Chapter 2: Body's Defense Strategies

• The body is analogous to a medieval castle, with defensive strategies protecting against microbial invasion.
• Successful invading bacteria (pathogens) have evolved virulence strategies to overcome the body’s defenses.

Avoiding Exposure

• Preventing exposure to pathogens is the best line of defense.
• This includes using gloves, protective clothing, and eyewear; disinfecting instruments and surface areas.

Reducing Bacterial Numbers

• Reducing contact with bacteria limits the risk of colonization and infection.
• Natural and artificial agents can kill or slow down microbial growth.
• Disinfectants/sanitizers are for inanimate objects, antiseptics/germicides for body surfaces, and antibiotics/antimicrobials for ingestion/injection.
• Handwashing with soap and water, and alcohol-based gels, limit exposure risks.

Body's Defense Strategies

• The body has physical and biochemical barriers.
• The immune system mounts a counteroffensive against invading microbes.
• Vaccination and therapeutic strategies can further bolster the defense system.

Skin and Mucosal Membranes

• Skin and mucosal membranes have complex activities and functions.
• They prevent most bacteria from entering tissues and the bloodstream.
• They confine them to the skin's surface or guarded mucosal areas like the oronasopharyngeal, gastrointestinal, and urogenital tracts.
• Few bacteria can bypass these defenses and cause disease.

Epithelial Cells

• Epithelia are cell layers covering external and internal body surfaces exposed to the environment.
• They are an important initial defense against pathogens, with varied properties depending on the body site.
• Skin has two layers: the epidermis (outer) and the dermis (inner).
• Cells of the dermis are continuously replaced as they die and become the epidermis.
• Mucosal epithelia in the respiratory, intestinal, and urogenital tracts are tightly packed cells attached by tight adherens junctions and desmosomes.
• This tight binding prevents bacteria from transiting an epithelial layer unless they exploit wounds or invade cells.
• Endothelium (lining blood and lymphatic vessels) is not tightly bound, allowing immune cell movement but also bacterial transit.
• Epithelia of skin and mucosal surfaces act as barriers against foreign invaders.

Polarized Cells

• Epithelial cells have asymmetrical surfaces: the basolateral surface faces inward, and the apical surface faces outward.
• Epithelial cells are attached to the basement membrane (basal lamina), covering loose connective tissue.
• The extracellular matrix (ECM) contains polysaccharides (glycosaminoglycans) attached to fibrous collagens.
• Collagens bind to fibronectins, which bind collagens to integrins for cell-cell and cell-ECM interactions.
• Laminins bind to collagens and other ECM components to form networks resisting tensile forces in the basal lamina.
• Pathogenic bacteria can attach to and manipulate or mimic ECM components during infection.

Epithelial Cell Diversity

• Epithelial cells vary in shape, size, number of layers, and function depending on the body site.
• Simple epithelium (single layer) is found where absorption or secretion occurs (e.g., intestinal tract).
• Stratified epithelium (multiple layers) is found on surfaces like the skin or female cervix.
• Squamous epithelium (flattened shape) lines cavities like the mouth, heart, and lungs, and forms outer layers of skin.
• Cuboidal epithelium (cube-shaped) lines kidney tubules and gland ducts, and forms germinal epithelium for egg and sperm cells.
• Columnar epithelium (tall and thin) lines the stomach and intestine.

Epithelial Defense

• Stratified epithelia cover surfaces exposed to the environment (e.g., skin and mouth), while simple epithelia are in internal areas (e.g., intestinal tract or lungs).
• Simple epithelia are more vulnerable to bacterial invasion.
• Multiple defenses protect Epithelia.
• Tears contains lysozyme degrading bacterial cell walls.
• Mucus and ciliated cells protect the respiratory tract.
• The urinary tract epithelium is protected by a sphincter and the washing action of urination.

Normal Microbiota

• Resident (or commensal) microbiota are bacterial populations residing at particular body sites without causing disease.
• Skin microbiota, like Staphylococcus epidermidis and Propionibacterium acnes, protect against pathogens.
• They do this by occupying sites, competing for nutrients, and producing antagonistic compounds.
• Commensal microbiota hampers colonization by potential pathogens.

