Chapter 5 Pathogenesis of microbial disease
If a microorganism is capable of causing disease, it is called a pathogen. Fortunately, only a minority of the vast multitude of microorganisms in nature are pathogenic. Whereas some organisms are highly virulent and cause disease in healthy individuals, even with a small inoculum, others cause disease only in compromised individuals when their defences are weak. The latter are called opportunistic organisms, as they take the opportunity offered by reduced host defences to cause disease. These opportunists are frequently members of the body’s normal flora.
Virulence is a quantitative measure of pathogenicity and is related to an organism’s toxigenic potential and invasiveness. Virulence can be measured by the number of organisms required to cause disease and is designated as LD50 or ID50: the LD50 (50% lethal dose) is the number of organisms needed to kill half the hosts, and ID50 (50% infectious dose) is the number needed to cause infection in half the hosts. These values are determined by inoculation of laboratory animals.
Infections are called ‘communicable diseases’ if they are spread from host to host. Many, but not all, infections are communicable; for example, tuberculosis is communicable, as it is spread by airborne droplets produced by coughing, but staphylococcal food poisoning is not, as the exotoxin produced by the organism and present in the contaminated food affects only those eating that food. If a disease is highly communicable, it is called a ‘contagious disease’ (e.g. chickenpox).
A number of organisms may elicit an inapparent or subclinical infection, without overt symptoms, where the individual remains asymptomatic although infected with the organism. On the other hand, once infected, the body may not completely eliminate the pathogen after recovery and some individuals may become chronic carriers of the organism (e.g. Salmonella typhi, hepatitis B virus); they may shed the organism while remaining healthy. Some infections result in a latent state, after which reactivation of the growth of the organism and recurrence of symptoms may occur at a later stage (e.g. after primary herpes infection, the virus may reside in a latent state in the trigeminal ganglion, causing recurrent herpes labialis from time to time). All the above groups may unknowingly shed pathogenic organisms and spread disease.
Bacterial pathogenicity is a vast subject. The following is a brief outline of the ways and means by which bacteria cause disease. The major steps are transmission, adherence to host surfaces, invasiveness and toxigenicity.
Most infections are acquired by transmission from external sources; i.e. they are exogenous in origin. Others are caused by members of the normal flora behaving as opportunist pathogens; i.e. they are endogenous in origin. Transmission can be by:
|Portal of entry||Pathogen||Disease|
|Hepatitis B virus||Hepatitis B|
|Respiratory tract||Streptococcus pneumoniae||Pneumonia|
|Epstein–Barr virus||Infectious mononucleosis|
|Gastrointestinal tract||Shigella dysenteriae||Dysentery|
|Salmonella typhi||Typhoid fever|
|Hepatitis A virus||Infectious hepatitis|
|Genital tract||Neisseria gonorrhoeae||Gonorrhoea|
|Human immunodeficiency virus (HIV)||Acquired immune deficiency syndrome (AIDS)|
|Candida albicans (fungus)||Vaginitis|
Adherence is the first step in infection. Unless organisms have the ability to stick or adhere to host surfaces, they will be unable to cause infection. Some bacteria and fungi have specialized structures or produce substances that facilitate their attachment to the surface of human cells or prostheses (e.g. dentures, artificial heart valves), thereby enhancing their ability to colonize and cause disease. These adherence mechanisms are critical for organisms that attach to mucous membranes; mutants that lack these mechanisms are often non-pathogenic (e.g. the hair-like pili of Neisseria gonorrhoeae and Escherichia coli mediate their attachment to the urinary tract epithelium; the extracellular polysaccharides of Streptococcus mutans help it adhere to enamel surfaces).
Once the organisms adhere to a host surface they usually tend to aggregate and form intelligent communities of cells called biofilms. A biofilm is defined as an aggregate of interactive bacteria attached to a solid surface (such as a denture prosthesis or an intravenous catheter) or to each other, encased in an extracellular polysaccharide matrix. Up to 65% of human infections are thought to be associated with microbial biofilms. Dental plaque on solid enamel surfaces is a classic example of a biofilm. As biofilms are ubiquitous in nature and form on hulls of ships, warm water pipes, dental unit water systems and so on, their study has rapidly evolved during the past few decades, leading to many discoveries on communal behaviour of microbes.
As mentioned, biofilms are intelligent communities. Structurally, they are not flat and compressed but comprise a complex architecture with towers and mushroom or dome-shaped structures with water channels that permit transport of metabolites and nutrients (Figs 5.1–5.3). Bacteria in biofilms maintain the population level by constantly secreting low levels of chemicals called quorum-sensing molecules (e.g. homoserine lactone), which tend to repulse incoming bacteria or activate the communal bacteria to seek new abodes. Further, specific gene activation may lead to production of virulence factors or reduction in metabolic activity (especially those living deep within the matrix).
Fig. 5.1 The ultrastructure of (A) an early biofilm on a dental appliance showing the deposition of coccal and bacillary forms; (B) a mature dental plaque biofilm on a dental appliance showing the advancing edge and the complex architecture.
(Courtesy of Dr Bernard Low.)
Fig. 5.2 A schematic diagram depicting the various developmental stages of a biofilm from the initial adherent phase (left) of the organisms to gradual maturation and subsequent fully developed polymicrobial biofilm (extreme right). EPS, extracellular polysaccharide.
It is now known that infections associated with biofilms are difficult to eradicate as sessile organisms in biofilms exhibit higher resistance to antimicrobials than their free-living or planktonic counterparts. The reasons for this appear to be (Fig. 5.4):
(Modified from Stewart and Costerton Lancet 2001; 358; 135–138 with permission.)
Some examples of important recalcitrant human infections mediated by biofilms, difficult to manage by antimicrobials alone, include Pseudomonas aeruginosa infections of the respiratory tract in cystic fibrosis patients, Staphylococcus aureus infections in central venous catheters, chronic candidal infections of HIV-infected individuals and chronic periodontal infections due to dental plaque.
|Organism||Virulence factor||Used in vaccine|
|Streptococcus pneumoniae||Polysaccharide capsule||Yes|
|Streptococcus pyogenes||M protein||No|
|Staphylococcus aureus||Protein A||No|
|Neisseria meningitidis||Polysaccharide capsule||Yes|
|Haemophilus influenzae||Polysaccharide capsule||Yes|
|Klebsiella pneumoniae||Polysaccharide capsule||No|
|Escherichia coli||Protein pili||No|
|Salmonella typhi||Polysaccharide capsule||No|
|Mycobacterium tuberculosis||Mycolic acid cell wall||No|
Macrophages and T cells predominate in this type of inflammation. The most notable organism in this category is Mycobacterium tuberculosis. Here, the bacterial antigens stimulate the cell-mediated immune system, resulting in sensitized T-lymphocyte and macrophage activity. Although the phagocytic activity of macrophages kills most of the tubercle bacilli, some survive and grow within these cells, leading to granuloma formation. The organisms reside within phagosomes, which are unable to fuse with lysosomes, resulting in protection from degradative enzymes therein. Many fungal diseases are also characterized by granulomatous lesions.