During medieval times, castles were built to serve not only as a residence for the feudal lord and his family and subjects, but also as a fortress to keep marauding enemies out. The most effective castles were designed by medieval engineers to last a long time, with high stone walls to withstand the onslaught of an enemy attack or prolonged siege. They were built in strategic locations surrounded by challenging terrain, such as on high ground with impassable moats or on top of steep cliffs. They were also poorly accessible, often with at least one side facing a waterfront, such as a river, lake, or ocean. Roads leading to the castle were usually twining and inclined to restrict access by wagons and hinder passage of large invading armies. Vigilant soldiers standing at the gates and archers placed along the top of the walls and in lookout towers guarded the castle against any would-be invaders that did approach the castle walls. And, if these barriers were still breached, the knights would mount fierce battles to protect the castle’s inhabitants. Like these medieval castles, our bodies are built as nearly impregnable fortresses, with analogous defensive strategies that protect the body against siege and invasion by potential microbial adversaries. Clearly, an attacking army required considerable ingenuity to breach the castle’s defenses. And, like the more successful medieval invader, the more successful invading bacteria (i.e., pathogens) have evolved clever virulence strategies to overcome those defenses of the body.

The Best Defense: Avoid, Reduce, and Prevent Exposure!

How is it possible that researchers and health care workers, who on a daily basis work with or are exposed to highly pathogenic microorganisms, do not get sick that often? This is because they have learned that the best line of defense is preventing exposure to a pathogen in the first place. In a research or health care setting, this can be achieved by avoiding direct contact through the use of gloves, protective clothing, and eyewear; disinfection of instruments and surface areas; and proper ventilation facilities. In the event that exposure does occur, other effective strategies come into play for preventing the pathogen from gaining entry into the body and establishing an infection. Of course, it helps to know the identity and properties of the pathogen that can be targeted for specific neutralization and also to bear in mind that any potential pathogen must always be treated with the utmost respect.

Reducing the number of bacteria that the body comes into contact with is a highly effective strategy to limit the risk of colonization and infection. There are many agents, natural (e.g., antibiotics, alcohols, and natural acids such as vinegar or citrus juice) or artificial (e.g., organic chemicals, drugs, and detergents), that can be used to kill or slow down the growth of microbes. Some of these agents can only be used externally on inanimate objects (e.g., disinfectants, sanitizers) or body surfaces (e.g., antiseptics, germicides) due to their harsh or toxic properties, but others are safe to ingest or inject in appropriate amounts (e.g., antibiotics, other antimicrobials). Personal hygiene through the use of handwashing with soap and water, as well as application of alcohol-based antiseptic gels, can also achieve the purpose of limiting exposure risks. We will revisit this topic later in chapter 15, when we discuss antimicrobial compounds.

Unfortunately, even with extra precautions and containment measures to reduce contact, accidental exposure can still occur through ingestion, inhalation, or direct contact with mucosal surfaces, such as the eyes or nose or through injury with sharp objects, needles, or abrasives. When this happens, it is comforting to know that the body has a number of impressive defense strategies already in place that make establishing an infection extremely difficult for the pathogen. The first of these strategies is a nearly impregnable physical and biochemical barrier that divides the external environment from the interior of the body. The second is the body’s ability to mount a massive counteroffensive against any invading microbe through the ever-vigilant immune system. This chapter and the ones that follow are intended to provide an overview of the defenses of the human body that limit colonization and prevent infection. We will begin the discussion of these host defenses in this chapter with the physical and biochemical surface barriers and will continue in chapters 3 and 4 with discussion of the internal defenses and protection provided by the immune system. Finally, as covered later in chapter 17, “Vaccination: an Underappreciated Component of the Modern Medical Armamentarium,” we will discuss how it is possible to further bolster this amazing defense system through vaccination and other therapeutic strategies.

Barriers: Skin and Mucosal Membranes

The skin and mucosal membranes of the human body are not simply inert physical barriers that keep good things in and bad things out. They comprise the body’s largest organ, which has a complex array of activities and functions that are only now beginning to be fully appreciated. As humans and other life-forms evolved, they were forced to contend in a bacteria-dominated world in which bacteria tended to view them as a free lunch. Survival meant developing defenses to keep these bacteria at bay. As such, these fortress-like defenses are extremely effective against bacterial incursions, preventing most bacteria from entering human tissues and the bloodstream and instead relegating them to the surface of the skin or confining them to certain closely guarded mucosal areas of the human body, such as the oronasopharyngeal (mouth, nose, and pharynx/throat), gastrointestinal, and urogenital tracts. Fortunately for us, only a tiny minority of bacteria is able to bypass these defenses and cause disease. To understand the mechanisms by which pathogenic bacteria cause disease, it is first essential to know what obstacles those few bacteria that do cause disease must overcome.

The Layers of Cells That Protect the Body

Epithelia are the layers of cells covering all of the external and internal surfaces of the body that are exposed to the external environment. These epithelial cell layers are an important initial defense against potential pathogens. The epithelial cells found in different body sites differ considerably in their properties, but they have some features in common.

Skin consists of a lining of living cells composed of two layers, the epidermis (outer layer) and the dermis (inner layer) (Figure 2-1). Cells of the dermis are continuously replaced as they die and become a tough, dry outer layer called the epidermis. The epithelia that line the respiratory, intestinal, and urogenital tracts are the mucosal epithelia and consist of tightly packed cells that are attached to each other by protein structures called tight adherens junctions and desmosomes (Figure 2-2). The tight binding of epithelial cells to each other prevents bacteria from transiting an epithelial layer. To get through the epithelial layer, bacteria must either take advantage of wounds or be capable of invading epithelial cells, passing between or through them to get to the underlying tissue.

Figure 2-1. Structure of the skin. The thick epidermis (outer layer, top) consists of keratinized, stratified squamous cells, the top layers of which are dead and continuously shed. When these cells are sloughed, they carry adhering bacteria with them. The inner layer is the dermis (middle). Sebaceous (fat) glands, sweat glands, and hair follicles, which produce antibacterial substances, provide openings in the skin through which pathogenic bacteria occasionally enter. The skin also has an adaptive defense system, the skin-associated lymphoid tissue (SALT). Langerhans cells serve as phagocytic cells in this system.

Figure 2-2. Intestinal epithelial cells showing tight, junctional, and adherens junctions, and desmosomes. JAM, junctional adhesion molecules.