P. Acnes

• P. acnes colonizes sebaceous glands.
• Digests oily sebum to generate a low pH environment.
• Increased sebum production during puberty can lead to clogged follicles (comedones), infection, and inflammation (acne).
• Treatment includes antibiotics, benzoyl peroxides, and washing with soap and water.

Mucosal Microbiota

• Most mucosal surfaces are protected by normal resident microbiota, the species composition varies by body site.
• The large intestine harbors a rich assortment of normal microbiota, mostly anaerobes or facultative anaerobes.
• Resident microbes synthesize and secrete vitamins and other nutrients.
• Indigenous bacteria play a crucial role in gut and immune development during early postnatal life like stimulating development of certain tissues.

Opportunistic Infections

• Members of the skin microbiota normally do not cause infections unless introduced into the body.
• Staphylococcus epidermidis has been implicated in postsurgical and catheter-related infections.
• Biofilms can allow bacteria to grow and cause serious infections.
• Catheters provide skin-associated bacteria with a conduit into the bloodstream.
• Catheter-associated infections have become a serious problem in hospitals.

Historical Breaches

• Four U.S. presidents were assassinated.
• Garfield and McKinley died from infections resulting from wounds, partly due to unhygienic medical practices.
• Surgical wound infections and catheter-associated infections have become more prevalent due to antibiotic resistance.

Handwashing and Disinfection

• Handwashing and disinfection add a barrier to infection and reduce transmission.
• Ignaz Semmelweis introduced handwashing in maternity wards in the mid-1800s.
• Compliance with hygiene practices by health care workers is sometimes low.
• Life-threatening nosocomial infections are correlated with wearing long or artificial fingernails.

Antibiotic Resistance

• Some antibiotics are exuded in sweat.
• Ointments containing antibiotics are widely used in the treatment of skin conditions.
• Skin bacteria like S. epidermidis have become increasingly resistant to a variety of antibiotics.
• Growth of bacteria in biofilms increases any antibiotic resistance that already exists.

Skin Defenses

• Bacteria cannot penetrate intact skin unaided.
• Skin infections are associated with wounds, burns, or insect bites.
• The epidermis consists of stratified squamous cells, mostly keratinocytes, which are not readily degraded by microorganisms.
• Keratinized cells form the skin surface and are continuously shed (desquamation).
• Skin is dry and slightly acidic (pH ∼5), inhibiting bacterial growth.
• Skin temperature (34 to 35°C) is lower than the body interior (37°C).
• Hair follicles, sebaceous glands, and sweat glands are potential breaches in the skin, normally protected by lysozyme and lipids.
• Some bacteria can infect these follicles or glands, leading to boils and acne.

Mucosal Surface Defense

• The respiratory, gastrointestinal, and urogenital tracts are exposed to the environment.
• Internal surface areas (mucosal epithelia) are comprised of only one epithelial layer.
• These areas are continuously bathed in fluids, with a temperature of around 37°C and a pH of 7.0 to 7.4, which are ideal for bacterial growth.
• Mucosal epithelia have chemical and physical barriers.
• Mucosal cells are regularly replaced, with old cells sloughed off into the lumen.
• Chemical and innate defenses help reduce bacterial growth rates for bacteria elimination.

Mucus

• Mucus is a mixture of secreted glycoproteins (mucin) produced by goblet cells.
• It acts as a lubricant and traps bacteria, preventing them from reaching epithelial cells.
• Bacteria trapped in mucus blobs are shed from the site.
• Peristalsis and liquid flow remove mucus blobs in the gastrointestinal and urinary tracts.

Antibacterial proteins

• Mucus can bind proteins that have antibacterial activity.
• Lysozyme is a major host defense protein in tears, saliva, milk, and mucus.
• It targets peptidoglycan of the bacterial cell wall.
• Phospholipase is found in tears and degrades the cytoplasmic membrane.
• Lactoferrin is an iron-binding protein that sequesters iron, depriving bacteria of this essential nutrient.
• Lactoperoxidase uses hydrogen peroxide (H2O2) to generate highly reactive oxygen species that kill bacteria.

Antimicrobial Peptides

• Paneth cells secrete toxic antimicrobial peptides, such as defensins, cathelicidins, and histatins.
• These have cationic regions that interact with negatively charged phospholipids and bacterial cell membranes.
• Defensins kill bacteria by forming channels or holes in their membranes and depolarizing the cell.
• They disrupt the proton-motive force that is essential for bacterial survival.
• These 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.

