD86 and IL-12. As PDCs mature and migrate to the draining
viruses. The result of the signaling and activation of the TLR is that lymph node, they serve as antigen-presenting cells, driving the adap-
within 4 hours, the activated cell is producing multiple cytokines, tive immune response. Additionally, TLRs activate monocytes and
including IL-1, IL-2, IL-6, IL-10, IL-12p40, IL-15, IL-23, IL-27, TNF- macrophages to secrete the regulatory cytokines, IL-10 and IL-12, and
α, and interferon-α (IFN-α) and IFN-β (see Table 4-4). Through the liver Kupffer cells to secrete IL-18.124,125 IL-12 and IL-18 cooperatively
induction of IL-10 and IL-12, TLR signaling initiates a cascade that promote secretion of IFN-γ by natural killer (NK) cells, driving specific
leads to the production of IFN-γ and IL-4, which are crucial cytokines immunity toward type 1 (Th1) T-cell responses characterized by high
for adaptive immune response. As with all other biologic systems, TLR levels of interferon production, development of delayed-type hyper-
signaling also has a feedback system, which induces signals that attenu- sensitivity, and defense against intracellular microbes. TLR activation
ate this response, mainly IL-10. of monocytes also produces IL-10, which inhibits IL-12 production,
Genetic analysis has allowed precise determination of inherited stimulates B-cell proliferation and immunoglobulin synthesis, and
defects (so-called experiments of nature), and the first genetic defi- drives specific immunity toward Th2 responses, which are character-
ciency in Toll receptor signaling, IRAK-4 (interleukin-1 receptor- ized by high levels of IL-4 production and synthesis of antibody, par-
associated kinase-4), has been described.14 Children with no detectable ticularly IgE. Type 2 (Th2) antibody responses are crucial for the
IRAK-4 in their cells had recurrent infections and poor inflammatory defense against some viruses, encapsulated bacteria, and large extracel-
responses. Further investigation of cells from these patients showed lular eukaryotes, especially worms.
that the cells did not produce TNF-α, IL-1β, IL-12p40, or IL-6 in The pathogen can also strongly influence the innate response and
response to a range of TLR ligands, including LPS. These children were subsequent biasing of the immune response. Helminth infections
susceptible only to a narrow range of bacterial infections, showing the strongly polarize the immune response toward a Th2 profile because
following: (1) the apparent multireceptor family redundancy built into the oligosaccharides lacto-N-fucopentaose and lacto-N-neotetraose of
the innate immune system; and (2) the likelihood that this defect will the schistosome egg are Th2 biasing and suppress Th1 responses.126,127
be passed on and potentially expanded in the era of antibiotic therapy, This Th2 biasing may be mediated through IL-25 and IL-33, both of
which prolongs their lives into reproducing adults. It is highly likely which are stimulated by helminths.128 These sugars also are found in
that similar defects in innate immunity will be elucidated in the future, human milk, which may reflect the adaptation of the innate process
which this accounts in part for the inherited propensity to die from an to increase the likelihood of an antibody response in the neonate to
infectious disease (see Fig. 4-1). compensate for the loss of maternal antibodies.
A recent discovery is a third type of CD4 T cell, Th17, which pro-
duces the proinflammatory IL-17 family of cytokines (see Table 4-4).
