148 J. Carrisoza-Urbina et al.
protein 204 (IFI204). Knockdown of the IFI204
in immortalized and primary murine macro-
phages blocked IFN-β production (Liu et al.,
2017). The balance between IL-1 and IFN-β is
important in defining the outcome of bovine
tuberculosis and their role in the therapy of
tuberculosis requires further research.
10.7 Natural Resistance to M. bovisTuberculosis does not always develop in individ-
uals who are exposed to pathogenic mycobacte-
ria. Some individuals may not exhibit evidence
of infection and this may be due to the multifac-
torial risk of tuberculous mycobacteria, where
host factors, pathogens and the environment are
involved. Among the factors involved in the host,
it is known that genetics and innate and acquired
immunity have an essential role in this natural
resistance to tuberculosis.
Natural disease resistance to bacterial intra-
cellular pathogens was identified in cattle using
a Brucella abortus in vivo challenge of non-
vaccinated pregnant cows. Results from this
experiment segregated cattle into two groups,
one that was resistant (R) to infection and a sus-
ceptible (S) group that developed active infection
and aborted. The frequency of natural resistance
to brucellosis was shown to be 18% in cross-bred
cattle. Selective breeding of naturally resistant
cows increased this frequency to 53.6% in the F1
progeny (Adams and Templeton, 1998). A mac-
rophage bactericidal assay was established to test
if superior bactericidal activity of macrophages
from brucellosis resistance cattle was also opera-
tional against M. bovis BCG, Salmonella Dublin
and Salmonella Typhimurium, and would hence
have use as in vitro correlate of the resistance
phenotype. A value of 65% bacterial survival for
M. bovis BCG correlated highly with actual num-
bers of animals designated as resistant, and
therefore was considered a phenotypic marker of
the resistant trait (Qureshi et al., 1996).
Macrophages from R and S cattle also dif-
fered significantly (p < 0.01) in controlling viru-
lent M. bovis intracellular growth. A virulent
M. bovis strain survived better in both R and S
macrophages than BCG; however, macrophages
from R cattle were superior to those from S cat-
tle in controlling in vitro intracellular replica-
tion (Gutiérrez-Pabello and Adams, 2003).
Experimental evidence identified that M. bovis-
infected macrophages from R cattle produced
more nitric oxide and were slightly more prone
to undergo apoptosis than S cells. The blockade
of nitric oxide production enhanced the replica-
tion of M. bovis in both R and S cells but had no
effect on apoptosis induction. As a result, NO
was identified as a major determinant of macro-
phage resistance to M. bovis infection in cattle
(Esquivel-Solís et al., 2013). Alternative activa-
tion modified the macrophage response against
M. bovis. Macrophage IL-4 treatment increased
the number of bacilli phagocytized in both R and
S macrophages; however, intracellular survival
was augmented mainly in S macrophages. Alter-
native activation decreased gene expression of
pro-inflammatory cytokines, NO production
and DNA fragmentation mainly in R macro-
phages, in this way minimizing the functional
differences that existed between R and S macro-
phages (Castillo-Velázquez et al., 2011).
A macrophage pro-inflammatory gene
expression profile was a common feature after
M. bovis infection regardless of bacterial viru-
lence; however, superior expression of pro-
inflammatory genes in S macrophages was
induced by the attenuated strain, whereas in R
macrophages increased pro-inflammatory gene
expression was driven by the virulent M. bovis
strain. A macrophage pro-inflammatory profile
is intended to control M. bovis intracellular
growth. However, the host resistant phenotype
plays a determinant role in it, since R macro-
phages had better intracellular bacterial control
than S cells.
Genetic polymorphisms associated with
innate immunity are also involved in resistance
and susceptibility to tuberculosis. For example,
gene polymorphisms in genes encoding TLRs,
vitamin D receptors, as well as immunity effec-
tor molecules like TNFα, have been associated
with a higher susceptibility to tuberculosis infec-
tion (Azad et al., 2012). In the case of Holstein
cattle from China, it has been documented that a
TLR1 gene polymorphism has been associated
with a higher susceptibility to active tuberculo-
sis (Sun et al., 2012). Similarly, it has been found
that the genetic variability in Bos indicus cattle
confers a more resistant phenotype on them
compared to Bos taurus cattle (Ameni et al.,
2007). Bermingham et al. (2014) showed that
while variation in the resistance and