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Defense against infections

Last update 2-7-2009

Elements of the defense against infections

This part of the site provides an overview of the elements of the defense mechanisms against infection. The intention is to provide an insight into which elements there are and what each element does.
Behind each summarized stage a more extensive story is (will be) told. Please click through where possible.

Many cells have a role in the defense against infections. An overview of these cells can be found here. Below only the most important cells are described.

The elements of the defense against infections
Element Purpose
Diet The diet has a dual function in the maintenance of normal host defense levels to infections:
  1. The diet may direct or indirectly modulate the gut microflora and therewith influence colonization resistance, the bone marrow as well as other interactions with the host organism.
  2. The diet (nutritional status of the host) has direct and indirect effects on the host defense mechanisms.
So the diet has a significant influence on the defense against infections, although it is not part of it.
In bad hygienic conditions the diet is also a major source of potential pathogen microorganisms that may cause infections.
Skin The skin and the mucous membranes provide a to microorganisms impenetrable barrier and thereby forms part of the defense against infections.

Hypothesis: The skin provides a habitat for many microorganisms. These, in conjunction with other factors help defend the body against (potential) pathogens in a form of colonization resistance. E.g. the microorganisms that normally inhabit the skin also help defend it against infections.

Microorganisms
Microorganisms Microorganisms live on all surfaces of the body, including the inside of the gut.
Microorganisms can be divided in the following groups:
  1. Bacteria, both oxygen loving (aerobic) and those who cannot live with oxygen (anaerobic).
  2. Archaea - bacteria like microorganisms. So far as known they do not cause diseases.
  3. Eucaryotes, such as yeasts and fungi.
Some strains of bacteria and possibly archaea live permanently on the body, often in very large numbers. These are tolerated by the defense system. By being there in large numbers they take up space and food that could also be used by (potential) pathogens. As such they are a cornerstone of the colonization resistance.
(Potential) pathogens Microorganisms that can - potentially - cause infections. This requires them to do three things:
  1. Adhere to the body wall (also see colonization resistance)
  2. Penetrate the body (gut) wall (also see gastro-intestinal wall)
  3. Cause illness by producing toxins and/or by destroying body cells
Toxins Pathogenic microbes are often armed with (produce) poisonous substances (toxins) that produce harmful effects on the host.
Toxins are synthesized in the cytoplasm and released from the cell. Each toxin has a distinctive effect. Toxins are generally heat labile (inactivated by 60-100 °C for 30 minutes).
Important toxin producers are:
  • Coryne bacterium diphtheriae cause diphtheria
  • Clostridium tetani cusing tetanus
  • Clostridium botulinimum causing botulism (a type of paralysis)
  • some Staphylococus aureaus strains producing enterotoxin causing gastro-enteritis. This enterotoxin is tome some extend heat-resistant as it resists 30 min in boiling water
  • Vibrio cholerae the cause of cholera
  • Shigella dysenteriae causing dysentry
  • Yersinia pestis the cause of plague
Microbes other than bacteria may also produce toxins like aflotoxin by fungi and lysins by parasites.
Autochtonous /
Indiginous /
Permanent microflora
The autochtonous microflora consists of a set of microorganisms (bacteria) that are recognized by the adaptive immune system as 'self', after tolerance to them is formed, and are therefore not actively attacked and live inside the gut for many years. This tolerance is formed in the first few weeks after birth and is specific for each individual.
The autochtonous microflora may also be called the Indiginous microflora or the Permanent microflora.
Antibodies Parts of microorganisms have specific antigens (different from host 'self') so that they can trigger part of the adaptive defense to produce antibodies, thus protecting the host organism against infections.
Transfer of Genetic resistance Many microorganisms can and do transfer parts of their DNA to other microorganisms. This happens predominantly between members of the same species but also across species. This transferable resistance is not located on the chromosome but on a plasmid in the cytoplasma of the microbes. Transfer can occur sexually during mating but also without mating freely via the environment.