Gastrointestinal Tract Defenses

• Different regions of the gastrointestinal tract have special antibacterial features.
• The stomach has an extremely acidic environment (pH ∼2).
• Helicobacter pylori lives in the mucin layer, which covers and protects the stomach lining.
• It does this because, cells in the stomach lining secrete carbonate, which buffers the mucin layer to near neutral pH.
• Some foodborne pathogens have an acid tolerance response, allowing them to survive short periods of time at pH 4.
• People with achlorhydria have increased susceptibility to infections of the lower intestinal tract.
• Proton-pump inhibitor (PPI) drugs may increase the risk of intestinal infection.

Bile Salts & Colon flow rate of contents

• Bile salts in the small intestine and colon are steroids with detergent-like properties produced in the liver and are released into the intestine.
• They have disruption bacterial membranes along with help neutralizing stomach acid while also helping emulsify lipids in food to enable fat digestion and absorption through the intestinal wall.
• The rapid flow of contents in the small intestine, in combination with the bile salts and the rapid turnover of intestinal mucosal cells, keeps high concentrations of bacteria from developing.
• The contents flow rate passage changes from a rapidly flowing stream (small intestine) to a nearly stagnant pond (colon).

Bacterial Pathogens

• Bacterial pathogens that cause intestinal infections (gastroenteritis) can swim to and attach to the mucosa of the small intestine.
• People who develop blind loops have problems due to the buildup of bacteria within those regions.

Urogenital Tract Defenses

• The female and male urogenital tracts offer different environments, Urinary defenses includes secretion of mucin and flushing from urination.
• The urethra sphincter prevents bacteria from ascending to the bladder and kidney. The prostate gland in men secretes defensins.
• Altered pH or obstructions can facilitate pathogens to colonize the urethra and cause UTIs, especially in women.
• In the vagina, a cervical plug protects the uterus and fallopian tubes.
• The vagina is lined by a stratified epithelium and has resident microbiota the Lactobacillus species, which are the major resident vaginal bacteria found in healthy humans.
• Bacteria ferment glycogen, producing hydrogen peroxide and lactic acid, maintaining a weakly acidic environment.

Respiratory Tract Defenses

• The respiratory system has a ciliated epithelial cell layer and goblet cells that secrete mucin.
• Ciliated columnar cells propel mucus blobs out of the area.
• Airway epithelial cells secrete collectins, defensins, antimicrobial peptides, and proteases.
• A cough reflex and mucociliary clearance remove pathogens.
• The upper and lower respiratory tracts have different environments and microbes: the lower respiratory tract lacks microbiota.
• Potential pathogens that commonly colonize the upper respiratory tract are notable for there ability to cause infection when the immune system is impaired.

Lung Diseases

• In asthma, cystic fibrosis, and chronic obstructive pulmonary disease, pathogens colonize the lungs.
• Colonization of the lower respiratory tract with Bordetella pertussis always leads to whooping cough symptoms.

Immune Defenses

• Specialized portions of the immune system back up the skin and mucosa barriers.
• Langerhans cells (dendritic cells) process invading bacteria and activate immune cells of the skin-associated lymphoid tissue (SALT).
• Mucosal surfaces contain a population of phagocytic cells and immune cells.
• The mucosa-associated lymphoid tissue (MALT) is a mucosal defense system.
• The gastrointestinal-associated lymphoid tissue (GALT), bronchial-associated lymphoid tissue (BALT), nasopharyngeal-associated lymphoid tissue (NALT).
• These systems consist of macrophages, T cells, B cells, and M cells, and secrete IgA (sIgA), an antibody that increases the stickiness of mucin.

Barrier Defense Models

• Animal models (e.g., burned-rodent model for skin infections, rabbit model for eye infections) are used to study infections.
• Caenorhabditis elegans (worms) and Drosophila (flies) are not very useful for studies of skin infections, the zebra fish is a better model.
• Rodents have been widely used to investigate pathogens.
• Autoclaved feces, inoculated only with the bacterium of interest, are implanted to mimic the effects of surgical penetration of the colonic mucosa.
• A rabbit ileal loop model is used to monitor the impact of toxins on the small intestine.
• Genetically engineered mice (transgenic mice or knockout mice) are used to study the interaction of the normal microbiota and the intestinal mucosal cells.