In contrast, the cells that line the surfaces of the interior of the body (the endothelium), such as blood vessels or lymphatic vessels, are not tightly bound to each other in order to allow the cells of the immune defense system to move freely from blood to tissues. Unfortunately, this feature also allows bacteria to move into and out of blood and lymphatic vessels by moving between the endothelial cells. Thus, once bacteria gain entry into the body at one site, it is possible for them to readily gain access to other parts of the body. Because of this vulnerability, it is imperative that the epithelia of skin and mucosal surfaces function as barriers against foreign invaders.

The membrane surface of an epithelial cell that faces toward the interior tissues of the body and is attached to other cells or to connective tissues (basolateral surface) has a different protein composition from the membrane surface that faces outward (apical surface). Cells with this asymmetrical surface property are said to be polarized cells. A feature of epithelial cells is that they are attached to a thin sheet of connective tissue called the basement membrane (basal lamina). The basal lamina covers regions of loose connective tissue (Figure 2-3), comprised of extracellular matrix (ECM) secreted by elongated fibroblast cells. The ECM composition varies with tissue type, but primarily contains a network of interlocking gels of polysaccharides called glycosaminoglycans (such as chondroitin sulfate, hyaluronan, keratan sulfate, and heparan sulfate) attached to fibrous collagens, the most abundant protein type in the ECM. Collagens bind to adhesion glycoproteins called fibronectins, which in turn bind collagens to transmembrane cell surface proteins called integrins that mediate cell-cell and cell-ECM interactions and cytoskeletal responses. Other ECM proteins called laminins bind to collagens and other ECM components to form fibrous networks that resist tensile forces in the basal lamina. There are numerous examples of pathogenic bacteria that attach to components of the ECM and manipulate or mimic ECM components during the course of infection.

Figure 2-3. Different types of epithelial cells and their relationships to underlying tissue. Shown are (A) simple squamous epithelium; (B) simple cuboidal epithelium; (C) stratified squamous epithelium (upper layers of cells are dead, typical of skin); (D) simple columnar epithelium; (E) ciliated columnar epithelium showing goblet cells, which secrete mucus (mucin); and (F) typical structure of connective tissue under an epithelial cell layer. Panel F modified from Cooper GM, Hausman RE. 2007. The Cell—A Molecular Approach, 4th ed. ASM Press, Washington, DC.

Epithelial cells in different body sites vary in shape, size, and number of layers (Figure 2-3), as well as in functional properties. Epithelial layers that cover surfaces where absorption or secretion is taking place (e.g., in the intestinal tract) usually consist of a single layer of epithelial cells (simple epithelium). Other surfaces, such as the female cervix or the skin, are composed of many layers of epithelial cells (stratified epithelium). Some have a flattened shape (squamous epithelium) and form the lining of cavities (such as the mouth, heart, and lungs) and the outer layers of the skin. Some are cube-shaped (cuboidal epithelium) and form the lining of kidney tubules and gland ducts and constitute the germinal epithelium that develops into egg and sperm cells. Others are tall and thin (columnar epithelium) and form the lining of the stomach and intestine.

Most of the surfaces that are exposed directly to the environment (e.g., the skin and mouth) are covered by stratified epithelia, whereas simple epithelia are found in internal areas, such as the intestinal tract or the lungs. Simple epithelia are more vulnerable to bacterial invasion than stratified epithelia because invading bacteria only have to pass through one layer of cells to gain access to the tissue underneath. We will use the terms mucosa epithelia, epithelial cells, mucosal layer, or mucosal cells to denote the simple epithelia of these internal areas.

Epithelia are protected by an array of innate and adaptive defenses. Some of these defenses are listed in Table 2-1 for the skin and Table 2-2 for mucosal surfaces. Other defenses, listed in Table 2-3, are more specific to certain areas of the body, such as the eyes and the respiratory, gastrointestinal, and urogenital tracts. For example, tears contain an enzyme (lysozyme) that degrades bacterial cell walls. Tears also provide a washing action that removes particles and bacteria from the eyes. Entry to the respiratory tract is protected by mucus and by specialized ciliated cells that propel bacteria-laden blobs of mucus out of the lungs. The urinary tract epithelium is protected by a sphincter at the end of the urethra, the tube that leads up to the bladder. This barrier makes it difficult for bacteria to enter the tube that leads to the bladder. Also, the washing action of urine during urination flushes out any bacteria that may have gained access to the bladder and urethra.

Table 2-1. Defenses of the skin

Table 2-2. Defenses of mucosal surfaces

Table 2-3. Special defenses of specific sites

Normal Microbiota of the Skin and Mucosa

The defenses of the skin do not completely prevent bacterial growth, as is evident from the fact that there are some bacteria capable of colonizing skin and mucosal surfaces. Immediately after birth, a wide range of microbes colonize humans, particularly on the skin and in the oronasopharyngeal, gastrointestinal, and urogenital tracts. The members of a bacterial population that are found residing at a particular body site without causing disease are called the resident (or commensal) microbiota of that site.

The skin microbiota, consisting primarily of the Gram-positive bacteria Staphylococcus epidermidis and Propionibacterium acnes, help protect against pathogenic bacteria by occupying sites that might be colonized by pathogenic bacteria. They also compete with incoming pathogens for essential nutrients. Some resident bacteria also produce antagonistic bactericidal compounds (e.g., pore-forming toxins such as bacteriocins or growth inhibitors, which target other bacteria). The commensal microbiota does not completely prevent colonization of skin by potential pathogens, but hampers it enough that colonization by pathogenic bacteria is usually transient.

In the case of P. acnes, this anaerobic bacterium colonizes sebaceous (fat) glands and digests the oily sebum, composed of triglycerides, waxy esters, squalene, and free fatty acids, to help generate a low pH environment that is protective against other bacteria. Sebum production and secretion by sebaceous glands is increased by testosterone. During puberty, testosterone levels increase, particularly in males, and cause overgrowth of P. acnes in response to the abundance of sebum production. Air-oxidized sebum plugs the hair follicle or gland duct and gives rise to a clogged follicle (called a comedo) that is open (also known as a blackhead) (Figure 2-4). Dried sebum causes dead skin cells to adhere at the opening of the fat gland, which gives rise to a comedo that is closed and accumulates sebum (also known as a whitehead). The resulting anaerobic environment further enhances bacterial growth, causing infection and inflammation that manifests as acne (i.e., pimples or zits), or in severe cases as cysts or boils. Treatment with antibiotics and benzoyl peroxides found in most acne medications work against P. acnes. Washing with warm water and soap can also help reduce acne by keeping the pores open and free of dried sebum.