Through this mechanism the genetic code that helps a microorganism to be resistant against defensins and therefore also against antibiotics can be spread rapidly.
Innate defense
Innate defense A defense system that:
  1. Recognizes microorganisms
  2. Can enhance binding them to phagocytes
  3. Which then can clear microorganisms by phagocytosis, killing and digestion
Killing of microorganisms can be accomplished outside as well as inside host cells by defensins.
Innate immune recognition distinguishes self from nonself perfectly (a condition not always met by the adaptive immune response).
The innate immune system uses receptors which are ancient in their lineage.
Defensins This site uses 'defensins' as a generic term for broad-spectrum antimicrobial peptides.
Defensins are broad-spectrum antimicrobial peptides with three intra-molecular cystein disulfide bonds.

NOTE: Defensins are also called magainens and 'substances anti-microbiele'.

The vertebrate defensin family contains two branches, designated α-defensins and β-defensins.
Although similar in shape to α-defensins, β-defensins are slightly larger and differ in the placement and connectivity of their six conserved cysteine residues.
There are three sources of defensins:
  1. Defensins of host origin (Host Defensins or HD)
  2. Defensins of microorganism origin, including InDigenous microflora origin (ID)
  3. Artificially produced defensins for treatment (AD)

NOTE: Defensins are - like other antibiotics - rapidly inactivated aspecifically upon release so that they are only active within a short range from their source (host cell or other microorganism).

Schematically this would lead to the following summary:
  • HD active to newly ingested bacteria which are:
    1. For the greatest part sensitive and have no chance to colonize
    2. A few if any may be resistant and find conditions (nutrients etc.) to colonize
  • ID produced by colonizing bacteria (that are resistant to HD and resistant to those of other colonizing bacteria):
    1. Can work out positively (stronger and more diverse production)
    2. Can work out negatively i.e. reduce the type and amount of ID
  • AD (antibiotics applied orally for treatment) reach the intestinal tract and are mostly inactivated. The small fraction that is not inactivated will:
    1. kill the sensitive part of the microflora (and thereby reduce the colonization resistance
    2. provide the opportunity to resistant microorganisms to reach high numbers in the gut, colonize and - if opportunistic - translocate
Aspecific inactivation Rendering antibiotics (both medically applied and those produced by other microorganisms) inactive and therefore ineffective by molecules of host origin. This is a reversible process that depends on the concentration of the 'inactivation molecules'.
Also see here for more information on inactivation.
Specific inactivation Rendering antibiotics (both medically applied and those produced by other microorganisms) inactive and therefore ineffective by enzymes of microorganism origin. This is an irreversible process.
Also see here for more information on inactivation.
Complement system The complement system is a biochemical sequence of events (cascade), consisting of over 20 small enzymes. Once triggered the 'membrane attack complex' kills the targeted cells by osmotic lysis. Also complement coated cells are flagged for attack by Kupffer cells and other macrophage cell types.
There are several ways the compement system can be triggered:
  1. The classical pathway - through antibodies such as IgG, IgM and IgE
  2. The alternate pathway - through hydrolysis of one specific complement protein on the cell surface of the target cell
  3. The lectin pathway - through binding of another specific complement protein to other parts of the target cell surface
As upon activation the complement system could be very damaging to the host's tissue, it is tightly regulated by the complement control proteins.
Phagocytosis Attachment, engulfing and killing and digestion of microorganisms that have entered the tissues. Phagocytosis is done by neutrophile leucocytes and macrophages.
Colonization resistance The Colonization Resistance (CR) of the digestive tract is defined as:

the resistance to colonization of the alimentary canal by newly ingested microorganisms.