CELLULAR DISTRIBUTION OF TOLL-LIKE RECEPTORS
IL-1, IL-6, IL-23, TGF-β, and TNF-α are required for the differentia-
Specificity of effects of the innate response are achieved through the tion and effector function of Th17 cells. IL-17 is critical for neutrophil
distribution of subsets of TLRs on different types of immune effector homeostasis and maintenance of the intestinal epithelial barrier. Th17
cells (Table 4-5) and the selective signaling through each receptor.7,8,122 cells have been implicated in host defense against pathogens such as
TLR-1 and TLR-6 are expressed on all cell subtypes. TLR-2 is highly M. tuberculosis, as well as in allergic and autoimmune diseases.129
expressed on monocytes. Plasmacytoid dendritic cells (PDCs) and B
cells express strong levels of TLR-7 and TLR-9. B cells express high
TOLL-LIKE RECEPTOR SIGNALING AND INITIAL
levels of TLR-10, however, and PDCs show weak expression of this
INFLAMMATORY RESPONSE
TLR. This is a snapshot of the profile in the resting state, and prelimi-
nary data have indicated that the regulation of these receptors will be Three of the major inflammatory cytokines, IL-1, TNF-α, and IL-6,
as fluid as the cytokine profile that they trigger. induced through TLR and other PRR signaling are largely responsible
for triggering the initial inflammatory response. First, these molecules
act as pyrogens, altering the temperature set point and resulting in a
TOLL-LIKE RECEPTOR SIGNALING AND INITIATION
febrile response. These cytokines also induce the synthesis in the liver
AND BIASING OF ADAPTIVE IMMUNITY
of many initial inflammatory response proteins, including C-reactive
The activation of the innate immune system has several important protein,130 LPS-binding protein,131 serum amyloid A, haptoglobin,
effects on the adaptive immune response.123 When stimulated through ceruloplasmin, fibrinogen, α1-acid glycoprotein, complement compo-
the TLR pathways, PDCs synthesize the costimulatory molecules nents C3, C4, C9, factor B, C1 inhibitor, and C4b binding protein,
transferrin, procalcitonin, prealbumin, natural anticoagulants, such as
protein C, protein S, antithrombin plasminogen, tissue plasminogen
TABLE
Distribution of Toll-like Receptors (TLRs) in Resting activator, urokinase, vitronectin, plasminogen-activator inhibitor 1,
4-5 Human Plasmacytoid Dendritic Cells, Monocytes, α1-antitrypsin, α1-antichymotrypsin, β2-macroglobulin, pancreatic
Natural Killer Cells, B Cells, and T Cells
secretory trypsin inhibitor, granulocyte colony-stimulating factor,
Toll-like fibronectin, ferritin, angiotensinogen, α-fetoprotein, thyroxine-
Receptor PDCs Monocytes NK Cells B Cells T Cells
binding globulin, and factor XII.132 These omnipresent proteins
TLR-1 + ++ ++ ++ + increase the number and function of phagocytic cells and facilitate the
TLR-2 − ++ + ± ± delivery of humoral and cellular components to sites of inflammation
TLR-3 − − + ± ± and constitute a marker of inflammation.133 The initial inflammatory
TLR-4 − ++ ± ± ± response is mediated by a host of cells of the immune system, including
TLR-5 − + + ± + monocytes, Kupffer cells, and T cells;123 reactions of preexisting
TLR-6 + + + ++ ± humoral defenses; and de novo production of active regulatory mol-
TLR-7 + ± ± + ± ecules (e.g., cytokines and chemokines, prostaglandins, and other eico-
TLR-8 − + ± ± ± sanoids) by phagocytes, lymphocytes, and endothelial cells.
TLR-9 ++ ± ± + ±
TLR-10 ± ± ± + ±
CHEMOKINES AND CHEMOTAXIS
++, more than 100 mRNA copies/103 cells; +, more than 20 mRNA copies/103 cells;
±, detectable mRNA in 103 cells; −, below limit of detection of the assay. Two main families of chemokines direct leukocyte migration.27,134-136
NK, natural killer; PDCs, plasmacytoid dendritic cells.
From Hornung V, Rothenfusser S, Britsch S, et al. Quantitative expression of Toll-like
Members of the CXC family, whose first two cysteines are separated
receptor 1-10 mRNA in cellular subsets of human peripheral blood mononuclear cells by a single amino acid, stimulate chemotaxis of PMNs, eosinophils,
and sensitivity to CpG oligodeoxynucleotides. J Immunol. 2002;168:4531-4537. monocytes, dendritic cells, NK cells, and T lymphocytes. Members of
44 Part I Basic Principles in the Diagnosis and Management of Infectious Diseases

the CC family, whose first two cysteines adjoin each other, stimulate that prevent the maturation of pro-IL1β146 Second, the virus-infected
all these leukocytes except PMNs, which do not express receptors for cells also secrete a soluble IL-1β receptor, effectively reducing the
CC chemokines. More than 45 chemokines, 11 receptors for CC che- serum concentration of this important cytokine.147 Fungi are often first
mokines, and 6 receptors for CXC chemokines have been described. detected by the CLR. These receptors bind the surface glycans of fungi.
