Innate immunity and normal flora

The innate immune system, which consists of the normal flora, physical barriers such as the skin, antibacterial proteins and phagocytic cells, is an important defence mechanism against infection. Many responses to 'harm' are detected by pattern recognition molecules such as the Toll-like receptors (TLRs), which trigger cascades that activate phagocytes and the immune response. For example, TLR-4 recognizes lipopolysaccharide and TLR-9 recognizes unmethylated CpG dinucleotides. The main components of the system are listed in the Table. Variation in the expression/ composition of each component affects an individual's resistance to infection.

Normal flora
Bacterial cells forming part of the normal flora outnumber human cells in the body. The normal flora provides protection by competing with pathogens for colonization sites and producing antibiotic substances (bacteriocins) that suppress other bacteria. Anaerobic bacteria produce toxic metabolic products and free fatty acids that inhibit other organisms. In the female genital tract lactobacilli produce lactic acid that lowers the pH, so preventing colonization by pathogens.

Antibiotics suppress normal flora, which allows colonization and infection by naturally resistant organisms, such as Candida albicans. The infective dose of Salmonella typhi is lowered by concomitant antibiotic use. Antibiotics may upset the balance between organisms of the normal flora, allowing one to proliferate disproportionately, for example Clostridium difficile, which results in a severe diarrhoeal disease (see Clostridium).

Physical and chemical barriers
The skin provides a physical barrier, with secreted sebum and fatty acids inhibiting bacterial growth. Many pathogens can penetrate the skin, either via the bite of a vector (e.g. Aedes aegypti that transmits dengue) or by invasion through intact skin (e.g. Leptospira and Treponema). Some organisms colonize mucosal surfaces and use this route to gain access to the body (e.g. Streptococcus pneumoniae).

If skin integrity is broken by intravenous cannulation or by medical or non-medical injection, blood-borne viruses, such as hepatitis B or the human immunodeficiency virus (HIV), can be transmitted. Diseases of the skin, such as eczema or burns, permit colonization and invasion by pathogens (e.g. Streptococcus pyogenes).

	The innate immune system: the location of barriers to infection, the mechanisms and consequences of deficiency.
	Component	Compromise		Consequence
	Normal flora
	Pharynx	Antibiotics		Oral thrush
	Intestine	Antibiotics		Pseudomembranous colitis; colonization with antibiotic-resistant organisms
	Vagina	Antibiotics		Vaginal thrush
	Skin	Burns, vectors		Cutaneous bacterial infection, infection with pathogenic viruses, bacteria, protozoa and metazoa
	Turbinates and mucociliary clearance	Kartagener’s syndrome, cystic fibrosis, bronchiectasis		Chronic bacterial infection
	Lysozyme in tears	Sjögren’s syndrome		Ocular infection
	Urinary flushing	Obstruction		Recurrent urinary infection
	Phagocytes, neutrophils, macrophages	Congenital, iatrogenic, infective		Chronic pyogenic infection, increased susceptibility to bacterial infection
	Complement	Congenital deficiency		Increased susceptibility to bacterial infection, especially Neisseria and Streptococcus pneumoniae

Mucociliary clearance mechanisms protect the respiratory tract. Air is humidified and warmed as it is drawn in by passing over the turbinate bones and through the nasal sinuses. Any particles settle on the sticky mucus of the respiratory epithelium and debris is then transported by the cilial 'conveyor belt' to the oropharynx where it is swallowed. As a result only particles with a diameter of less than 5 µm reach the alveoli, so the respiratory tract is effectively sterile below the carina.

Secreted antibacterial compounds include mucus, which contains polysaccharides of similar antigenic structure to the underlying mucosal surface; organisms bind to the mucus and are removed. Other antibacterial compounds secreted by the body include lysozyme in tears, which degrades Gram-positive bacterial peptidoglycan; lactoferrin in breast milk, which binds iron and inhibits bacterial growth; lactoperoxidase, a leucocyte enzyme, which produces superoxide radicals that are toxic to microorganisms.

Gastric acid protects from intestinal pathogens - acid suppression increases the risk of intestinal infection.

Urinary f?lushing protects the urinary tract, with the flushing action of urinary flow keeping the tract sterile, except near the urethral meatus. Obstruction by stones or tumours, benign prostatic hypertrophy or scarring of the urethra or bladder may cause a reduction of urinary flow and stasis, increasing the risks of subsequent bacterial urinary infection.

Phagocytes
Neutrophils and macrophages ingest particles, including bacteria, viruses and fungi. Opsonins (e.g. complement and antibody) may enhance phagocytic ability; for example, S. pneumoniae are not phagocytosed unless their capsule is coated with an anticapsular antibody. The action of macrophages in the reticuloendothelial system is essential for resistance to many bacterial and protozoan pathogens, such as S. pneumoniae and malaria. Congenital deficiency of neutrophil function leads to chronic pyogenic infections, recurrent chest infections and bronchiectasis. Following splenectomy, patients have defective macrophage function and diminished ability to remove capsulate organisms from the blood.

Complement and other plasma proteins
Complement is a system of plasma proteins that collaborate to resist bacterial infection, which is activated by antigen-antibody binding (the classical pathway) or by direct interaction with bacterial cell wall components (the alternative pathway). The products of both processes attract phagocytes to the site of infection (chemotaxis), activate phagocytes, cause vasodilatation and stimulate phagocytosis of bacteria (opsonization). The final three components of the cascade form a 'membrane attack complex' that can lyse Gram-negative bacteria. Complement deficiencies render patients susceptible to acute pyogenic infections, especially with Neisseria meningitidis, Neisseria gonorrhoeae and S. pneumoniae.

Transferrin captures iron, which limits the amount available to invading microorganisms. Other acute-phase proteins that are directly antibacterial include mannose-binding protein and C-reactive protein (CRP), which binds to bacteria and activates complement.