Molecular Virulence Mechanisms of Mycobacterium bovis 115
and IL-12p40 (Chen et al., 2012). This would
suggest that MPB83 could be involved in media-
tion of innate immune responses.
Experiments investigating the role of
MPB70 have been less clear. There is some vari-
ability in responses, but most of the work done
on MPB70 has focused on its ability to induce an
anamnestic immune response in patients with
TB and infected animals. Roche examined T-cell
responses in patients with TB and healthy indi-
viduals who had received the BCG vaccine, or
were tuberculin positive and in contact with TB
patients. It was found that peripheral blood
mononuclear cell (PBMC) from these groups did
show increases in lymphocyte proliferation fol-
lowing stimulation with MPB70 (Roche et al.,
1994). Other groups repeated this showing T-cell
responses, including proliferation and IFNγ
secretion in response to MPB70, in both patients
with TB and healthy individuals who had been
BCG vaccinated (Mustafa et al., 1998). Similar
experiments have been carried out in cattle, look-
ing at PBMC responses to MPB70 from cattle
who had been treated with M. bovis or that were
BCG-Pasteur vaccinated. These indicated that
PBMC from M. bovis-infected cattle showed pro-
liferative responses, but BCG- vaccinated cattle
did not, although the response seen was weaker
than for other mycobacterial proteins (including
ESAT-6 and MPB64) ( Vordermeier et al., 1999).
An experimental infection of cattle with M. bovis
also showed cell proliferation in response to
MPB70 in PBMC as well as increases in IFNγ
secretion (Rhodes et al., 2000).
Whether the genes controlled by SigK
regulon are involved in virulence, pathogenesis
or transmission is unclear. While individual
M. bovis mutants for SigK, MPB70, MPB83, etc.
and their role in infection has not been reported,
a sigK KO mutant in M. tuberculosis was not
attenuated for infection of murine models
(Schneider et al., 2014), but its role in the viru-
lence of M. bovis could be very different given the
evidence of a selective advantage to certain
animal- adapted species in constitutive SigK acti-
vation. Worth noting in this regard is the work
of Collins et al. (2005), who generated a large
deletion (~10 kb) at the M. bovis SigK locus and
noted attenuation of the resulting mutant in
guinea pigs; while multiple genes were deleted it
is intriguing to speculate that some of the atten-
uation of this mutant may have been due to loss
of SigK and hence lack of expression of genes in
the SigK regulon.8.7 ConclusionsVirulence is a complex concept, a unique con-
figuration of factors that allow a pathogen to
adapt to and inflict damage on its preferred host.
Although here we have highlighted and dis-
cussed discreet factors as important in causing
disease, bacterial virulence is the result of a
highly organized and complex interdependent
system between pathogen and host that we still
only poorly understand. Host factors that can
have a major role in the ability of a pathogen to
cause disease include the genetic background of
the host, the resident microbiome, immune sta-
tus, etc. Much of the work defining pathogen
virulence systems employs model organisms and
in vitro cellular systems, which is a good initial
step to identify the broad effects of particular
proteins. However, given the varying host prefer-
ences of the MTBC, studying virulence in multi-
ple species and with variations in the host
environment could be key to understanding the
true role of virulence factors.
This chapter has highlighted some of the
key factors that have been discovered that con-
tribute to the virulence of M. bovis. Almost all of
these factors are shared by M. tuberculosis, and
allow both bacteria to survive and cause TB in
their respective hosts. However, there are also
unique factors that may govern the host prefer-
ences of these species. The majority of research
into mycobacterial virulence has focused on
human TB and the human-adapted M. tubercu-
losis pathogen; however, much of this has also
been relevant for our understanding of M. bovis.
Future research looks certain to provide greater
insight into virulence across all the constituent
species of the MTBC, and hence provide the
knowledge that will aid in the eradication of
both human and animal TB.AcknowledgementsA.S. is funded by the Wellcome Trust through
the UCD Computational Infection Biology PhD
Programme grant 102395/Z/13/Z.