The defect in the chemokine receptor CCR5 is most known for provid- Several fungal species, including Candida and Pneumocystis, produce
ing resistance to HIV infection. However, loss of this chemokine recep- different sugar patterns in their surface glycans during different stages
tor has also been shown to be associated with increased susceptibility of life, making them invisible to the CLR pathway.148 Viruses have
to symptomatic West Nile virus infection.137 This effect is related in evolved a number of ways to block the intracellular signaling pathways
some way to the loss of chemokine’s known effects of upregulation of involved in innate immunity, including inactivation of IRF-3 and
adhesion molecules, stimulation of leukocyte migration, and lowering IRF-7, as described.149 The first example of viral inference with innate
the threshold for T-cell activation. Cytokines, especially TNF-α and immunity was the blockage of the proteins responsible for the antiviral
IL-1, also increase expression of adhesion molecules on endothelial effects of interferons.150,151 Interestingly anthrax toxin subunit lethal
cells, PMNs, NK cells, and monocytes, which aid in the binding and factor also has a profound effect on the innate immune signaling
transmigration of these cells into sites of inflammation. pathway, specifically targeting the MAP kinase pathway for proteolytic
Although the interactions of chemokines on target cell populations degradation.152 This also induces apoptosis of infected cells, promoting
are extraordinarily complex, IL-8 and eotaxin are the predominant the pathogenesis of the organism.
chemokine modulators of PMN and eosinophil migration. Resting T As noted, the third major site of pathogen interference in innate
cells express few chemokine receptors, but these are strongly upregu- immune signaling is inhibition of the activation of the transcription
lated by IL-2 in conjunction with stimulation via the antigen receptor. factors that turn on the initial response genes. First, the vaccinia
The most vigorous immigration of T cells to inflammatory sites occurs protein K1L blocks NF-κB activation153 and the leader proteinase,
in conjunction with acquired immunity rather than during the innate L(pro), of foot-and-mouth disease virus digests this important tran-
response. scription factor.154 Taken together, these adaptations demonstrate the
diverse approaches that microbes have taken to establish infection.
METABOLIC CHANGES
Many other metabolic changes reflect mobilization of the host’s Impairment and Exaggeration
resources for defense. These include increased production of thyroid- of General Nonspecific and
stimulating hormone, vasopressin, insulin, and glucagon. Profound
catabolism of muscle protein also can occur as amino acids are used
Innate Immunity
for synthesis of defensive cells and proteins, and as resting muscle Impaired natural immunity, most conveniently detected by testing for
metabolic activity or shivering increases to raise body temperature. cutaneous delayed hypersensitivity, can occur as a consequence of
A decrease in serum iron long has been recognized as a component numerous illnesses. In the United States, end-stage cancer, renal
of the initial inflammatory response. Many microorganisms must disease, AIDS, liver disease, and alcoholism are the most common
scavenge iron from their environment for optimal growth. Transfer- underlying illnesses resulting in diminished immune responsiveness.
rin, an iron-binding protein secreted by hepatocytes under the influ- Worldwide, malnutrition is the leading cause of increased susceptibil-
ence of IL-6, complexes with free iron and limits its availability to ity to and severity of several infections. These include life-threatening
microorganisms. Macrophages internalize iron-transferrin complexes, bacterial infections of the middle ear, pervasive dental caries, HIV
retain the iron, and recycle transferrin, further reducing the availability infection, and common childhood infections, especially measles.155,156
of free and total serum iron to any potential invader.138 However, An impaired or dysfunctional immune system is also a crucial deter-
polymorphisms in the lactoferrin gene has been associated with sus- minant of the outcome in sepsis (see Chapter 70).157
ceptibility to traveler’s diarrhea.139
Zinc levels decline significantly during acute inflammation. This
NUTRITION
metal, which has no known tissue stores, enhances lymphocyte respon-
siveness, aids wound healing, and participates in protein synthesis.140 It is well established that persons with malnutrition, whether preexist-
Zinc plays a crucial role in regulation of DNA transcription and RNA ing (protein-energy malnutrition) or disease-induced (cytokine-
translation. Its decrease in infection may reflect its increased use by induced malnutrition), have more severe infections.158 Vitamins A and
actively metabolizing cells. D play central roles.156,159,160 Cellular immune dysfunction is affected
disproportionately, and nutritional support has a demonstrable ben-
eficial effect on outcome.161 Before the advent of antibiotics, tubercu-
Pathogen Interference with Innate losis often was treated by nutrition-based therapies that in some
patients included consumption of 20 to 30 eggs daily (see Chapter 10).
