 Portal of Entry: To cause disease, most pathogens must gain access to the host, adhere to host tissues, penetrate or evade host defenses. And damage the host tissues.  Pathogens can gain entrance to the human body and other hosts through several avenues, which are called portals of entry.

 Mucous Membranes:  Many bacteria and viruses gain access to the body by penetrating mucous membranes lining the respiratory tract, gastrointestinal tract, genitourinary tract, and conjunctiva, a delicate membrane that covers the eyeballs and lines the eyelids.  Most pathogens enter through the mucous membranes of the gastrointestinal and respiratory tracts.

 Skin:  The skin is the largest organ of the body in terms of surface area and weight and is an important defense against disease.  Unbroken skin is impenetrable by most microorganisms. Some microbes gain access to the body through openings in the skin, such as hair follicles and sweat gland ducts.

 The Parenteral Route :  Some microorganisms gain access to the body when they are deposited directly into the tissues beneath the skin or into mucous membranes when these barriers are penetrated or injured. This route is called the parenteral route.  Punctures, injections, bites, cuts, wounds, surgery, and splitting of the skin or mucous membrane due to swelling or drying establish parenteral routes.  The hepatitis viruses and bacteria that cause tetanus gangrene can be transmitted parenterally.

Many microbes have a preferred portal of entry which is a prerequisite to cause disease. Example: Streptococcus pneumoniae that are inhaled can cause pneumonia; if swallowed generally don’t cause disease.

 Almost all pathogens have some means of attaching themselves to host tissues at their portal of entry.  For most pathogens, this attachment, called adherence (or adhesion), is a necessary step in pathogenicity. (Of course, nonpathogens also have structures for attachment.)  The attachment between pathogen and host is accomplished by means of surface molecules on the pathogen called adhesins or ligands that bind specifically to complementary surface receptors on the cells of certain host tissues.  Adhesins may be located on a microbe’s glycocalyx or on other microbial surface structures, such as pili, fimbrae, and flagella.

 The majority of adhesins on the microorganisms studied so far are glycoproteins and lipoproteins.  The receptors on host cells are typically sugars, such as Mannose.

1. Capsules:  Some bacteria make glycocalyx material that forms capsules around their cell walls; this property increases the virulence of the species.  The capsule resists the host's defenses by impairing phagocytosis, the process by which certain cells of the body engulf and destroy microbes.  Example: polysaccharide capsule is Streptococcus pneumoniae, the causative agent of pneumococcal pneumonia. and Klebsiella pneumoniae, a causative agent of bacterial pneumonia.

2. Cell Wall Components:  M protein:  cell walls of certain bacteria contain chemical substances that contribute to virulence.  For example, Streptococcus pyogenes produces a heat- resistant and acid-resistant protein called M protein.  Found on both the cell surface and fimbriae.  The M protein mediates attachment of the bacterium to epithelial cells of the host and helps the bacterium resist phagocytosis by white blood cells.

 Fimbrae and Opa:  Neisseria gonorrhoeae grows inside human epithelial cells and leukocytes.  These bacteria use fimbriae and an outer membrane protein called Opa to attach to host cells.  Following attachment by both Opa and fimbriae, the host cells take in the bacteria.  Bacteria that produce Opa form opaque colonies on culture media.

 Mycolic Acid:  The waxy lipid (mycolic acid) that makes up the cell wall of Mycobacterium tuberculosis also increases virulence by resisting digestion by phagocytes, and can even multiply inside phagocytes.