Figure 2-4. Skin infection with the commensal bacteria. Overgrowth of the commensal bacterium Propionibacterium acnes can lead to formation of a comedo that is open but plugged with air-oxidized sebum (blackhead) or closed by sebum-glued skin cells (whitehead). Inflammation of the comedo leads to acne (pimples).

Although most mucosal surfaces are protected by normal resident microbiota (exceptions being the uterus and upper female genital tract and the urinary tract), the species composition of the microbiota found at different parts of the body varies from one site to another. Nonetheless, all have in common the predominance of Gram-positive resident bacteria. Shifts in these populations can be pathological, as is seen from diseases such as periodontal disease and bacterial vaginosis. The large intestine (colon) harbors an abundant and rich assortment of normal microbiota, the majority (97%) of which are anaerobes or facultative anaerobes. Many of these bacteria use carbohydrates and fats that are not digested by the stomach or absorbed by the small intestine. In return, some resident microbes provide a beneficial function to the host by synthesizing and secreting vitamins (e.g., vitamin K, vitamin B12, and other B vitamins) and other nutrients that the intestine can absorb. Recent experimental evidence indicates that indigenous bacteria play a crucial inducive role in gut and immune development during early postnatal life. They stimulate development of certain tissues, in particular the caecum and Peyer’s patches, the latter of which stimulate production of cross-reactive antibodies that prevent infection by related bacteria that may be pathogens (more on this later).

Members of the skin microbiota normally do not cause human infections unless they are introduced into the body by abrasions, catheters, or surgery. Staphylococcus epidermidis, a common skin bacterium, has been implicated in postsurgical and catheter-related infections. (S. epidermidis was the bacterial villain in the surgeon-transmitted infections described in Box 2-1.) Relatively nonpathogenic bacteria like S. epidermidis would normally be rapidly killed by the defenses of the bloodstream, but if they can reach an area that is somewhat protected from host defenses, such as the plastic surface of a heart valve implant, they can grow into surface-attached biofilms and produce quite serious infections. Catheters can provide skin-associated bacteria with a conduit into the bloodstream, thus bypassing the defenses of the epidermis and dermis. Catheter-associated infections have become a serious enough problem in hospitals that catheter companies are developing plastic catheters that are impregnated with antibacterial compounds.

Box 2-1.

Notable Breaches in Host Defenses that Changed the Course of U.S. History

Four presidents of the United States were assassinated during their presidencies: Abraham Lincoln (16th president: 1861–1865), James A. Garfield (20th president: 1881), William McKinley, Jr. (25th president: 1897–1901), and John F. Kennedy (35th president: 1961–1963). Kennedy died shortly after being shot, Lincoln died about nine hours afterward, and McKinley survived for about a week before dying, whereas Garfield lasted for 11 weeks before succumbing. Lincoln and Kennedy clearly died from complications due to the damage from the bullets’ impact. In contrast, Garfield and McKinley did not die from the impact of the bullets that hit them, but instead they succumbed to the subsequent infections resulting from the wounds. In both cases, the lethal infections were caused by bacteria introduced by the physicians trying to remove the bullets lodged in their bodies.

In Garfield’s case, one bullet grazed his shoulder and another hit his back, barely missing his spine before lodging in his pancreas, where doctors could not find it. Garfield was shot on July 2, 1881, and although his condition fluctuated with apparent signs of recovery alternating with fevers from infection, his illness worsened over the summer. Blood poisoning (sepsis) eventually took hold, and pus-filled abscesses formed all over his body. He finally died from uncontrolled septicemia (bacteria in bloodstream) and a ruptured splenic aneurysm on September 19, 1881. Most historians and medical experts are convinced that Garfield might have lived had the physicians of his time believed in aseptic technique while probing for the bullet, instead of using unwashed fingers and instruments.

Twenty years later, on September 14, 1901, McKinley died from gangrene resulting from bullet wounds received on September 6. Again, one bullet grazed McKinley while the other entered his abdomen and could not be found. Initially, he seemed to be on the mend, but his condition deteriorated rapidly on September 13 and he died early the next day. Although medical practices and precautions against infections were much improved by 1901, autopsy revealed that the bullet had penetrated the stomach, colon, kidney, and peritoneum along its way. These breaches to the normal epithelial barriers introduced the contents from the stomach and colon into the body’s tissues and the bloodstream, leading to the subsequent sepsis and death.

Sources:

Leech M. 1959. In the Days of McKinley. Harper and Brothers, New York, NY.

Peskin A. 1978. Garfield: A Biography. The Kent State University Press, Kent, OH.

Surgical wound infections and catheter-associated infections caused by skin bacteria, especially S. epidermidis, have become an ever more prevalent problem due to the fact that many of these skin bacteria are now resistant to most available antibiotics. How has this happened? It is clear that at least some antibiotics are exuded in sweat. Also, ointments containing antibiotics are widely used in the treatment of skin conditions such as acne and rosacea (unnaturally red skin) over the course of months or years. Thus, it is not surprising that skin bacteria like S. epidermidis have become increasingly resistant to a variety of antibiotics. Moreover, growth of bacteria in biofilms increases any antibiotic resistance that already exists. Bacteria-containing biofilms will be discussed in a later chapter.

Since transient colonization with pathogens can occur and since even normally harmless skin bacteria can cause infections under certain conditions, handwashing and disinfection of hands adds yet another barrier to infection, and reduces transmission to other people with whom one may come into contact. In the mid-1800s, Ignaz Semmelweis first introduced the concept of handwashing and cleanliness in maternity wards (see Box 2-2). The low-tech, but very effective, protective barrier provided by handwashing and the frequent changing of gloves has probably been a key contributing factor toward the good safety record of research scientists. However, despite strong and convincing experimental data and persistent promotion of good hygiene policies by health care officials, compliance of health care workers with the recommended hygiene practices is still low, with rates of compliance sometimes lower than 50%. An added source of concern is the strong correlation between life-threatening nosocomial infections and the wearing of long or artificial fingernails, despite scrubbing practices. For example, from 1997 to 1998 the death of 16 babies in the neonatal ICU at a hospital in Oklahoma City was linked to a particular strain of P. aeruginosa found under the nails of three nurses.

Box 2-2.

Handwashing Past and Present: A Lesson in Learning and Forgetting

The idea that physicians and nurses should wash their hands before treating a new patient is actually not a recent innovation. Ignaz Semmelweis, the man credited with making handwashing a standard part of medical practice, lived and practiced medicine in the mid-1800s. Although he was not the first physician to make the connection between contaminated hands and the spread of disease by physicians to their patients, he was the first to prove that proper disinfection of hands could dramatically reduce hospital-acquired infections.