Immune Responses
Pathogenic bacteria, viruses, and fungi have all evolved ways of avoid-
AGING
ing the innate immune response. This ability provides a means for the
pathogen to become relatively well established. The sites of pathogen Although the data regarding the effects of aging on immunity and
interference parallel the three major steps in innate immunity—PAMP infection are confusing and sometimes conflicting, the aging process
recognition, intracellular signaling, and chemokine-cytokine expres- has an impact on the immune system that can be summarized best as
sion triggered by the activated transcription factors. immunosenescence.162 Superimposed and interrelated with this gener-
Alterations in PAMP structure that develop so as to avoid activation alized impairment are social isolation and age-related decrements in
of the PRR is an important first step in the establishment of infection organ structure and function. Regardless of the setting, there is a
for a number pathogens. TLR4 recognizes the lipid A structure of higher incidence in older persons of pneumonias (twofold), cholecys-
lipopolysaccaride,141 Helicobacter,142 Coxiella,143 Legionella, and Rhizo- titis (two- to eightfold), appendicitis (15- to 20-fold), diverticulitis,
bium all have altered lipid A structures that are not recognized by bacteremia (threefold), asymptomatic bacteriuria, urinary tract infec-
TLR4.144 Alteration in the flagellum structure in Helicobacter also tions (five- to 10-fold), reactivation of varicella-zoster virus and tuber-
blocks signaling by TLR5 by this organism.142,145 Other PRRs are also culosis (10-fold), bacterial meningitis (threefold), and bacterial
blocked by specific pathogens. An effector arm of the NLR pathway is endocarditis (two- to threefold). The case-fatality rate is conspicuously
activation of IL1β. Pox viruses have devised two ways of interfering high in patients older than 65 years infected with severe acute respira-
with this PRR pathway. First, infected cells secrete a caspase inhibitor tory syndrome (SARS)–associated coronavirus.163 The greatest impact
 4 Innate (General or Nonspecific) Host Defense Mechanisms 45

of aging is on cell-mediated immunity; there is a lesser but substantial (tropism). This fact is taken into consideration when the clinician
impact on humoral immunity.164 decides whether a particular organism is behaving in a pathogenic
fashion. Bacteria and fungi comprise commensal and symbiotic organ-
isms. Protozoa are less ubiquitous, almost always reside in the gastro-
STRESS
intestinal tract, and are more prevalent in developing countries.
A growing body of evidence has shown an inverse relation between Mycoplasmas and viruses are much less prevalent members of the host
stress and immune function; the end result is an increased susceptibil- commensal flora.
ity to infection.165 The feedback pathways responsible for this effect The species that make up the normal commensal flora are influ-
remain obscure. enced by environmental factors, such as diet, sanitary conditions, air
pollution, and hygienic habits.167,168 Lactobacilli are common intestinal
commensals whenever dairy products compose a significant propor-
HORMONES
tion of the dietary intake, protozoa are common intestinal inhabitants
Increased production of adrenocorticotropic hormone occurs during of persons living where sanitation is poor, and a patient with underly-
the inflammatory response and seems to augment the host’s survival ing chronic bronchitis is more likely than others to harbor Haemophi-
potential. The depressive effect of excess corticosteroids on inflamma- lus influenzae in the tracheobronchial tree.
tion is well known and probably represents an important feedback Hormones also may influence the normal commensal flora. Pre-
mechanism to modulate an inflammatory response. menarcheal and postmenopausal vaginal flora differ significantly from
Estrogen affects the lining of the vagina, resulting in increased non- those present during the childbearing period. The normal commensal
specific resistance. T-cell function is blunted during pregnancy,166 flora also are influenced by genetically determined host cell receptors
which may account for the severity of certain infections, such as those to which microorganisms adhere and that determine or select the
caused by poliomyelitis virus, Coccidioides immitis, group A β-hemolytic microbes that colonize a particular host (see earlier, section on tissue
streptococci, influenza virus, and N. gonorrhoeae, particularly in the tropisms and heredity).
