Defenses of the skin and Mucosa
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 the skin. The dead cells of the epidermis are continuously shed (desquamation). Thus, bacteria that manage to bind to epidermal cells are constantly being removed from the body.
Skin is dry and has an acidic pH (pH 5), two features that inhibit the growth of many pathogenic bacteria, which prefer a wet environment with a neutral pH (pH 7). The temperature of the skin (34 C to 35 C) is lower than that of body interior. Accordingly, bacteria that succeed in colonizing the skin must be able to adapt to the very different internal environment of the body if they manage to reach underlying tissue.
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 protected by the peptidoglycan-degrading lysozyme and by lipids that are toxic to many bacteria.
The defenses of the skin do not completely prevent bacterial growth, as is evident from the fact that there are bacteria capable of colonizing the surface of the skin. The consist primarily of gram-positive bacteria, a mixture of cocci and rods. The commensal microbiota of the skin helps to protect against pathogenic bacteria by occupying sites that might be colonized by pathogenic bacteria. It also competes with incoming pathogens for essential nutrients. Some resident bacteria also produce bactericidal compounds which target other bacteria. The commensal microbiota does not completely prevent colonization of the skin by potential pathogens but hampers it enough so that the colonization by pathogenic bacteria is usually transient.
The respiratory tract, gastrointestinal tract, and urogenital tract are topologically “inside” the body, but they are exposed constantly to the outer environment and foreign materials.
Internal surface areas/mucosal epithelia are comprised of only one epithelial layer. Mucosal epithelia have a temperature of around 37 C and a pH of 7.0 to 7.4. Mucosal epithelia are continuously bathed in fluids.
Mucosal cells are regularly replaced and old cells are ejected into the lumen. Thus, bacteria that manage to reach and colonize a mucosal surface are constantly being eliminated from the mucosal surface and can remain in the area only if they can grow rapidly enough to colonize newly produced cells.
Chemical and other innate defenses help to 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.
Mucus is an important defense that protect mucosal from bacteria. Mucus is a mixture of glycoproteins produced by goblet cells, a specialized cell type incorporated into the epithelial layer. Mucus has a viscous, slimy consistency, which allows it to act as a lubricant. Mucus plays a protective role because it traps bacteria and prevents them from reaching the surfaces of the mucosal. Mucus is constantly being produced, and excess mucus is shed in blobs that are expelled. Bacteria trapped in mucus are thus eliminated from the site.
In the gastrointestinal and urinary tracts, peristalsis and the rapid flow of liquids through the area remove the mucus blobs, along with the lumen contents.
In the respiratory tract and in the fallopian tubes, there are specialized cells, ciliated columnar cells, whose elongated protrusions (cilia) are continuously waving in the same direction. The waving action of the cilia propels mucus blob out of the area. Mucus has proteins that have antibacterial activity and these proteins include lysozyme, lactoperoxidase, toxic antimicrobial peptides (defensins, cathelicidins, histatins). Lactoferrin sequesters iron and deprives bacteria of this essential nutrient.
Most mucosal surfaces are protected by a normal resident microbiota, except uterus and upper female genital tract and the urinary tract. Resident microbiota on mucosal surface predominately consists of gram-positive bacteria.
Special defenses of the gastrointestinal tract
The lumen of the stomach is an extremely acidic environment (pH ~2), which acts as a protective barrier to prevent bacteria from reaching more vulnerable areas, such as the small intestine and colon, where conditions are more favorable for bacterial growth. Bacteria ingested in foods are probably protected somewhat from the full impact of stomach acid by the buffering capacity of the food. Food increase the chance that some of the bacteria might survive long enough in the stomach to reach the small intestine.
Bile salts are steroids with detergent-like properties that are produced in the liver, stored in the gall bladder, and then released through the bile duct into the intestine. The detergent-like properties of bile salts help to disrupt bacterial membranes, especially those of gram-negative bacteria.
Defenses of The Innate Immune System
Skin and mucosal surfaces (barriers) are highly effective in preventing pathogenic bacteria from entering tissue and blood, but from time to time, bacteria succeed in breaching these surfaces. Bacteria that get this far encounter a formidable defense force, the phagocytic cells (neutrophils, monocytes, macrophages, and dendritic cells), natural killer cells, and the proteins that help organize their activity. These cells, together with a set of blood proteins called complement and another set of proteins called cytokines are called the innate immune system. Innate immune system plays a key role in the defence reactions against foreign invaders and correlates with inflammation.
The Firepower of Innate Immune System
The firepower of the innate immune system is very effective in killing bacteria. The phagocyte first forms pseudopods that engulf the bacterium. After engulfment, the bacterium is encased in an endocytic vesicle called phagosome. Various lysosomal enzymes, antimicrobial peptides, membrane-permeabilizing proteins, and degrading proteins mediate nonoxidative killing. Oxidative killing occurs through the formation of toxic reactive oxygen species.
Unlike phagocytic cells, NK cells do not ingest their targets, although their mode of killing resembles that of phagocytes in many respects. NK cells store their toxic substances in granules. Binding to an infected human target cell stimulates the release of these granules. To distinguish a infected cell from a healthy cell, the NK cell use the MHC-I molecule. Healthy cells express MHC-I protein on their surfaces, and MHC-I binds to a second inhibitory receptor on the NK cell surface and halts the activation of the cytotoxic response. In contrast, infected cells express much less MHC-I on their surfaces than normal cells, and the activation response of the NK cell proceeds, leading to an attack on the infected cell. Thus, instead of ingesting a bacterium or infected cell, the innate cytotoxic NK cells bombard infected cells. Cytotoxic-cell granules contain a protein called perforin that insets into the membrane of a target cell and causes channels to form. These channels allow other granule proteins, a set of proteases called granzymes, to enter the target cell. One effect of this assult appears to be forcing the target cell to initiate apoptosis.
C3a and C5a are proinflammatory molecules that stimulate mast cells to release their granules, which contain vasoactive substance that increase the permeability of blood vessels and thus facilitate the movement of phagocytes from blood vessels into tissue. C5a also acts together with cytokines to signal phagocytes to leave the bloodstream and to guide them to the infection site. Once PMNs or monocytes have left the bloodstream, they move along a gradient of C5a to find the locus of infection. At the site of infection, C3b binds to the surface of the invading bacterium and makes it easier for phagocytes to ingest the bacterium. This activity is called opsonization.
Another role of activated complement components is direct killing of the bacterium. Activated components C5b recruits C6, C7, C8, and C9 to form a membrane-damaging complex in the membranes of some types of microorganisms. This complex is called the membrane attack complex (MAC). Formation of the MAC inactivates enveloped viruses and kills bacteria by punching holes in their membranes.
Correlations Between Innate Immune System and Inflammation
Inflammation is one imporant response of vascular tissues to harmful stimuli, such as damaged tissues and the release of irritants, caused by infection. The inflammatory response recruits innate-immune cells from the blood vessels to the site of infection. Proinflammatory cytokines are induced by the complement cascade (C3a and C5a, phagocytes have receptors for C3b on their surface) and by mast cells (mast cells secrete vasoactive amines including histamine and serotonin) and activated phagocytes.