final report - ARCHIVE: Defra

Pathogenesis
where the expression of genes encoding virulence factors is often demonstrably different from that
occurring in vivo.
3.3.3 The above ideas were originally formulated by Harry Smith (University of Birmingham) in the 1960s
and expanded during subsequent decades (Smith, 1968, 1989). Since then it has become apparent
that, firstly, there are situations where regulation and coordination of the expression of genes governing
virulence is an additional ‘layer’ of complexity in defining pathogenicity at a molecular level. Where
virulence is multifactorial, coordinated expression of virulence genes may be necessary to achieve a
particular effect. Secondly, environmental influences on virulence gene expression may be the key
to initiation of pathogenic processes. These are often regarded as stress responses in the pathogen
consequent upon exposure to the in vivo environment.
3.3.4 Subsequently, a very constructive extension of the intellectual framework of pathogenicity research
was contributed by Stanley Falkow, who has defined a series of ‘molecular Koch’s postulates’ (Falkow,
1988, 2004). These are devised to allow for the identification of virulence genes. Candidate genes may,
for example, be knocked out by molecular biological methods and the effect on pathogenesis assessed
in a model or ‘real’ infection scenario. In parallel with Koch’s ideas on aetiology of disease, confirmation
of the role of a gene in such an experiment should be confirmed by complementation tests, looking
for restoration of the phenotype. Such an approach is crucial in defining vaccine candidate genes,
since immune responses to virulence factors are often, if not usually, capable of providing protective
immunity against infection.
3.4 Current state of knowledge regarding pathogenesis
3.4.1 A general impression from the literature strongly suggests a widespread assumption that the basic
pathogenic mechanisms in bTB are essentially the same as those in human TB (de la Rua-Domenech et
al., 2006; Pollock et al., 2006). This is supported by extremely high genomic sequence conservation.
However, one or more of the genomic differences that do exist between the Mtb and Mb lineages (Ernst
et al., 2007; Garnier et al., 2003; Hewinson et al., 2006) presumably underpin the differences in host
range (de la Rua-Domenech, 2006) seen in the two species.
3.4.2 There is a considerable amount of pathogenesis research on Mtb, and (understandably) relatively little
on Mb. It would seem an appropriate and efficient strategy to (a) use the information gathered from
Mtb and apply to Mb and (b) focus novel research on Mb-specific aspects of biology. There is evidence
that Defra has followed the latter approach. For example, the Functional Genomics programme has
specifically looked at aspects that are different between Mtb and Mb. This led to work demonstrating a
non-functioning glycolysis pathway in Mb in comparison to Mtb (Keating et al., 2005), which explained
long-standing physiological observations on Mb growth requirements.
3.4.3 One aspect that is unclear is how it can be established that pathogenesis is functionally similar in the
two pathogens. Some research uses Mb BCG as a tool, and similarities between Mtb and BCG can
(usually) be extrapolated as being also present in Mb. (The proviso is that it is known that BCG has
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