13.2 Chemical Defenses

Learning Objectives

• Describe how enzymes in body fluids provide protection against infection or disease
• List and describe the function of antimicrobial peptides, complement components, cytokines, and acute-phase proteins
• Describe similarities and differences among classic, alternate, and lectin complement pathways

In addition to physical defenses, the innate nonspecific immune system uses a number of chemical mediators that inhibit microbial invaders. The term “chemical mediators” encompasses a wide array of substances found in various body fluids and tissues throughout the body. Chemical mediators may work alone or in conjunction with each other to inhibit microbial colonization and infection.

Some chemical mediators are endogenously produced, meaning they are produced by human body cells; others are produced exogenously, meaning that they are produced by certain microbes that are part of the microbiome. Some mediators are produced continually, bathing the area in the antimicrobial substance; others are produced or activated primarily in response to some stimulus, such as the presence of microbes.

Chemical and Enzymatic Mediators Found in Body Fluids

Fluids produced by the skin include examples of both endogenous and exogenous mediators. Sebaceous glands in the dermis secrete an oil called sebum that is released onto the skin surface through hair follicles. This sebum provides an additional layer of defense by helping seal off the pore of the hair follicle, preventing bacteria on the skin’s surface from invading sweat glands and surrounding tissue (Figure 13.7). Certain members of the microbiome can use lipase enzymes to degrade sebum, using it as a food source. This produces oleic acid, which creates a mildly acidic environment on the surface of the skin that is inhospitable to many pathogenic microbes. Oleic acid is an example of an exogenously produced mediator because it is produced by resident microbes and not directly by body cells.

Environmental factors that affect the microbiota of the skin can have a direct impact on the production of chemical mediators. Low humidity or decreased sebum production, for example, could make the skin less habitable for microbes that produce oleic acid, thus making the skin more susceptible to pathogens normally inhibited by the skin’s low pH. Many skin moisturizers are formulated to counter such effects by restoring moisture and essential oils to the skin.

The digestive tract also produces a large number of chemical mediators that inhibit or kill microbes. In the oral cavity, saliva contains mediators such as lactoperoxidase enzymes, and mucus secreted by the esophagus contains the antibacterial enzyme lysozyme. In the stomach, highly acidic gastric fluid kills most microbes. In the lower digestive tract, the intestines have pancreatic and intestinal enzymes, antibacterial peptides, bile produced from the liver, and specialized Paneth cells that produce lysozyme. Together, these mediators are able to eliminate most pathogens that manage to survive the acidic environment of the stomach.

In the urinary tract, urine flushes microbes out of the body during urination. Furthermore, the slight acidity of urine (the average pH is about 6) inhibits the growth of many microbes and potential pathogens in the urinary tract.

The female reproductive system employs lactate, an exogenously produced chemical mediator, to inhibit microbial growth. The cells and tissue layers composing the vagina produce glycogen, a branched and more complex polymer of glucose. Lactobacilli in the area ferment glycogen to produce lactate, lowering the pH in the vagina and inhibiting transient microbiota, opportunistic pathogens like Candida (a yeast associated with vaginal infections), and other pathogens responsible for sexually transmitted diseases.

In the eyes, tears contain the chemical mediators lysozyme and lactoferrin, both of which are capable of eliminating microbes that have found their way to the surface of the eyes. Lysozyme cleaves the bond between NAG and NAM in peptidoglycan, a component of the cell wall in bacteria. It is more effective against gram-positive bacteria, which lack the protective outer membrane associated with gram-negative bacteria. Lactoferrin inhibits microbial growth by chemically binding and sequestering iron. This effectually starves many microbes that require iron for growth.

In the ears, cerumen (earwax) exhibits antimicrobial properties due to the presence of fatty acids, which lower the pH to between 3 and 5.

The respiratory tract uses various chemical mediators in the nasal passages, trachea, and lungs. The mucus produced in the nasal passages contains a mix of antimicrobial molecules similar to those found in tears and saliva (e.g., lysozyme, lactoferrin, lactoperoxidase). Secretions in the trachea and lungs also contain lysozyme and lactoferrin, as well as a diverse group of additional chemical mediators, such as the lipoprotein complex called surfactant, which has antibacterial properties.

• What are difference substances produced by the body or the body’s microbiome, that help protect against microbial invaders?
• Describe how pH affects antimicrobial defenses.

Antimicrobial Peptides

The antimicrobial peptides (AMPs) are a special class of nonspecific cell-derived mediators with broad-spectrum antimicrobial properties. Some AMPs are produced routinely by the body, whereas others are primarily produced (or produced in greater quantities) in response to the presence of an invading pathogen. Research has begun exploring how AMPs can be used in the diagnosis and treatment of disease.

