Damage to Tissues

DAMAGE TO TISSUES

Damage caused to the host organism through infection can be direct and related to the destructive presence of microorganisms (or to their production of toxins) in particular target organs; or it can be indirect and related to interactions of the antigenic components of the pathogen with the host’s immune system. Effects can therefore be closely related to, or remote from, the infected organ.

Symptoms of the infection can in some instances be highly specific, relating to a single, precise pharmacological response to a particular toxin; or they might be nonspecific and relate to the usual response of the body to particular types of trauma. Damage induced by infection will therefore be considered in these categories.

1) DIRECT DAMAGE

a) Specific effects

For the host, the consequences of infection depend to a large extent upon the tissue or organ involved. Soft tissue infections of skeletal muscle are likely to be less damaging than, for instance, infections of the heart muscle and central nervous system. Infections associated with the epithelial cells that make up small blood vessels can block or rupture them to produce anoxia or necrosis in the tissues that they supply. Cell and tissue damage is generally the result of a direct local action by the microorganisms, usually concerning action at the cytoplasmic membranes. The target cells are usually phagocytes and are generally killed (e.g. by Brucella, Listeria, Mycobacterium). Interference with membrane function through the action of enzymes such as phospholipase causes the affected cells to leak. When lysosomal membranes are affected, the lysosomal enzymes disperse into the cells and tissues causing them, in turn, to autolyse. This is mediated through the vast battery of enzyme toxins available to these organisms. If these toxins are produced in sufficient concentration they may enter the circulatory systems to produce a generalized toxaemia. During their growth, other pathogens liberate toxins that possess very precise, singular pharmacological actions. Diseases mediated in this manner include diphtheria, tetanus and scarlet fever.

In diphtheria, the organism C. diphtheriae confines itself to epithelial surfaces of the nose and throat and produces a powerful toxin which affects an elongation factor involved in eukaryotic protein biosynthesis. The heart and peripheral nerves are particularly affected, resulting in myocarditis (inflammation of the myocardium) and neuritis (inflammation of a nerve). Little damage is produced at the infection site.

Tetanus occurs when Cl. tetani, ubiquitous in the soil and the faeces of herbivores, contaminates wounds, especially deep puncture type lesions. These might be the result of a minor trauma such as a splinter, or a major one such as a motor vehicle accident. At these sites, tissue necrosis, and possibly also microbial growth, reduce the oxygen tension to allow this anaerobe to multiply. Its growth is accompanied by the production of a highly potent toxin that passes up peripheral nerves and diffuses locally within the central nervous system. The toxin has a strychnine like action and affects normal function at the synapses. As the motor nerves of the brainstem are the shortest, the cranial nerves are the first affected, with twitches of the eyes and spasms of the jaw (lockjaw).

A related organism, Cl. botulinum, produces a similar toxin that may contaminate food if the organism has grown in it and if conditions are favourable for anaerobic growth. Meat pastes and pâtés are likely sources. This toxin interferes with acetylcholine release at cholinergic synapses and also acts at neuromuscular junctions. Death from this toxin eventually results from respiratory failure.

Many other organisms are capable of producing intoxication following their growth on foods. Most common among these are the staphylococci and strains of B. cereus. Some strains of Staph. aureus produce an enterotoxin which acts on the vomiting centres of the brain. Nausea and vomiting therefore follow ingestion of contaminated foods and the delay between eating and vomiting varies between 1 and 6 hours depending on the amount of toxin ingested. B. cereus also produces an emetic toxin but its actions are delayed and vomiting can follow up to 20 hours after ingestion. The latter organism is often associated with rice products and will propagate when the rice is cooked (spore activation) and subsequently reheated after a period of storage.

Scarlet fever is produced following infection with certain strains of Strep. pyogenes. These organisms produce a potent toxin that causes an erythrogenic skin rash that then accompanies the more usual effects of a streptococcal infection.

b) Nonspecific effects

If the infective agent damages an organ and affects its functioning, this can manifest itself as a series of secondary disease features that reflect the loss of that function to the host. Thus, diabetes may result from an infection of the islets of Langerhans, paralysis or coma from infections of the central nervous system, and kidney malfunction from loss of tissue fluids and its associated hyperglycaemia. In this respect virus infections almost inevitably result in the death and lysis of the host cells. This will result in some loss of function by the target organ. Similarly, exotoxins and endotoxins can also be implicated in nonspecific symptoms, even when they have welldefined pharmacological actions. Thus, a number of intestinal pathogens (e.g. V. cholerae, E. coli) produce potent exotoxins that affect vascular permeability. These generally act through adenylate cyclase, raising the intracellular levels of cyclic AMP (adenosine monophosphate). As a result of this the cells lose water and electrolytes to the surrounding medium, the gut lumen. A common consequence of these related, yet distinct, toxins is acute diarrhoea and haemoconcentration. Kidney malfunction might well follow and in severe cases lead to death. Symptomologically there is little difference between these conditions and the food poisoning induced by ingestion of staphylococcal enterotoxin (above).

2) INDIRECT DAMAGE

Inflammatory materials are released not only from necrotic cells but also directly from the infective agent. Endotoxins are derived from constituents of the bacterial cell rather than being deliberately exported cellular products. Thus, during the growth and autolysis of Gram-negative bacteria components of their cell envelopes, such as lipopolysaccharide  are shed to the environment. Endotoxins tend to be less toxic than exotoxins and have much less precise pharmacological actions. Indeed, it is not always clear to what extent these can be related to actions by the host or by the pathogen. Reactions include local inflammation, elevations in body temperature, aching joints, and head and kidney pain. Inflammation causes swelling, pain and reddening of the tissues, and sometimes loss of function of the organs affected. These reactions may sometimes be the major sign and symptom of the disease.

While various toxic effects have been attributed to these endotoxins, their role in the establishment of the infection, if any, remains unclear. The most notable effect of these materials is their ability to induce a high body temperature (pyrogenicity). The pyrogenic effect of lipopolysaccharide relates to the action of the lipid A component directly upon the hypothalamus and also to its direct action on macrophages and phagocytes. Elevation of body temperature follows within 1–2 hours. In infections such as meningitis the administration of antibiotics may cause such a release of pyrogen that the resultant inflammation and fever is fatal. In such instances antibiotics are co-administered with steroids to counter this effect. The pyrogenic effects of lipid A are unaffected by moist heat treatment (autoclave). Growth of Gram-negative organisms such as Pseudomonas aeruginosa in stored water destined for use in terminally sterilized products will cause the final product to be pyrogenic. Processes for the destruction of pyrogen associated with glassware, and tests for the absence of pyrogen in water and product, therefore form an important part of parenteral drug manufacture.

Many microorganisms minimize the effects of the host’s defence system against them by mimicking the antigenic structure of the host tissue. The eventual immunological response of the host to infection then leads to its autoimmune self-destruction. Thus, infections with Mycoplasma pneumoniae can lead to production of antibody against normal group O erythrocytes, with concomitant haemolytic anaemia.

If antigen released from the infective agent is soluble, antigen–antibody complexes are produced. When antibody is present at a concentration equal to or greater than the antigen, such as in the case of an immune host, these complexes precipitate and are removed by macrophages present in the lymph nodes. When antigen is present in excess, the complexes, being small, continue to circulate in the blood and are eventually filtered off by the kidneys, becoming lodged in kidney glomeruli and in the joints. Localized inflammatory responses in the kidneys are sometimes then initiated by the complement system. Eventually the filtering function of the kidneys becomes impaired, producing symptoms of chronic glomerulonephritis.