Semmelweis had noted that two maternity wards in the Vienna Lying-in Hospital had very different mortality rates. In one, the death rate due to puerperal “childbed” fever (a common cause of death in women of the period) was over 10%, whereas in the second ward it was less than 3%. This fact was well known to women entering the hospital, who considered assignment to the first ward to be a virtual death sentence. Both wards were equally crowded, with three patients sharing each bed and the sick mixed indiscriminately with the well. Both wards contained women of similar socioeconomic status. The only difference between the two clinics was that the first clinic was used for teaching medical students, who also were dissecting cadavers in between delivering babies, and the second was used for teaching midwives, who were not exposed to potential disease-carrying cadavers.

Semmelweis deduced that the medical students were transmitting childbed fever (which we now know is caused most frequently by the bacterium Streptococcus pyogenes) to their patients because they failed to cleanse their hands properly. In 1846, he instituted a policy requiring that all midwives and medical students wash their hands with a chlorinated lime solution before examining patients. The mortality rate in both wards promptly dropped to 1% (red box in figure). Unfortunately, Semmelweis’ colleagues and detractors did not believe him and refused to follow his recommendations. His discovery remained controversial for many years, and it was only in the early 1900s that handwashing was universally accepted as an essential medical practice.

Today, proper disinfection of hands is one of the most basic and firmly entrenched of clinical procedures, especially for surgeons. Nonetheless, the advent of antibiotics and the consequent decrease in deaths due to hospital-acquired infections has led some surgeons to neglect this important practice. More recently, a surgeon in a large northeastern U.S. hospital, who started bypassing the rigorous surgical scrub procedure because he was troubled by dermatitis on his hands, provided a particularly dramatic example of this. The surgeon trusted the two pairs of surgical gloves, which were commonly worn during operations. But tiny holes in gloves can be made by contact with sharp objects or bone fragments. Also, the surgeon was using mineral oil to ease the irritation to his hands, and mineral oil undermines the integrity of surgical gloves. During the course of his duties, this physician managed to contaminate heart valve implants in a number of patients with Staphylococcus epidermidis before he was identified as the source of the outbreak.

S. epidermidis is commonly found as part of the resident microbiota of the skin, where it is not normally pathogenic, but it can cause infections if introduced into the body through wounds. Infections of heart valve implants usually cannot be treated effectively with a simple course of antibiotics, not only because of the high resistance level of S. epidermidis strains, but also because of the formation of bacterial biofilms that are more resistant than individual bacteria to antibiotics. Thus, the patients with the infected valves had to endure a second operation to remove and replace the infected valves, not to mention additional damage to the heart due to the infection.

As is evident from the date on the reference cited at the end of this box, this case occurred in the 1980s. Does this mean that such cases have ceased to occur? Not at all! This case was used because it is a classic example of the handwashing problem, but there have been many other cases since. The difference between the 1980s and the 21st century is that the surgeon in this case would probably have been identified today before he infected so many people because infectious disease surveillance systems in hospitals have improved dramatically. But the attitude and behavior that sparked this episode do still sometimes occur in hospitals.

The silver lining in this particularly black cloud is that accountants for health insurance agencies have figured out how much the lack of handwashing and improper use of gloves are costing them, and they are mounting increasingly vigorous campaigns in favor of handwashing and against health care workers who ignore these simple but effective precautions. In fact, relatives of hospital patients are being urged to question unhygienic practices they witness. The lawyers are circling. Together these trends will continue to increase the safety of hospitals.

Sources:

Semmelweis I. 1983. Etiology, Concept and Prophylaxis of Childbed Fever. Series: History of Science and Medicine (Book 2). (Codell Carter K, translator.) University of Wisconsin Press, Madison, WI.

Carter KC, Carter B. 2005. Childbed Fever: A Scientific Biography of Ignaz Semmelweis. Transaction Publishers, Piscataway, NJ.

Boyce JM, Potter-Bynoe G, Opal SM, Dziobek L, Medeiros AA. 1990. A common-source outbreak of Staphylococcus epidermidis infections among patients undergoing cardiac surgery. J Infect Dis 161:493–499 .[PubMed][CrossRef]

To make matters worse, an alarming number of recent infectious outbreaks have been attributed to hospital-acquired pathogens (such as Klebsiella pneumoniae, Pseudomonas aeruginosa, Candida albicans, methicillin-resistant Staphylococcus aureus (MRSA), and Serratia marcescens) that also are resistant to multiple antibiotics. We will cover this serious problem in much more detail in chapters 15 and 16, when we discuss the topics of antimicrobial compounds and how bacteria become resistant to antibiotics.

Defenses of the Skin

Bacteria are unable to penetrate intact skin unaided. That is why skin infections are usually associated with breaches of skin caused by wounds, burns, or insect bites (Table 2-4). See Box 2-1 for a few examples of infections that changed the course of history due to the dire consequences of breaches in barrier defenses resulting from wounds.

Table 2-4. Some consequences of breaching barrier defenses

Why is intact skin such an effective barrier to bacterial invasion? A number of characteristics combine to make skin inhospitable to bacterial growth, as well as difficult to penetrate (Figure 2-1). The epidermis consists of stratified squamous cells, most of which are keratinocytes. Keratinocytes produce the protein keratin, which is not readily degraded by most microorganisms. As cells from the dermis are pushed outward into the epidermal region, they produce copious amounts of keratin and then die. This layer of dead keratinized cells forms the surface of skin. The dead cells of the epidermis are continuously shed (desquamation). Thus, any bacteria that manage to bind to epidermal cells are constantly being removed from the body.

Skin is dry and slightly acidic (pH ∼5), two features that inhibit the growth of many pathogenic bacteria, which prefer a wet, neutral (pH ∼7) environment. Also, the temperature of skin (34 to 35°C) is lower than that of the body interior (37°C). Accordingly, bacteria that succeed in colonizing skin must be able to adapt to the very different internal environment of the body if they manage to reach underlying tissue. Interestingly, the causative agent of leprosy, Mycobacterium leprae, has an optimal growth temperature of 35°C, which may account for its predilection for the skin and mucosa of the upper respiratory tract.

Hair follicles, sebaceous (fat) glands, and sweat glands are composed of simple epithelial cells and offer sites for potential breaches in the skin that could be used by some bacteria to move past the skin surface. These sites are normally protected by peptidoglycan-degrading lysozyme (Figure 2-5) and by lipids that are toxic to many bacteria. However, some pathogenic bacteria are capable of infecting hair follicles or sweat glands, which is why skin infections such as boils (furuncles) and acne (pustules) are commonly centered at hair follicles.

