Manifestation of Disease

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Chapter: Pharmaceutical Microbiology : Principles Of Microbial Pathogenicity And Epidemiology

Once established, the course of a bacterial infection can proceed in a number of ways. These can be related to the relative ability of the organism to penetrate and invade surrounding tissues and organs.




Once established, the course of a bacterial infection can proceed in a number of ways. These can be related to the relative ability of the organism to penetrate and invade surrounding tissues and organs. The vast majority of pathogens, being unable to combat the defences of the deeper tissues, consolidate further on the epithelial surface. Others, including most viruses, penetrate the epithelial layers, but no further, and can be regarded as partially invasive. A small group of pathogens are fully invasive. These permeate the subepithelial tissues and are circulated around the body to initiate secondary sites of infection remote from the initial portal of entry (Figure 7.1).


Other groups of organisms may cause disease through ingestion by the victim of substances produced during microbial growth on foods. Such diseases may be regarded as intoxications rather than as infections and are considered later. Treatment in these cases is usually an alleviation of the harmful effects of the toxin rather than elimination of the pathogen from the body.



Bordetella pertussis (the aetiological agent of whooping cough) is probably the best described of these pathogens. This organism is inhaled and rapidly localizes on the mucociliary blanket of the lower respiratory tract. This localization is very selective and is thought to involve agglutinins on the organism’s surface. Toxins produced by the organism inhibit ciliary movement of the epithelial surface and thereby prevent removal of the bacterial cells to the gut. A high molecular weight exotoxin is also produced during the growth of the organism which, being of limited diffusibility, pervades the subepithelial tissues to produce inflammation and necrosis. Corynebacterium diphtheriae (the causal organism of diphtheria) behaves similarly, attaching itself to the epithelial cells of the respiratory tract. This organism produces a diffusible toxin of low molecular weight, which enters the blood circulation and brings about a generalized toxaemia.


In the gut, many pathogens adhere to the gut wall and produce their effect via toxins that pervade the surrounding gut wall or enter the systemic circulation. V. cholerae and some enteropathic E. coli strains localize on the gut wall and produce toxins that increase vascular permeability. The end result is a hypersecretion of isotonic fluids into the gut lumen, acute diarrhoea and, as a consequence, dehydration that may be fatal in young or elderly people. In all these instances, binding to epithelial cells is not essential but increases permeation of the toxin and prolongs the presence of the pathogen.




Some bacteria, and most viruses, are able to attach to the mucosal epithelia and then penetrate rapidly into the epithelial cells. These organisms multiply within the protective environment of the host cell, eventually killing it and inducing disease through erosion and ulceration of the mucosal epithelium. Typically, members of the genera Shigella and Salmonella utilize such mechanisms in infections of the gastrointestinal tract. These bacteria attach to the epithelial cells of the large and small intestines, respectively, and, following their entry into these cells by induced pinocytosis, multiply rapidly and penetrate laterally into adjacent epithelial cells. The mechanisms for such attachment and movement are unknown but involve a transition from a nonmotile to motile phenotype. Some species of salmonellae produce, in addition, exotoxins that induce diarrhoea (section 6.1.4). There are innumerable serotypes of Salmonella, which are primarily parasites of animals but are important to humans in that they colonize farm animals such as pigs and poultry and ultimately infect foods derived from them. Salmonella food poisoning (salmonellosis), therefore, is commonly associated with inadequately cooked meats, eggs and also with cold meat products that have been incorrectly stored following contact with the uncooked product. Dependent upon the severity of the lesions induced in the gut wall by enteric pathogens, red blood cells and phagocytes pass into the gut lumen, along with plasma, and cause the classic ‘bloody flux’ of bacillary dysentery. Similar erosive lesions are produced by some enteropathic strains of E. coli.


Viral infections such as influenza and the ‘common cold’ (in reality 300–400 different strains of rhinovirus) infect epithelial cells of the respiratory tract and nasopharynx, respectively. Release of the virus, after lysis of the host cells, is to the void rather than to subepithelial tissues. The residual uninfected epithelial cells are rapidly infected, resulting in general degeneration of the tracts. Such damage not only predisposes the respiratory tract to infection with opportunist pathogens such as N. meningitidis and Haemophilus influenzae but also causes the associated fever.