 Microbial Enzymes :  Coagulases  Kinases  Hyaluronidases  Collagenases  IgA Proteases  Lecithinase  Necrotizing factor  Protease

Severe gangrene caused by Clostridium perfringens. Source: Tropical Medicine and Parasitology, 1997 Tissue Damage Caused by Microbial Enzymes of Clostridium perfringens

 Some pathogens can alter their surface antigens, by a process called antigenic variation.  By the time the body mounts an immune response against a pathogen, the pathogen has already altered its antigens and is unaffected by the antibodies.  Some microbes can activate alernative genes, resulting in antigenic changes.  Example: Opa encoding genes of N. Gonorrohoeae and Influenza Virus

 Eukaryotic cytoplasm has a complex internal structure consisting of protein filaments called microfilaments, intermediate filaments, and microtubules that comprise the cytoskeleton.  A major component of the cytoskeleton is a protein called actin, which is used by some microbes to penetrate host cells and by others to move through and between host cells.  Salmonella strain and E.coli make contact with the host cell plasme membrane. This leads to dramatic changes in the plasma membrane at the point of contact. The microbes produce surface proteins called invasins that rearrange nearby actin filaments of the cytoskeleton.

 When S. typhimurium makes contact with a host cell, invasins of the microbe cause the appearance of the host cell plasma membrane to resemble the splash of a drop of a liquid hitting a solid surface. This effect, called membrane ruffling, is the result of disruption in the cytoskeleton of the host cell. The microbe sinks into the ruffle and is engulfed by the host cell.

 By using host nutrients  By causing direct damage in the immediate vicinity  By producing toxins, tranported by blood and lymph, that damage sites far removed from the original site of invasion  By inducing hypersensitivity reactions

Iron is required for the growth of most pathogenic bacteria.  However, the concentration of iron in the human body is fairly low because most of the iron is tightly bound to iron- transport proteins, such as lactoferrin, transferrin, and ferritin, as well as hemoglobin.  Some pathogens secrete Siderophores.  When a pathogen needs iron, siderophores are released into the medium where they take the iron away from iron- transport proteins by binding the iron even more tightly.  Once the iron-siderophore complex is formed, it is taken up by siderophore receptors on the bacterial surface.  Then the iron is brought into the bacterium.

 Once pathogens attach to host cells, they can cause direct damage as the pathogens use the host cell for nutrients and produce waste products.  As pathogens metabolize and multiply in cells, the cells usually rupture. Many viruses and some intracellular bacteria and protozoa that grow in host cells are released when the host cell ruptures.  Following their release, pathogens that rupture cells can spread to other tissues in even greater numbers.  Some bacteria, such as E. coli, Shigella, Salmonella and Neisseria gonorrhoeae, can induce host epithelial cells to engulf them by a process that resembles phagocytosis.  These pathogens can disrupt host cells as they pass through and can then be extruded from the host cells by a reverse phagocytosis process, enabling them to enter other host cells.  Some bacteria can also penetrate host cells by excreting enzymes and by their own motility; such penetration can itself damage the host cell.  Most damage by bacteria, however, is done by toxins

 Toxins are poisonous substances that are produced by certain microorganisms.  They are often the primary factor contributing to the pathogenic properties of those microbes.  The capacity of microorganisms to produce toxins is called toxigenicity.  The term toxemia refers to the presence of the toxin in the blood.  Toxin are of generally two types: Exotoxin and Endotoxin

 Exotoxins are proteins, and many are enzymes that catalyze only certain biochemical reactions.  produced inside some bacteria as part of their growth and metabolism and are secreted by the bacterium into the surrounding medium or released following lysis.  The body produces antibodies called antitoxins that provide immunity to exotoxins.  When exotoxins are inactivated by heat or by formaldehyde, iodine, or other chemicals and no longer cause diseases, they are called toxoid.

 Exotoxins are divided into 3 types-  A-B toxin (type III)  Membrane disrupting toxin (type II)  Superantigens (type I)

1. A-B toxin (type III):  They consist of two parts designated A and B, both of which are polypeptides.  Most Exotoxins are are A-B toxin.  The A part is the active enzyme component and The B part is the binding component.

 In the first step, the A-B toxin is released from the bacterium.  The B part bind to a surface receptor on the host cell, usually a carbohydrate. Following binding, the A- B toxin is transported across the plasma membrane into the host cell cytoplasm.  Within the cells, the A-B component separate.TheA part inhibits protein synthesis and kills the host cell while the b part is releasd from the cell.