Figure 2-5. Action of lysozyme. Lysozyme targets the peptidoglycan in bacterial cell walls of mainly Gram-positive bacteria and hydrolyzes the link between N-acetylmuramic acid and N-acetyl-D-glucosamine. It can also degrade the peptidoglycan of Gram-negative bacteria if the outer membrane is first disrupted by bile salts.

Defenses of Mucosal Surfaces

The respiratory, gastrointestinal, and urogenital tracts are topologically inside the body, but they are exposed constantly to the outer environment and foreign materials. Unlike the many dead layers found in skin, internal surface areas (called mucosal epithelia) are comprised of only one epithelial layer. The role of mucosal epithelial cells is absorption or secretion, so they are continuously bathed in fluids, having a temperature of around 37°C and a pH of 7.0 to 7.4. These warm, neutral, and moist conditions are ideal for growth of bacteria. To protect from bacterial colonization, these vulnerable epithelia have evolved a formidable array of chemical and physical barriers (see Table 2-2).

Mucosal cells are regularly replaced, with old cells sloughed off into the lumen. In fact, mucosal cells are one of the fastest dividing populations of cells in the body. Thus, bacteria that do manage to reach and colonize a mucosal surface are constantly eliminated from the mucosal surface and can only remain in the area if they can grow rapidly enough to colonize newly produced cells. Chemical and other innate defenses help reduce the growth rates of bacteria sufficiently to allow ejection of mucus blobs and sloughing of mucosal cells to clear the bacteria from the area.

An important protection of many internal epithelia is mucus. Mucus is a mixture of secreted glycoproteins (mucin) produced by goblet cells, a specialized glandular, modified columnar epithelial cell type incorporated into the epithelial layer. (The basic structure of glycoproteins is reviewed in Box 3-1). Mucus has a viscous, slimy consistency, which allows it to act as a lubricant. It also plays a protective role because it traps bacteria and prevents them from reaching the surface of the epithelial cells. Mucus is constantly being produced, and bacteria trapped in the mucus blobs are shed from the site. In the gastrointestinal and urinary tracts, peristalsis and the rapid flow of liquids through the area removes the mucus blobs along with the lumen contents. Indeed, infections can occur when this flow is disrupted, as may occur in the case of bedridden patients with urethral catheterization, which keeps the urethral entrance open and does not allow for flushing action, instead causing a slow, constant drain.

Another protective role of mucus is to bind proteins that have antibacterial activity (Table 2-2). Lysozyme is a major host defense protein found in tears, saliva, milk, and mucus and is also secreted by Paneth cells found at the bottom of crypts along the small intestine. Lysozyme is an enzyme that targets the peptidoglycan of the bacterial cell wall and hydrolyzes the linkage between N-acetylmuramic acid and N-acetyl-D-glucosamine (Figure 2-5). It is most effective against the cell walls of Gram-positive bacteria, but it can also digest and weaken the cell walls of Gram-negative bacteria, especially if membrane-disrupting substances, such as the detergent-like bile salts found in the intestine, first breach the outer membrane. Phospholipase is an enzyme found in tears and secreted by Paneth cells that degrades the cytoplasmic membrane to lyse bacterial cells. Lactoferrin is an iron-binding, secreted protein found in mucus that sequesters iron and deprives bacteria of this essential nutrient.

Lactoperoxidase is another protein with antibacterial activity that is found in secretory fluids (e.g., milk, tears, saliva, and airway mucus). Lactoperoxidase is a heme-containing peroxidase that uses hydrogen peroxide (H2O2) as an oxidant to generate highly reactive oxygen species that kill bacteria. An important substrate is thiocyanate (SCN-), which is converted into hypothiocyanite (OSCN-), a potent bactericidal reagent. It is believed that exposed thiol groups (-SH) of enzymes and other proteins on the bacterial membrane surface are the primary targets of these reactive oxidants, which oxidize the thiols and thereby disrupt the normal function of the bacterial surface proteins.

Paneth cells also secrete toxic antimicrobial peptides (Figure 2-6), such as defensins (known as cryptdins in mice), cathelicidins, and histatins, which contain highly cationic (basic) regions that enable them to interact with negatively charged phospholipids and interact with or insert into bacterial cell membranes. These defensins kill bacteria by forming channels or holes in their membranes and depolarizing the cell by collapsing the proton-motive force (the potential energy stored as an electrochemical gradient across a membrane) that is essential for bacterial survival. This type of activity is responsible for the effectiveness of one of the first antibiotics, gramicidin, which is a pore-forming protein that kills bacteria. Defensins and other antimicrobial peptides have been found in the mouth, on the tongue, on skin, in the vagina, in the lungs, and in the crypts of the small and large intestines.

Figure 2-6. Three types of bacterial membrane permeabilization by gut antimicrobial peptides. Several antimicrobial peptides (AMPs) secreted by epithelial and Paneth cells in the intestine kill bacteria by forming pores in membranes. (A) α-defensin is expressed as an inactive propeptide that is processed and activated by proteases (MMP7 in mice and trypsin in humans). (B) REG3α is expressed as an inactive propeptide that is processed by proteolytic cleavage. The activated REG3α then binds to bacterial peptidoglycan and oligomerizes to form a hexameric pore in bacterial membranes. (C) Cathelicidins, such as LL-37, first bind to bacterial membranes via electrostatic interactions, then form α-helical structures in the presence of lipids and insert into the bacterial membrane to form pores. Adapted from Mukherjee S, Hooper LV. 2015. Immunity 42:28–39, with permission.

In the mouth, defensins may be the reason why infections of the tongue are so rare and why animals lick wounds. In the crypts of the intestinal mucosa, they are presumably protecting the intestinal stem cells, which divide constantly to replenish the cells of the intestinal mucosa. These peptides probably have some antibacterial effects that protect these locations from bacteria. It is worth keeping in mind, however, that the membrane-disrupting activity of these peptides can be inhibited by physiological salt concentrations or by serum. Consequently, their most important antibacterial activities may be exerted largely in another location where they are found: vacuoles inside phagocytic cells that engulf and kill bacteria.

Special Defenses of the Gastrointestinal Tract

Different regions of the gastrointestinal tract (Figure 2-7) have special antibacterial features that serve as barriers to pathogens. The lumen of the stomach has an extremely acidic environment (pH ∼2). It was previously thought that most bacteria could not survive there, but scientists have found DNA from 128 different species of bacteria occupying the stomach. The only bacterium inhabiting this harsh environment that has been studied in detail is Helicobacter pylori, which causes gastritis, gastric ulcers, and even gastric cancer. In fact, H. pylori does not actually live in the lumen of the stomach, but rather in the mucin layer that covers and protects the stomach lining. Cells in the stomach lining secrete carbonate, which buffers the mucin layer to near neutral pH. H. pylori has the ability to protect itself long enough to reach the mucin layer and thus is not killed as readily as many bacteria are when they are exposed to the highly acidic environment of the stomach.

