I.1. BACTERIA: PATHOGENICITY FACTORS – 41
bacterial ligands and cellular receptors proceeds sequentially, inducing host membrane
extension and bacterial uptake through a “zippering” mechanism (Cossart and Sansonetti,
2004). Various pathogens such as Helicobacter pylori (Kwok et al., 2002), Listeria
monocytogenes (Lecuit et al., 1997), Neisseria spp. (McCaw, Liao and Gray-Owen, 2004)
and some streptococci (Dombek et al., 1999) use this type of mechanism. With the trigger
mechanism of entry, bacteria bypass the first step of adhesion and interact directly with
the cellular machinery. Effectors are injected through a type III secretory system and the
bacterial signals sent to the host cell induce prominent membrane ruffling and
cytoskeletal rearrangements resulting in macropinocytosis and almost passive entry of
bacteria (Finlay and Cossart, 1997). This type of system is used by Salmonella spp.
(Hayward et al., 2002) and Shigella flexneri (Van Der Goot et al., 2004). Generally,
invasion into normally non-phagocytic cells establishes a protected cellular niche for
bacterial replication, survival and persistence.
It must be stressed that a same single invasion strategy may not be shared by all
members of a species. Streptococcus pyogenes strains have been shown to trigger
different uptake events via distinct mechanisms. For instance, in S. pyogenes strain A40,
the protein SfbI (Streptococcal fibronectin binding protein) has been shown to be the
main factor for attachment and invasion and uptake is characterised by the lack of actin
recruitment and the generation of large membrane invaginations (Molinari et al., 1997).
Whereas in S. pyogenes strain A8, the SfbI gene is absent and uptake involves major
rearrangements of cytoskeletal proteins leading to recruitment and fusion of microvilli
and the generation of cellular leaflets (Molinari et al., 2000).
There is little distinction between the extracellular proteins which promote bacterial
invasion and various extracellular protein toxins or exotoxins which damage the host.
The action of an invasin is usually proximal to the site of bacterial growth and may not
kill the cells, whereas exotoxins may act at sites distant to those of bacterial growth and
are usually cytotoxic. In general, exotoxins are more targeted and result in greater
pathology than invasins (Henderson, Poole and Wilson, 1996; Al-Shangiti et al., 2004).
However, some exotoxins such as diphtheria toxin or anthrax toxin play a role in invasion
while some invasins (e.g. staphylococcal leukocidin) have a relatively specific cytopathic
effect. Table 1.2 lists some extracellular proteins which act as invasins. Host damage by
exotoxins is more fully discussed in the section “Ability to damage or kill host”.
Evasion of host immune response and multiplication in host
Microbial infections rarely cause disease without first multiplying within the host.
Usually, multiplication is the main cause of disease associated with bacterial infection.
Following entry into a host cell, most bacteria, including pathogens, are killed by
macrophages and polymorphonuclear leukocytes. The incubation period reflects the time
needed for the bacteria to overcome these early defenses and increase in number.
The potential of a pathogen to cause a successful infection is reflected in the infective
dose (ID). There can be wide variations in IDs, depending on the nature of the bacterial
strain, the route of exposure (oral, inhalation, etc.), age (IDs would likely be lower for the
very young and the very old) and the immune status of the host. Since the success of
many pathogens relies on their ability to circumvent, resist or counteract host defense
mechanisms, pathogens have developed numerous ways to avoid and manipulate host
responses. This is reflected in the constant evolution of host defenses and bacterial
pathogenic mechanisms.