Bacterial Pathogenesis. Brenda A. Wilson
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.