Figure 2-7. The gastrointestinal tract. Different types and quantities of bacteria, mostly strict or facultative anaerobes, colonize along the gastrointestinal tract as the environments change with pH, bile, mucus content, digestive enzymes, and transit time. Data from Sartor RB. 2008. Gastroenterology 134:577–594.

Other bacteria, including a number of foodborne pathogens (e.g., E. coli, Salmonella, and Campylobacter), have a response to acid that makes them better able to survive for short periods of time at pH 4 (acid tolerance response). This is higher than the pH of the stomach interior, so how could it be protective? One speculation is that bacteria ingested in foods are protected from the full impact of stomach acid by the buffering capacity of the food, although they would still be exposed to conditions well below pH 7. Even though they still cannot survive in the stomach for prolonged periods of time, the bacteria capable of mounting an acid tolerance response may be able to survive long enough to reach the small intestine.

That many bacteria do not survive passage through the stomach to areas more favorable for bacterial growth, like the small intestine and colon, shows how the acidic environment of the stomach lumen does not just contribute to the digestion of food, but also acts as a protective barrier. Another indicator of the protective effect of the acidic environment of the stomach is that people who have achlorhydria, a condition that results in a less acidic stomach pH, have increased susceptibility to infections of the lower intestinal tract. Likewise, the U.S. Food and Drug Administration (FDA) has cited the widespread use of proton-pump inhibitor (PPI) drugs that block gastric acid production and reduce stomach acidity as a potential risk for increased intestinal infection.

For those bacteria that manage to survive the acid barrier of the stomach, bile salts await them in the small intestine and colon. Bile salts are steroids with detergent-like properties that are produced in the liver, stored in the gallbladder, and then released through the bile duct into the intestine when food is passing through. Bile salts help neutralize the stomach acid and are used to emulsify lipids in food to enable fat digestion and absorption through the intestinal wall. The detergent-like properties of bile salts help disrupt bacterial membranes, especially those of Gram-negative bacteria.

An equally important protection of the small intestine is the rapid flow of contents through the small intestine. This rapid flow, together with the bile salts and the rapid turnover of intestinal mucosal cells, helps keep high concentrations of bacteria from developing in the small intestine. High concentrations of bacteria would not only increase the chance that bacteria could invade the small intestinal mucosa, but also allow bacteria to compete more effectively for the nutrients (e.g., simple sugars, amino acids) that the small intestine is designed to absorb. In the colon, the flow rate of contents is drastically reduced compared to the flow rate in the small intestine. Some scientists have compared the difference to the passage from a rapidly flowing stream (small intestine) to a nearly stagnant pond (colon).

The importance of the rapid flow rate of contents through the small intestine as a protection against bacterial colonization is underscored by the fact that bacterial pathogens that cause intestinal infections such as gastroenteritis (diarrhea and pain) generally are able to swim to the mucosa of the small intestine and attach to the mucosal cells, thus keeping them from being washed out of the colon. Another illustration of the importance of rapid flow of contents is the fact that people who develop blind loops, or regions of outpouching that have rather stagnant contents, have problems due to the buildup of bacteria within those regions. At one time, the intentional surgical introduction of blind loops in the small intestine was tried as a means of weight reduction. Not surprisingly, a side effect of this in some people was the development of sepsis caused by an invasion of some of the bacteria that reached high concentrations in the blind loop and were thus better able to penetrate the fragile mucosal layer.

Special Defenses of the Urogenital Tract

The female and male urogenital tracts (Figure 2-8) offer different environments and so different bacteria are associated with the different areas. As with other mucosal areas, the epithelial layer of the urinary tract system (the kidneys, ureters, bladder, and urethra) is protected by secretion of mucin, blocking the bacteria from gaining access to the surface. The bladder is typically sterile in both males and females, and a number of defenses protect the urinary tract. The urethra sphincter prevents further ascent of the bacteria to the bladder and kidney. Urine itself is antiseptic, and flushing of the bladder with urine helps remove bacteria that manage to ascend the urethra. The prostate gland in men secretes defensins.

Figure 2-8. Comparison of the female and male urogenital tracts. Anatomical differences between the female and male urogenital tracts result in different environments and physical barriers that lead to different bacteria colonizing different sites. Physical barriers include a sphincter at the opening of the urethra that prevents ascent of microbes to the bladder and kidney. The urethra is shorter in females than males. Flushing of the bladder and urethra with urine removes adherent bacteria. Secretion of mucin blocks microbes from gaining access to the epithelial surface. A cervical mucus plug protects the uterus and fallopian tubes in females. Lactobacillus species, major resident bacteria in healthy females, protect the vaginal cavity from other bacteria that might enter from the anal area, which is relatively close to the vaginal opening. Sexually active partners exchange their resident microbiota with each other.

Altered conditions, such as pH changes or obstructions, can facilitate certain pathogens (e.g., E. coli, Proteus mirabilis, Staphylococcus saprophyticus, and Klebsiella species) to colonize the urethra and cause urinary tract infections (UTIs), especially in women. Almost 95% of UTIs are attributed to bacteria that normally reside at the opening of the urethra and travel up to the bladder and occasionally as far as the kidney. Women are more likely to get UTIs because in females the urethra is much shorter and closer to the anus. Some anatomical obstructions of the ureter or the urethra, such as prostate enlargement, kidney transplant, or bladder or kidney dysfunction, as well as indwelling catheter use, can impair bacterial clearance by urine and promote bacterial growth and infection.

In the vagina, a cervical plug protects the uterus and fallopian tubes from invasion by bacteria. The vagina is lined by a stratified epithelium, which produces a variety of protective defense mechanisms, including lysozyme, lactoferrin, small antimicrobial cationic peptides, and proteins (such as secreted IgA and IgG antibodies, secretory leukocyte protease inhibitors, and various cytokines and chemokines). The resident microbiota plays an important protective function against pathogens in the female genital tract. The application of molecular sequencing technologies over the past decade has contributed greatly to our understanding of urogenital microbiome composition and dynamics. In sexually active partners, the microbiota exchange freely and influence each other. There are also age-specific changes to the microbiomes and immune functions that occur, especially in response to hormones in women. Resident vaginal bacteria are thought to help prevent acquisition of sexually transmitted infections, such as HIV.