third trimester. An important beneficial effect of the normal flora on the immune
system is to keep it primed and more rapid and efficient in its response
to invading microorganisms. Antigens normally are presented to the
DYSREGULATION
immune system in an ordered and specified way. T cells recognize
The compilation of initial nonspecific response is usually effective for antigens only after they are displayed on the surface of a macrophage
controlling microbial invasion. With overwhelming microbial invasion (or other antigen-presenting cell) in physical association with an MHC
and release of large amounts of microbial products, however, the failure molecule. Normally, 75% to 85% of circulating monocytes in adults
of feedback control may lead to the catastrophic syndrome of septic maintain relatively high levels of MHC molecule expression. MHC
shock159 (see Chapter 70). As discussed earlier there is debate about the expression is much lower on the monocytes of human newborns,
primary cause of death triggered by the 1918 influenza epidemic.32-34 In neonatal mice, and germ-free animals. The constant stimulation by the
addition, if infections are not controlled and become chronic, some host’s indigenous microbial flora maintains the relatively high level of
metabolic derangements (e.g., decreased serum albumin, iron seques- MHC molecule expression on macrophages and perhaps other anti-
tration, muscle wasting) persist and can become profound. gen-presenting cells, which serves to keep the immune system primed.
This modulation results, at least in part, from low-level production of
IFN-γ, IL-4, and other cytokines and chemokines by activated T cells
NORMAL INDIGENOUS MICROBIAL FLORA
(see earlier section on cytokines and Table 4-4) and endothelial cells,
The normal commensal flora constitute a crucial ecosystem that plays and represents an important interface between the innate and adaptive
an important role in protecting the host from microbial invasion by immune systems. In contrast to these positive benefits, detrimental
pathogenic organisms.167 Its protective mechanisms include the fol- consequences of colonization with indigenous microflora include the
lowing: (1) competition for the same nutrients (interference); (2) com- stimulation of nonfunctional blocking antibodies,169 cross-reactive
petition for the same receptors on host cells (tropism); (3) production responses to host tissues, inappropriate T-cell responses,170 and chronic
of secreted products, such as bacteriocins (antibiotics), that are toxic low-grade inflammation that is an integral part of chronic degenerative
to other organisms, usually of the same species; (4) production of conditions, such as cardiovascular disease and cancer.133,171,172
volatile fatty acids or other metabolites that are toxic to competing
microbes; (5) continual stimulation of the immune system to maintain
NATURAL ANTIBODIES
low but constant levels of class II histocompatibility (HLA-DR) mol-
ecule expression on macrophages and other antigen-presenting cells; Natural antibodies is the term used to designate antibodies that are
and (6) stimulation of cross-protective immune factors, such as natural specific, but not of high affinity, to a microbe found in healthy people
antibodies (see later). without a previous history of infection with the microbe. These anti-
The ultimate effect of the first three protective mechanisms in the bodies are crucial to the immune defense against many bacteria, espe-
list above is to limit the quantity or dominance of any one species. cially encapsulated bacteria such as N. meningitidis and H. influenzae
Broad-spectrum antibiotic therapy decreases the total numbers of bac- type b.
teria in the gut. This activity results in an increased proportion of Some of these antibodies are stimulated as a result of colonization
normally commensal fungal species and resistant bacterial strains. of the oropharynx, gut, or other sites by organisms sharing cross-
When the antibiotic therapy is stopped, a natural rebound occurs, and reactive (cross-protective) antigens. Other antibodies apparently
the gut is repopulated. There is a selective advantage, however, to the develop independently of antigen stimulation, are polyreactive (i.e.,
faster growing aerobic Enterobacteriaceae over the slower replicating react individually with related epitopes), are found in serum and in
anaerobes. This advantage increases the probability of developing a secretions, and have been observed in newborns, nude mice, and
gram-negative bacteremia. Most colonizing organisms are transient, germ-free animals.173 These antibodies are not always beneficial,
but some persist for life, implying that the biologic cost to the host and however. Specific serum IgA antibodies to N. meningitidis may predis-
microorganism is low. pose an otherwise immune person to become susceptible by preferen-
The microbial flora harbored by the host can be divided into two tially attaching to the organism, blocking the beneficial bactericidal
groups: (1) normal resident flora that are regularly found and, if per- effect of protective IgG and IgM antibodies.169 The blood group anti-
turbed, promptly recolonize; and (2) a microbial flora that may colo- bodies are a consequence of colonization of the gut by microorganisms
nize the host transiently for periods ranging from hours to weeks. bearing cross-reactive antigens. These antibodies are often of low
Certain organisms characteristically colonize certain body sites avidity for most cross-reacting microorganisms.
46 Part I Basic Principles in the Diagnosis and Management of Infectious Diseases

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