Invasive pathogens either aggressively invade the tissues surrounding the primary site of infection (active spread) or are passively transported around the body in the blood, lymph, cerebrospinal, axonal or pleural fluids (passive spread). Some, especially aggressive organisms, move both passively and actively, setting up multiple, expansive secondary sites of infection in various organs.


a) Active spread


Active spread of microorganisms through normal subepithelial tissues is difficult in that the gel like nature of the intercellular materials physically inhibits bacterial movement. Induced death and lysis of the tissue cells produces, in addition, a highly viscous fluid, partly due to undenatured DNA. Physical damage, such as wounds, is rapidly sealed with fibrin clots, thereby reducing the effective routes for spread of opportunist pathogens. Organisms such as Strep. pyogenes, Cl. perfringens and, to some extent, the staphylococci, are able to establish themselves in tissues by virtue of their ability to produce a wide range of extracellular enzyme toxins. These are associated with killing of tissue cells, degradation of intracellular materials and mobilization of nutrients. A selection of such toxins will be considered briefly.


Haemolysins are produced by most of the pathogenic staphylococci and streptococci. They have a lytic effect on red blood cells, releasing iron containing nutrients.

Fibrinolysins are produced by both staphylococci (staphylokinase) and streptococci (streptokinase). These toxins indirectly activate plasminogen and so dissolve fibrin clots that the host forms around wounds and lesions to seal them. The production of fibrinolysins therefore increases the likelihood of the infection spreading. Streptokinase may be employed clinically in conjunction with streptodornase in the treatment of thrombosis.

Collagenases and hyaluronidases are produced by most of the aggressive invaders of tissues. These are able to dissolve collagen fibres and the hyaluronic acids that function as intercellular cements; this causes the tissues to break up and produce oedematous lesions.


Phospholipases are produced by organisms such as Cl. perfringens (αtoxin). These toxins kill tissue cells by hydrolysing the phospholipids that are present in cell membranes.

Amylases, peptidases and deoxyribonucleases mobilize many nutrients that are released from lysed cells. They also decrease the viscosity of fluids present at the lesion by depolymerization of their biopolymer substrates.


Organisms possessing the above toxins, particularly those also possessing leucocidins, are likely to cause expanding oedematous lesions at the primary site of infection. In the case of Cl. perfringens, a soil microorganism that has become adapted to a saprophytic mode of life, infection arises from an accidental contamination of deep wounds when a process similar to that seen during the decomposition of a carcass ensues (gangrene). This organism is most likely to spread through tissues when blood circulation, and therefore oxygen tension, in the affected areas is minimal.


Abscesses formed by streptococci and staphylococci can be deep  seated in soft tissues or associated with infected wounds or skin lesions; they become localized through the deposition of fibrin capsules around the infection site. Fibrin deposition is partly a response of the host tissues, but is also partly a function of enzyme toxins such as coagulase . Phagocytic white blood cells can migrate into these abscesses in large numbers to produce significant quantities of pus. Such pus, often carrying the infective pathogen, might be digested by other phagocytes in the late stages of the infection or discharged to the exterior or to the capillary and lymphatic network. In the latter case, blocked capillaries might serve as sites for secondary lesions. Toxins liberated from the microorganisms during their growth in such abscesses can freely diffuse to the rest of the body to set up a generalized toxaemia.


S. enterica serovar Typhi, S. enterica serovar Paratyphi and S. enterica serovar Typhimurium are serotypes of Salmonella (section 4.2) that are not only able to penetrate into intestinal epithelial cells and produce exotoxins, but are also able to penetrate beyond into subepithelial tissues. These organisms therefore produce a characteristic systemic disease (typhoid and enteric fever), in addition to the usual symptoms of salmonellosis. Following recovery from such infection the organism is commonly found associated with the gallbladder. In this state, the recovered person will excrete the organism and become a reservoir for the infection of others.


b) Passive spread


When invading microorganisms have crossed the epithelial barriers they will almost certainly be taken up with lymph in the lymphatic ducts and be delivered to filtration and immune systems at the local lymph nodes. Sometimes this serves to spread infections further around the body. Eventually, spread may occur from local to regional lymph nodes and thence to the bloodstream. Direct entry to the bloodstream from the primary portal of entry is rare and will only occur when the organism damages the blood vessels or if it is injected directly into them. This might be the case following an insect bite or surgery. Bacteraemia such as this will often lead to secondary infections remote from the original portal of entry.


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