Lactobacillus species are the major resident vaginal bacteria found in healthy humans. Lactobacillus bacteria ferment glycogen, which is abundantly produced in the vaginal tract. These bacteria produce hydrogen peroxide and lactic acid, which helps maintain a weakly acidic (pH 4–5) environment that serves to inhibit the growth of other microbes, thereby preventing infection by yeast (vulvovaginal candidiasis or vaginitis) and bacteria (bacterial vaginosis). Humans are unique among primates in having a vaginal microbiome dominated by Lactobacillus species, though it is not known why. How the vaginal mucosa tolerates chronic colonization with Lactobacillus species, while still protecting against colonization by other microbes, is an area of active research.

Special Defenses of the Respiratory Tract

The respiratory system is comprised of a ciliated epithelial cell layer that is interspersed with goblet cells that secrete mucin. In the respiratory tract (as well as in the fallopian tubes of the vaginal tract), there are specialized ciliated columnar cells, whose elongated protrusions (cilia) continuously wave in the same direction. The waving action of the cilia propels mucus blobs out of the area. Airway epithelial cells also secrete collectins (collagen-containing C-type lectins), including surfactants A and D that bind to bacterial lipopolysaccharide (LPS), defensins and other antimicrobial peptides, and proteases. Hospitals often encounter problems associated with comatose patients, in which the absence of a normal cough reflex and reduced mucociliary clearance result in an increased susceptibility to respiratory infections. Turbulence of airflow from breathing, coughing, and sneezing serves to expel microbes out of the lungs, sometimes at velocities reaching over 150 cm/sec. In hospitals, problems can occur with respirators, which introduce air with tiny water droplets potentially contaminated with pathogens directly into the lung, thereby bypassing the upper respiratory airflow and mucociliary defenses.

The upper and lower respiratory tracts have different environments, and different commensal and pathogenic microbes are associated with the different areas (Figure 2-9). A healthy lower respiratory tract lacks significant microbiota, while a few bacteria normally colonize the upper respiratory tract, most notably Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and nontoxigenic Corynebacterium diphtheriae, all of which are potential pathogens and are known to cause upper and lower respiratory infections when the immune system is impaired. In lung diseases such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease, other pathogens also colonize the lungs, including Pseudomonas aeruginosa, Burkholderia cepacia, and Mycoplasma pneumoniae. In humans, colonization of the lower respiratory tract with Bordetella pertussis always leads to disease symptoms of whooping cough.

Figure 2-9. The upper and lower respiratory tract. The respiratory system is comprised of a ciliated epithelial cell layer that secretes mucus. Turbulence of airflow and mucociliary action help keep the lungs clear of particles and microbes. The upper respiratory tract includes the nose, nasal cavity, mouth, throat (pharynx), and voice box (larynx). The upper respiratory tract is often colonized by Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and nontoxigenic Corynebacterium diphtheriae. These bacteria can be opportunistic pathogens under certain conditions or when they colonize the lower respiratory tract. The lower respiratory tract includes the trachea, bronchi, and lungs (alveoli). The lungs are normally clear of bacteria, but can be invaded by opportunistic or outright pathogens during infection or under certain conditions. Data from Madigan MT, Martinko JM, Stahl D, Clark DP. 2015. Brock Biology of Microorganisms, 13th ed. Pearson, Upper Saddle River, NJ.

Immune Defenses of the Skin and Mucosa

Although this chapter focuses on the protective physical and biochemical barriers provided by intact skin and mucosa, it is important to note that these barriers are backed up by specialized portions of the immune system, which will be described in more detail in subsequent chapters. For example, bacteria that manage to get past the epidermis through cuts or burns encounter a specialized cell type called Langerhans cells. Langerhans cells belong to a class of cells called dendritic cells (DCs) that process the invading bacteria and activate the immune cells of the skin-associated lymphoid tissue (SALT). We will discuss the role of phagocytes (e.g., macrophages and dendritic cells) in chapter 3 when we cover “The Innate Immune System: Always on Guard.”

As was the case with skin, mucosal surfaces generally have an underlying population of phagocytic cells and immune cells. This mucosal defense system, which is distinct from the system that controls immune cells in blood, lymph nodes, and other organs, is called the mucosa-associated lymphoid tissue (MALT). The mucosal surface of the small intestine is underlain with the gastrointestinal-associated lymphoid tissue (GALT), while the lungs have bronchial-associated lymphoid tissue (BALT) and the upper respiratory tract has nasopharyngeal-associated lymphoid tissue (NALT).

These mucosal defense systems at the interface of the innate and adaptive immune systems are composed of macrophages, T cells, B cells, and M cells (microfold cells that engulf gut lumen contents and present them to underlying antigen-presenting cells). Their primary function is to make secretory IgA (sIgA), an antibody that is secreted into mucus. Antibodies are proteins that bind to specific sites on bacteria or other pathogens. sIgA is thought to increase the stickiness of mucin by attaching to mucin sugars at one end, leaving its two other antigen-binding ends free to bind and trap bacteria trying to reach the mucosal layer. The sIgA-trapped bacteria are then sloughed off along with the mucin. We will return to the role of MALT in chapter 4.

Models for Studying Breaches of Barrier Defenses

Animal models have been widely used to study skin, eye, and mucosal infections. Because some of these animal models involve breaches such as cuts or burns that can be damaging and painful, experimental protocols must include explicit plans to monitor and minimize pain and discomfort to the animals as much as possible and to minimize the number of animals needed to obtain statistically significant results. When available, validated alternative infection models that do not involve animals should be used. In addition, a committee with expertise in animal welfare and experimentation must first approve the rationale for experiments on animals and the detailed protocols themselves before the experiments are performed. Some of the ethical and procedural issues that lead to appropriate animal experimentation are discussed later in chapter 8. For continuity, some of the models used to study eye, skin, and mucosal infections are mentioned here without this context.

One of the earliest models for studying skin infections is the burned-rodent model. A patch of skin on an animal that is anesthetized is shaved and then burned with an alcohol flame. Just as is the case with human burns, bacteria that could not infect intact skin can infect the burned rodent tissue. The eye is another surface of the body that is remarkably resistant to infection. Eye infections of the sort seen in patients who have been careless with contact lenses or have suffered small cuts in the cornea are mimicked by a rabbit model, in which small shallow cuts are made in the cornea of an anesthetized animal’s eye. Both of these models have been used extensively to study infections caused by P. aeruginosa, one of the main causes of burn and eye infections in humans.