The CR is different between microbial species (bacteria as well as fungi) and may even differ between strains of the same species.
The mechanisms involved in CR are multiple and of both microbial and host origin:
  1. Microbial factors participating in Colonization Resistance
    The autochtonous microflora plays a major role in the functioning of the CR. However, it still is not yet clear which microorganism groups of the indigenous flora are involved, as well as most biochemical mechanism(s) causing CR. Microbial products such as defensins, short chain fatty acids, extracellular enzymes, competition for nutrients, etc, all appear to be of importance.
  2. Host factors involved in Colonization Resistance
    Host factors contributing to CR involve secretion of saliva, swallowing, peristaltic movement, secretion of mucus (feeder layer), epithelial cell desquamation, the "Gut Associated Lymphoid Tissue" (GALT) producing sIgA, as well as nonspecific blocking factors for bacterial adherence.
    Several of these host factors are modulated by his/her autochtonous microflora vice versa.
The microflora of different individuals (even if they belong to the same species) differs so that the CR may also differ between these individuals. The daily oral intake of bacteria with food and beverages (the changing or 'transient' part of the microflora) may occasionally influence the CR and therewith, the colonization pattern.
The Colonization Resistance is therefore not a 'defense mechanism' in a strict sense. Rather it is an emergent effect of all factors involved.
Here another view is given of colonization resistance.
Stomach acid Microorganisms entering the stomach are exposed to a blast of strong hydrochloric acid. Many may die this way. Therefore the stomach acid could be regarded as an element of the defense against infections.
However it is not perfect:
  • If the microorganism is imbedded in food, the acid is neutralized and will not affect the microorganism
  • Once sufficient food fills the stomach all acid is neutralized by the food, so all anti-microorganism activity is eliminated.
  • Liquids pass through the stomach rapidly - so the acid blast is shorter for a microorganism is passing through with it, making it more likely they survive.
  • Some bacteria have a special wax-like coating making them insensitive to the acid.
    Helicobacter pylori even specializes in living in the stomach wall.
  • Many microorganisms have special features in their wall - ion channels - that allow them to fend off the acid blast long enough to pass through the stomach alive
Gastro-intestinal wall The gastero-intestinal wall has a very active epithelial lining (as compared to other epithelial tissues) that:
  • produces a range of molecules: antibiotics, defensins, enzymes for food processing
  • resorbes food molecules (small intestines) and water (large intestines)
  • has a very high rate of epithelial replacement; production of epithelial cell occurs in the crypts and epithelial cells move from there to the tips of the villi
Please read the page on the specific model for more information.
Epithelial cell desquamation The cells of the epithelial lining of the gut wall are produced very rapidly and are shed (desquamed) after a few days from the tips of the villi. This results in shedding microorganisms that had managed to attach themselves to the epithelial layer of the gut wall.
Gut peristaltic movement Movements of the gut that send the food mass forwards. This process eliminates microorganisms by removing them with the food mass to the outside world.
Nonspecific blocking factors for bacterial adherence Molecules which mimic bacterial cell wall binding sites thereby blocking bacterial attachment which prevents penetration into the cells.
Gut Associated Lymphoid Tissue (GALT) The GALT consists of the gut wall lymphoid structures, the mesenteric lymph nodes and the spleen._The GALT scans for information on microorganims that have managed to penetrate and signals B-cells to attack these microorganisms. These B-cells move through the entire body to end in the intestinal wall and other structures where they make IgA that specificly coats the microorganism. This causes suppression (prevention) of inflammatory responses.
Also the immunological tolerance to the autochtonous microflora is formed here, by formation of T-suppressor cells.
 