AMPs may induce cell damage in microorganisms in a variety of ways, including by inflicting damage to membranes, destroying DNA and RNA, or interfering with cell-wall synthesis. Depending on the specific antimicrobial mechanism, a particular AMP may inhibit only certain groups of microbes (e.g., gram-positive or gram-negative bacteria) or it may be more broadly effective against bacteria, fungi, protozoa, and viruses. Many AMPs are found on the skin, but they can also be found in other regions of the body.

A family of AMPs called defensins can be produced by epithelial cells throughout the body as well as by cellular defenses such as macrophages and neutrophils. Defensins may be secreted or act inside host cells; they combat microorganisms by damaging their plasma membranes. AMPs called bacteriocins are produced exogenously by certain members of the resident microbiota within the gastrointestinal tract.

• Why are antimicrobial peptides (AMPs) considered nonspecific defenses?

Plasma Protein Mediators

Many nonspecific innate immune factors are found in plasma, the fluid portion of blood. Plasma contains electrolytes, sugars, lipids, and proteins, each of which helps to maintain homeostasis (i.e., stable internal body functioning), and contains the proteins involved in the clotting of blood. Additional proteins found in blood plasma, such as acute-phase proteins, complement proteins, and cytokines, are involved in the nonspecific innate immune response.

Acute-Phase Proteins

The acute-phase proteins are another class of antimicrobial mediators. Acute-phase proteins are primarily produced in the liver and secreted into the blood in response to inflammatory molecules from the immune system.

The Complement System

The complement system is a group of plasma protein mediators that can act as an innate nonspecific defense while also serving to connect innate and adaptive immunity (discussed in the next chapter). The complement system is composed of more than 30 proteins that normally circulate as precursor proteins in blood. These precursor proteins become activated when stimulated or triggered by a variety of factors, including the presence of microorganisms. Complement proteins are considered part of innate nonspecific immunity because they are always present in the blood and tissue fluids, allowing them to be activated quickly.

Cytokines

Cytokines are soluble proteins that act as communication signals between cells. In a nonspecific innate immune response, various cytokines may be released to stimulate production of chemical mediators or other cell functions, such as cell proliferation, cell differentiation, inhibition of cell division, apoptosis, and chemotaxis.

Three important classes of cytokines are the interleukins, chemokines, and interferons. The interleukins were originally thought to be produced only by leukocytes (white blood cells) and to only stimulate leukocytes, thus the reasons for their name. Although interleukins are involved in modulating almost every function of the immune system, their role in the body is not restricted to immunity. Interleukins are also produced by and stimulate a variety of cells unrelated to immune defenses.

The chemokines are chemotactic factors that recruit leukocytes to sites of infection, tissue damage, and inflammation. In contrast to more general chemotactic factors, like complement factor C5a, chemokines are very specific in the subsets of leukocytes they recruit.

Interferons are a diverse group of immune signaling molecules and are especially important in our defense against viruses. Type I interferons (interferon-α and interferon-β) are produced and released by cells infected with virus. These interferons stimulate nearby cells to stop production of mRNA, destroy RNA already produced, and reduce protein synthesis. These cellular changes inhibit viral replication and production of mature virus, slowing the spread of the virus. Type I interferons also stimulate various immune cells involved in viral clearance to more aggressively attack virus-infected cells. Type II interferon (interferon-γ) is an important activator of immune cells (Figure 13.8).

Inflammation-Eliciting Mediators

Many of the chemical mediators discussed in this section contribute in some way to inflammation and fever, which are nonspecific immune responses discussed in more detail in Inflammation and Fever. Cytokines stimulate the production of acute-phase proteins, which act as opsonins, activating complement cascades through the lectin pathway.

Some cytokines also bind mast cells and basophils, inducing them to release histamine, a proinflammatory compound. Histamine receptors are found on a variety of cells and mediate proinflammatory events, such as bronchoconstriction (tightening of the airways) and smooth muscle contraction.

Certain cytokines also stimulate the production of prostaglandins, chemical mediators that promote the inflammatory effects of kinins and histamines. Prostaglandins can also help to set the body temperature higher, leading to fever, which promotes the activities of white blood cells and slightly inhibits the growth of pathogenic microbes (see Inflammation and Fever).

Another inflammatory mediator, bradykinin, contributes to edema, which occurs when fluids and leukocytes leak out of the bloodstream and into tissues. It binds to receptors on cells in the capillary walls, causing the capillaries to dilate and become more permeable to fluids.

• What are the proteins found in plasma that contribute to our defense?
• Name two important inflammation-eliciting mediators.

Table 13.3 provides a summary of the chemical defenses discussed in this section.