Microbial pathogenesis

Bacteria must overcome many types of host defences to cause disease. They devote a significant amount of their genetic resource to this. Many pathogenic processes involve complex, specialised and often surface-associated molecular structures, which function to breach natural cellular barriers and confound immune surveillance.

Investigators use structural, molecular biological, biochemical and cell biological techniques to investigate these processes in a number of different pathological organisms. Some of these normally reside in our nasopharynx and become pathogenic in certain situations and include Neisseria meningitidis (figure 1), Haemophilus influenzae and Moraxella catarrhalis (Darryl Hill).

Studies on these bacteria are directed towards identifying the molecular basis of bacterial interactions with human target receptors and also include identification of both host and microbial factors that lead to pathogenic conditions.

Figure 1. Coloured pictures are scanning electron micrographs and the insert are transmission EMs. Top: Neisseria meningitidis (pink coloured spheres) make contact with human cells and induce activity in target cells; here manifested as processes from cell surface (coloured ochre) which eventually engulf the bacteria. Initial attachment of cells requires long fibrous adhesins, pili (p) protruding from bacteria (b) seen in the black and white insert TEM. Below: A fractured human cell can be seen with numerous meningococci within the cell. The process of invasion requires other bacterial factors such as Opa and Opc, which are incorporated in the outer membrane.

Other studies investigate enteric pathogens including Shigella flexneri and enteropathogenic E. coli to investigate the basis of their virulence. Such studies are vital for the identification and mechanistic understanding of appropriate prophylactic or therapeutic targets and therefore will serve ultimately for the design of novel vaccines and drugs (Ariel Blocker).

Figure 2. Right: Shigella flexneri (long rod in centre), the agent of human bacillary dysentery, invading a region of an epithelial cell in culture. The bacterium orchestrates a membrane "splash" or "ruffle" to induce its own uptake into human intestinal cells. This interaction was visualised by scanning transmission electron microscopy at the European Molecular Biology Laboratory in Heidelberg (Germany) by Roger Wepf, Philippe Sansonetti and Ariel Blocker. Inset foreground: The "needle complex", a central part of the main virulence device of Shigella flexneri, a tiny surface appendage which it uses to inject the virulence factors required to induce cellular invasion into epithelial cells. This reconstruction was obtained using isolated complexes, transmission electron microscopy and image processing/reconstruction techniques (taken from Cordes et al., J. Biol. Chem. 278:17103-17107).

Fig 1. Neisseria meningitidis make contact with human cells.

Fig 2. Scanning electron micrograph (taken by Roger Wepf, Philippe Sansonetti and Ariel Blocker at the EMBL) of the rod-like Shigella flexneri entering a HeLa cell

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