Idiotypic Immunesystem The idiotypic network of multi-specific antibodies represent phylogenetically the oldest part of adaptive immune system; it could be regarded as an interface between innate and adaptive immunity. The role of this 'early' multi-specific system is self-maintainance, and therewith it is to be regarded as part of the 'innate'defense.
Adaptive defense
Adaptive defense Binding of pathogens trapped by the innate immune system. Requirements for potential targets by innate immune recognition:
  1. Molecular patterns recognized by the innate immune system must be shared by large groups of pathogens, and thus must represent general patterns rather then specific structures.
  2. These molecular patterns must be conserved products of microbial metabolism, which are not subject to antigenic variability. Although the immune system selects against these patterns, pathogens cannot 'change' them because they are essential for the survival or pathogenicity of the microorganisms. Any attempts to change them, will be lethal to the microbe or render it nonpathogenic.
  3. The overall effect of immune recognition and the destruction of the target requires that the recognized structures be absolutely distinct from self-antigens. The major consequence of this requirement is the ability of the innate immune system to discriminate between self and nonself
Lymphocytes Lymphocyte is a generic name for various cells that play a role in the adaptive defense. See below for examples.
Thymus Place where T-cells ripen into T1 (pre-killer or pre-suppressor cells) and T2 (pre-T-helpercells that assist B-cells).
T-cells T-cells are lymphocytes that mature in the thymus to become either T-helper cells, T-suppressor cells or cytoxic T-cells
Tolerance The adaptive immune system does not attack the body's tissues and some microorganisms. This is due to the T-suppressor cells that keep the other parts of the adaptive immune system in control - become tolerant.
The fact that some microorganisms are recognized as 'self' and therefore are not attacked, creates an autochtonous microflora.
B-cells B-cells are lymphocytes that develop and mature in the bone marrow to prepare them for their specialized task of antibody production following T-cell instruction and transforming into plasma cells
Antigens Antigens are parts of 'foreign' molecules as well as of 'self' origin that can bind to receptors of cells involved in development of specific immunity to such molecules. Self antigens induce tolerance, whereas foreign molecules induce formation of specific antibodies or cytotoxic T cells.
Immunoglobulins Immuboglobulins are complex molecules that perform a key role in the adaptive immune system.
There are three main types of immunoglobulins involved in defense:
IgA - is a form of antibody that suppresses inflammatory reactions (inside the body) or coats bacteria in the gut-lumen thereby preventing microorganisms to attach to the gut wall.
IgG - is a form of antibody that flags microorganisms for phagocytosis, so phagocytes can eliminate them more easily.
IgM - is a form of antibody that flags microorganisms for phagocytosis, so phagocytes can eliminate them more easily . This is more primitive than IgG and is less efficient in activation of the complement cascade and thereby starting an inflammatory reaction.
Neuro-endocrino control
Neuro-endocrino-immunoligy The emerging concept is that cells of the immune and inflammatory systems communicate directly with the peripheral and/or central nervous system. This connection or communication pathway is also mediated via the bloodstream and, therefore, involves hormonal communication.
The term hormones does not only signify the classical endocrine system, but also molecules released by the nervous or immune systems which have functional effects at some distance, such as, for example, catecholamines and a variety of neurotransmitters.
Thus, the brain and the nervous system are part of the neuroimmuno-regulatory network in which the various components of the network not only communicate with each other and affect each other, but also regulate additional sites through this mechanism.
Other elements
Bone marrow Bone marrow is the site where blood cells such as: lymphocytes, neutrophilic cells, monocytes, erythrocytes, thrombocytes are produced before release into the blood stream.
Spleen The spleen is an organ that lies in the abdomen and consists mostly of lymphoid tissue. Its most known role is that of blood reservoir. The spleen also destructs old red blood cells after their 100-120 day life.
The spleen is also an important place where T-lymphocytes and B-lymphocytes gather. Another key role of the spleen is that it holds part of the ReticuloEndothelial System (RES) which consists of phagocytic cells, such as monocytes and macrophages, that are located in the reticular connective tissue. Here the immune related cells survey the passing blood for 'antigens' or non-self tissue particles or even whole microorganisms.
Liver Synthesizes most of the complement proteins.
The liver also produces bile, that has bactericidal qualities.
Adrenal gland The adrenal gland is a gland for internal secretion of hormones, such as adrenalin and corticosteroids, that directly or indirectly influence the immune system.
Vomiting Vomiting can be seen as an emergency defense mechanism in these cases where it is triggered by spoiled food (microorganism produced toxins) and results in most of that food being expelled before it can do too much damage.
Diarrhea Diarrhea can be seen as an emergency defense mechanism in these cases where it is triggered by spoiled food (microorganism produced toxins) or similar situations where too many potential pathogen microorganisms exist in the gut. The result is that the gut content is expelled rapidly before it can do too much damage.
Also as the amount of water in the gut content increases, the passive inactivation of defensins (through adherence to large molecules) is reversed, so the gut lumen now has a non-zero active defensin content.