 Vibrio cholerae produces an enterotoxin (A-B toxin), called Cholera toxin.  Subunit B bind to epithelial cells  Subunit A causes cells to secrete large amounts of fluids and electrolytes that result in diarrhea.

 2. Membrane disrupting toxin (type II):  Membrane-disrupting toxins that kill phagocytic leukocytes (white blood cells) arc called leukocidins. They act by forming protein channels.  Membrane-disrupting toxins that destroy erythrocytes (red blood cells), also by forming protein channels, are called hemolysins. Important producers of hemolysins include staphylococci and streptococci.  Hemolysins produced by streptococci are called streptolysins. One kind is streptolysin O (SLO) is so named, because it is inactivated by atmospheric oxygen.  Another is Streptolysin S (SLS), beacuse it is stable in oxygen environment.

 3. Superantigens (type I):  antigens that provoke a very intense immune response.  bacterial proteins.  nonspecifically stimulate the proliferation of immune cells called T cells.  Cytokines are small protein molecules produced by various body cells, especially T cells, that regulate immune responses and mediate cell-to-cell communication.  The excessively high levels of cytokines released by T cells enter the bloodstream and give rise to a number of symptoms, including fever, nausea, vomiting, diarrhea, and sometimes shock and even death.

 Endotoxins are the part of the outer portion of the cell wall of gram-negative bacteria.  Gram Negative bacteria have an outer membrane surrounding the peptidoglycan layer of the cell wall.  This outer membrane consists of lipoproteins, phospholipids, and lipopolysaccharides (LPSs).  The lipid portion of LPS, called lipid A, is the endotoxin.  Endotoxins are released when gram-negative bacteria die and their cell walls undergo lysis, thus liberating the endotoxin.

 The fever (pyrogenic response) is caused by endotoxins  Gram-negative bacteria arc ingested by phagocytes.  As the bacteria are degraded in vacuoles, the LPSs of the bacterial cell wall arc released.  These endotoxins cause macrophages to produce cytokines called interleukin-1 formerly called endogenous pyrogen, necrosis factor alpha (TNF-a).  The cytokines are carried via the blood to the hypothalamus a temperature control center in the brain.  The cytokines induce the hypothalamus to release lipids called prostaglandins, which reset the thermostat in the hypothalamus at a higher temperature.  The result is a fever.

 Another consequence of Endotoxins, is the activation of blood-clotting proteins, causing the formation of small blood clots.  These blood clots obstruct capillaries and the resulting decreased blood supply induces the death of tissues.  This condition is referred to the disseminated intravascular clotting.

 Shock refers to any life-threatening decrease in blood pressure.  Shock caused by bacteria is called septic shock.  Gram-negative bacteria cause endotoxin slock.  Like fever, the shock produced by endotoxins is related to the secretion of a cytokine by macrophages.  Phagocytosis of gram-negative bacteria causes the phagocytes to secrete tumor necrosis factor (TNF).  TNF binds to many tissues in the body and alters their metabolism in a number of ways.  One effect of TNF is damage to blood capillaries; their permeability is increased, and they lose large amounts of fluid. The result is a drop in blood pressure that results in shock.

 Low blood pressure has serious effects on the kidneys, lungs, and gastrointestinal tract.  In addition, the presence of gram-negative  bacteria such as Haemophilus influenzae type b in cerebrospinal fluid causes the release of IL-1 and TNE These, in turn, cause a weakening of the blood- brain barrier that normally protects the central nervous system from infection.  The weakened barrier lets phagocytes in, but this also lets more bacteria enter from the bloodstream.

 Microbes also leave the body via specific routes called portals of exit in secretions, excretions, discharges, or tissue that has been shed.  In general, portals of exit are related to the part of the body that has been infected.  By using various portals of exit, pathogens can spread through a population by moving from one susceptible host to another.

 The most common portals of exit are the respiratory and gastrointestinal tracts.  Another important route of exit is the genitourinary tract.  Skin or wound infections are other portals of exit.