In the previous chapter, some unusual lower animal models were mentioned. Caenorhabditis elegans (worms) and Drosophila (flies) are not very useful for studies of skin infections, because the “skin” of these organisms is chitinous rather than epithelial. The zebra fish is a better model, especially for studies of the mucosal defenses. More recently, infection models have been developed based on tissues from, for example, chicken embryos. Rodents have been widely used to investigate pathogens, such as Salmonella, that bind to the intestinal mucosa. In rodents, these pathogens can sometimes cause more invasive infections than they cause in humans, but the interaction between the bacteria and the mucosa can nonetheless be followed even in these cases. A rodent model has been developed in which autoclaved feces, inoculated only with the bacterium of interest, are implanted in the intra-abdominal area of the rodent to mimic the effects of surgical penetration of the colonic mucosa.

The impact of toxins, such as diarrhea-causing toxins, on the small intestine can be monitored by the rabbit ileal loop model (Figure 2-10). In this model, the small intestine of an anesthetized rabbit is tied off into 5- to 10-cm sections by suture, the toxin or toxin-producing bacterium is injected into one of the sections (loops), and the organ is placed back into the peritoneal cavity. Many diarrheal toxins cause water to be lost by the intestinal tissues into the lumen of the gut, and this can be observed by a swelling of the section into which the toxin was injected. After 12 to 24 hours, the animal is sacrificed and the loop length and fluid volume (in ml/cm) are measured as readout. Distension (i.e., swelling) of the ileal loop section indicates release of the fluid into the lumen of the segment as a result of toxin action.

Figure 2-10. The rabbit ileal loop model of diarrheal disease. Shown are tied-off segments (loops) of rabbit ileal injected with culture filtrates from an E. coli strain producing cholera-like toxin that induces diarrhea. Loop 1 was injected with positive control solution of cholera toxin, loop 2 with negative control solution of phosphate-buffered saline, and loops 3 through 6 with increasing amounts of E. coli culture filtrates. After overnight exposure in the animal, the animal is sacrificed and the ileal loops are removed and examined for distension (swelling). Reproduced from Sack RB. 2011. Indian J Med Res 133:171–180, with permission.

Genetically engineered mice called transgenic mice or knockout mice are being increasingly used in experiments to probe the interaction of the normal microbiota and the intestinal mucosal cells because they have genes that have been altered or disrupted. Unexpectedly, some of the mice designed originally for studies of the immune system that were missing genes encoding the cytokines, interleukins IL-1 and IL-10 (see chapter 3), proved to be good models for a type of intestinal inflammation called inflammatory bowel disease (IBD). The presence of the normal bacterial microbiota of the colon seems to be responsible for the inflammatory bowel condition seen in some of these mice.

These examples are given to provide an introduction to the types of animal models that are available for studying the protective features of skin and mucosa and the consequences of breaching these barriers. Additional animal models used in connection with studying bacterial diseases, as well as alternatives to animal models such as mammalian host cells cultured in vitro in the laboratory, will be described in chapter 8 and other chapters covering specific types of infectious diseases.

SELECTED READINGS

Bik EM, Eckburg PB, Gill SR, Nelson KE, Purdom EA, Francois F, Perez-Perez G, Blaser MJ, Relman DA. 2006. Molecular analysis of the bacterial microbiota in the human stomach. Proc Natl Acad Sci USA 103:732–737.[PubMed][CrossRef]

Cooper GM, Hausman RE. 2007. The Cell—A Molecular Approach, 4th ed. ASM Press, Washington, DC.

Hooper LV. 2004. Bacterial contributions to mammalian gut development. Trends Microbiol 12:129–134.[PubMed][CrossRef]

Hooper LV, Wong MH, Thelin A, Hansson L, Falk PG, Gordon JI. 2001. Molecular analysis of commensal host-microbial relationships in the intestine. Science 291:881–884.[PubMed][CrossRef]

Mirmonsef P, Spear GT. 2014. The barrier to HIV transmission provided by genital tract Lactobacillus colonization. Am J Reprod Immunol 71:531–536.[PubMed][CrossRef]

Mukherjee S, Hooper LV. 2015. Antimicrobial defense of the intestine. Immunity 42:28–39.[PubMed][CrossRef]

Pronovost P, Needham D, Berenholtz S, Sinopoli D, Chu H, Cosgrove S, Sexton B, Hyzy R, Welsh R, Roth G, Bander J, Kepros J, Goeschel C. 2006. An intervention to decrease catheter-related bloodstream infections in the ICU. N Engl J Med 355:2725–2732.[PubMed][CrossRef]

Salemi C, Canola MT, Eck EK. 2002. Hand washing and physicians: how to get them together. Infect Control Hosp Epidemiol 23:32–35.[PubMed][CrossRef]

Servin AL. 2004. Antagonistic activities of lactobacilli and bifidobacteria against microbial pathogens. FEMS Microbiol Rev 28:405–440.[PubMed][CrossRef]

Strober W. 2006. Immunology. Unraveling gut inflammation. Science 313:1052–1054. [Review of an article in the same issue of the journal.][PubMed][CrossRef]

Toke O. 2005. Antimicrobial peptides: new candidates in the fight against bacterial infections. Biopolymers 80:717–735.[PubMed][CrossRef]

Winslow EH, Jacobson AF. 2000. Can a fashion statement harm the patient? Long and artificial nails may cause nosocomial infections. Am J Nurs 100:63–65.[PubMed]

Questions

1. In what sense are S. epidermidis infections an example of how changing human practices can provide new opportunities for bacterial pathogens? S. epidermidis is classified as an opportunist. Why is this the case?

2. Explain why infections of the skin occur more often in folds of the skin or under bandages than in regions of skin exposed to air.

3. How and why do the defenses of mucosal surfaces differ from those of the skin? How do they resemble each other?

4. Consider a bacterium that is ingested via contaminated water and locally colonizes the small intestine. What host defenses would hamper this type of colonization from occurring initially and from leading to an infection in an unimmunized person?

5. Resident microbiota are essential in preventing the colonization of pathogenic bacteria in certain parts of the body. Name the regions of the body where normal microbiota might be protective. Name some mechanisms by which they accomplish this protection. Name some organs that normally remain sterile to bacterial contamination and that do not contain a resident microbiota.

6. Why are people with indwelling catheters more susceptible to infection?

7. Explain the role that mucin plays in host defense.

8. Lysozyme is more effective against growing bacteria. Why might that be so? Why is lysozyme digestion often more effective against Gram-positive bacteria than Gram-negative bacteria?

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